Comparing prevalence and types of potentially inappropriate medications among patient groups in a post-acute and secondary care hospital.

Reducing potentially inappropriate medications (PIMs) is a challenge in post-acute care hospitals. Some PIMs may be associated with patient characteristics and it may be useful to focus on frequent PIMs. This study aimed to identify characteristic features of PIMs by grouping patients as in everyday clinical practice. A retrospective review of medical records was conducted for 541 patients aged 75 years or older in a Japanese post-acute and secondary care hospital. PIMs on admission were identified using the Screening Tool for Older Person's Appropriate Prescriptions for Japanese. The patients were divided into four groups based on their primary disease and reason for hospitalization: post-acute orthopedics, post-acute neurological disorders, post-acute others, and subacute. Approximately 60.8% of the patients were taking PIMs, with no significant difference among the four patient groups in terms of prevalence of PIMs (p = 0.08). However, characteristic features of PIM types were observed in each patient group. Hypnotics and nonsteroidal anti-inflammatory drugs were common in the post-acute orthopedics group, multiple antithrombotic agents in the post-acute neurological disorders group, diuretics in the post-acute others group, and hypnotics and diuretics in the subacute group. Grouping patients in clinical practice revealed characteristic features of PIM types in each group.

Angiotensin II AT1 receptor blockade abolishes brain microvascular inflammation and heat shock protein responses in hypertensive rats.

Endothelial dysfunction and inflammation enhance vulnerability to hypertensive brain damage. To explore the participation of Angiotensin II (Ang II) in the mechanism of vulnerability to cerebral ischemia during hypertension, we examined the expression of inflammatory factors and the heat shock protein (HSP) response in cerebral microvessels from spontaneously hypertensive rats and their normotensive controls, Wistar Kyoto rats. We treated animals with vehicle or the Ang II AT(1) receptor antagonist candesartan, 0.3 mg/kg/day, via subcutaneously implanted osmotic minipumps for 4 weeks. Spontaneously hypertensive rats expressed higher Angiotensin II AT(1) receptor protein and mRNA than normotensive controls. Candesartan decreased the macrophage infiltration and reversed the enhanced tumor necrosis factor-alpha and interleukin-1beta mRNA and nuclear factor-kappaB in microvessels in hypertensive rats. The transcription of many HSP family genes, including HSP60, HSP70 and HSP90, and heat shock factor-1 was higher in hypertensive rats and was downregulated by AT(1) receptor blockade. Our results suggest a proinflammatory action of Ang II through AT(1) receptor stimulation in cerebral microvessels during hypertension, and very potent antiinflammatory effects of the Ang II AT(1) receptor antagonist. These compounds might be considered as potential therapeutic agents against ischemic and inflammatory diseases of the brain.

Estrogen upregulates renal angiotensin II AT1 and AT2 receptors in the rat.

We studied renal AT1 and AT2 receptors in male, female, ovariectomized and ovariectomized-estrogen-treated Wistar-Hanover and Wistar-Kyoto rats. AT1 receptors and AT1A receptor mRNA predominated, with no significant differences between males and females. AT2 receptor expression was restricted in female rats to the capsule, the transition zone between outer and inner medulla, the endothelium lining the papilla, and arcuate arteries and veins. There were no AT2 receptors in male rats, while male mice express substantial numbers of estrogen-dependent AT2 receptors. Arcuate arteries and veins expressed AT1B mRNA in males and females, and AT2 mRNA in females only. AT1 receptor and AT2 receptor expression were estrogen-dependent, with increases in AT1 and AT2 receptor expression after estrogen treatment in ovariectomized rats. Estrogen treatment increased prostaglandin E2 (PGE2) and cGMP concentrations in the renal medulla, and eNOS expression in cortical arteries. In rodents, expression of renal Angiotensin II receptor types is estrogen-dependent, with significant species, strain and area differences. Our results support an important role for AT2 receptors in the regulation of renal function and in the protective effects of estrogen in the kidney.

Anti-stress and anti-anxiety effects of centrally acting angiotensin II AT1 receptor antagonists.

The brain and the peripheral (hormonal) angiotensin II systems are stimulated during stress. Activation of brain angiotensin II AT(1) receptors is required for the stress-induced hormone secretion, including CRH, ACTH, corticoids and vasopressin, and for stimulation of the central sympathetic activity. Long-term peripheral administration of the angiotensin II AT(1) antagonist candesartan blocks not only peripheral but also brain AT(1) receptors, prevents the hormonal and sympathoadrenal response to isolation stress and prevents the formation of stress-induced gastric ulcers. The mechanisms responsible for the prevention of stress-induced ulcers by the AT(1) receptor antagonist include protection from the stress-induced ischemia and inflammation (neutrophil infiltration and increase in ICAM-1 and TNF-alpha) in the gastric mucosa and a partial blockade of the stress-induced sympathoadrenal stimulation, while the protective effect of the glucocorticoid release during stress is maintained. AT(1) receptor antagonism prevents the stress-induced decrease in cortical CRH(1) and benzodiazepine binding and is anxiolytic. Blockade of brain angiotensin II AT(1) receptors offers a novel therapeutic opportunity for the treatment of anxiety and other stress-related disorders.

Angiotensin II AT1 receptor blockade reverses pathological hypertrophy and inflammation in brain microvessels of spontaneously hypertensive rats.

BACKGROUND AND PURPOSE: The spontaneously hypertensive rat (SHR) is vulnerable to brain ischemia and stress and exhibits a chronically stimulated brain angiotensin II system, cerebrovascular hypertrophy, and inflammation. Pretreatment with angiotensin II type 1 (AT1) receptor antagonists protects from brain ischemia and from stress and prevents the development of stress-induced gastric ulcers in part by reducing inflammation in the gastric mucosa. We studied whether AT1 receptor antagonists could exert antiinflammatory effects in the brain vasculature as a mechanism for their protective effects against ischemia. METHODS: Ten-week-old SHR and normotensive Wistar-Kyoto male rats received the AT1 receptor antagonist candesartan (0.3 mg/kg per day) or vehicle for 28 days via osmotic minipumps. We studied AT1 receptors, intercellular adhesion molecule-1 (ICAM-1), endothelial nitric oxide synthase (eNOS), and number of macrophages by immunohistochemistry and Western blots. RESULTS: We found increased endothelial AT1 receptor expression of brain microvessels and middle cerebral artery of SHR. Brain AT1 receptor inhibition reversed the pathological vascular hypertrophy, increased and normalized eNOS expression, and decreased ICAM-1 expression and the number of adherent and infiltrating macrophages in cerebral vessels of SHR. CONCLUSIONS: The antiinflammatory effects of AT1 receptor antagonists may be an important mechanism in protecting against ischemia.

Normalization of endothelial and inducible nitric oxide synthase expression in brain microvessels of spontaneously hypertensive rats by angiotensin II AT1 receptor inhibition.

Inhibition of angiotensin II AT1 receptors protects against stroke, reducing the cerebral blood flow decrease in the periphery of the ischemic lesion. To clarify the mechanism, spontaneously hypertensive rats (SHR) and normotensive control Wistar Kyoto (WKY) rats were pretreated with the AT1 receptor antagonist candesartan (0.3 mg. kg.(-1) d(-1)) for 28 days, a treatment identical to that which protected SHR from brain ischemia, and the authors studied middle cerebral artery (MCA) and common carotid morphology, endothelial nitric oxide synthase (eNOS) and inducible nitric oxide synthase (iNOS) messenger RNA (mRNA), and protein expression in cerebral microvessels, principal arteries of the Willis polygon, and common carotid artery. The MCA and common carotid artery of SHR exhibited inward eutrophic remodeling, with decreased lumen diameter and increased media thickness when compared with WKY rats. In addition, there was decreased eNOS and increased iNOS protein and mRNA in common carotid artery, circle of Willis, and brain microvessels of SHR when compared with WKY rats. Both remodeling and alterations in eNOS and iNOS expression in SHR were completely reversed by long-term AT1 receptor inhibition. The hemodynamic, morphologic, and biochemical alterations in hypertension associated with increased vulnerability to brain ischemia are fully reversed by AT1 receptor blockade, indicating that AT1 receptor activation is crucial for the maintenance of the pathologic alterations in cerebrovascular circulation during hypertension, and that their blockade may be of therapeutic advantage.

B7.1 immunogene therapy effectively activates CD(4+) tumor-infiltrating lymphocytes in the central nervous system in comparison with B7.2 gene therapy.

The B7 gene utilizing immunogene therapy is one of the most common methods against tumor growth. However, there is no known study that investigated the difference between B7.1 and B7.2 with regard to B7 gene therapy in the central nervous system (CNS). Therefore, to clarify the difference, we established B7.1 or B7.2 gene transduced tumor cells originating from the murine T cell lymphoma cell line EL4 (EL4-B7.1 or EL4-B7.2). First, we observed the survival time after intracranial inoculation of parent (IC-wt) or genetically modified tumor cells. All mice in control groups (IC-wt or IC-mock) were dead within 16 days. While there was significant survival elongation in the B7.2 modified group (IC-B7.2, p=0.0002), all mice in this group were dead of tumor growth within 22 days. On the other hand, 60% of mice inoculated with EL4-B7.1 (IC-B7.1) survived more than 120 days (p<0.0001). Second, to shed light on the anti-tumor immune response in situ, we tried to analyze CD(4+) tumor-infiltrating T lymphocytes (CD(4+) TIL). To purify and analyze CD(4+) TIL, we had to deplete F4/80(+) microglia because of the CD4 expression. In terms of activation marker expression in CD(4+) TIL, a small population was activated (CD25, 9.8%; CD69, 15.8%) in the control group (IC-wt). In contrast, the activation marker positive CD4+ TIL percentage both in IC-B7.1 (CD25, 25.1%; CD69, 40.1%) and IC-B7.2 (CD25, 16.2%; CD69, 28.3%) appeared to reflect the survival curve in both groups. These findings strongly suggest that, in the CNS, B7.1 gene therapy could effectively introduce CD(4+) TIL activation compared with B7.2 gene therapy. This is the first study clearly describing the difference between B7.1 gene therapy and B7.2 gene therapy in the CNS in terms of the activation status of CD(4+) TIL in situ.

Angiotensin II AT1 receptor blockade decreases brain artery inflammation in a stress-prone rat strain.

The spontaneously hypertensive rats (SHR) are a genetically hypertensive strain with vulnerability to brain ischemia and stress. In SHR, the brain Angiotensin II (Ang II) system is chronically stimulated, resulting in brain artery remodeling and inflammation. Pretreatment with Ang II AT(1) receptor antagonists protects from brain ischemia and prevents the hormonal and sympathoadrenal response to stress. In addition, the anti-inflammatory effects of AT(1) receptor antagonists are partially responsible for preventing the development of stress-induced gastric ulcers. We asked whether AT(1) receptor antagonists could exert anti-inflammatory effects in the brain vasculature as a mechanism for their protective effects against ischemia. As determined by immunohistochemistry, long-term inhibition of brain AT(1) receptors by peripheral administration of the AT(1) receptor antagonist candesartan (0.3 mg/kg/day for 28 days) normalized the pathologic remodeling, decreased expression of the intercellular adhesion molecule-1 and the number of associated macrophages, and normalized the endothelial nitric oxide synthase expression in cerebral vessels of SHR. The anti-inflammatory effects of AT(1) receptor antagonists may be an important mechanism for protection against ischemia and could participate in the anti-stress properties of this class of compounds.

Failure of B7.1-modified tumor to evoke full activation of CD8+ tumor-infiltrating lymphocytes in the central nervous system: prevention of parental tumor growth in the subcutaneous environment.

OBJECT: It is well known that the central nervous system (CNS) is an immunologically privileged site. To characterize CD8+ tumor-infiltrating lymphocytes (TILs) recovered from the CNS, the authors compared these cells with TILs recovered from subcutaneous tissue by using a B7.1 gene-modified tumor implantation model. METHODS: The authors established a B7.1 gene-modified EL4 murine lymphoma cell line (EL4-B7.1) and implanted the cells into the CNS to observe the duration of tumor-free survival. Although EL4-B7.1 cells were completely rejected in a subcutaneous implantation model, 40% of animals died after the CNS implantation (all animals in which the parent tumor was implanted died within 16 days). Therefore, the authors isolated TILs from each implantation site and analyzed the expressions of activation antigens CD25 and CD69 by performing the anti-CD8 magnetic beads separation method and flow cytometric analysis. After implantation of the parent tumor, there was no difference in the number of TILs from each site (CD25 1.7-3.2%, CD69 21.9-34.3%). After implantation of the B7.1-modified tumor, the CD25-expressing TIL population from the subcutaneous site was 4.68 times higher than that from the CNS site (17.8% compared with 3.8%). Based on these findings, the authors used a mitomycin C-treated EL4-B7.1 subcutaneous vaccination with various protocols. Vaccination before tumor challenge was sufficient to prevent the development of the tumor. For animals with established tumor, the vaccination protocol was able to prolong host survival (p = 0.0053). CONCLUSIONS: The data clearly demonstrate that the CNS environment fails to activate CD8+ TILs fully. These are the first data indicating in detail a difference between CD8+ TILs from the CNS and those from other sites based on a B7.1-modified tumor model.

Radiological response and histological changes in malignant astrocytic tumors after stereotactic radiosurgery.

Stereotactic radiosurgery is an encouraging approach to deliver higher doses of radiation boost for malignant gliomas safely and precisely. The purpose of this study was to investigate the radiation response and histological changes of malignant astrocytic tumors after stereotactic linac radiosurgery (SLRS). We studied an autopsy case of recurrent glioblastoma multiforme (GBM) and two surgical cases with gross total removal of recurrent GBM and anaplastic astrocytoma transformed from fibrillary astrocytoma treated with SLRS. Destructive changes, such as the disappearance of viable cells, coagulation necrosis, and fibrinoid degeneration of vascular walls, were observed in the center of the target of SLRS, which showed histologically similar radiobiological reactions to well-known delayed central nervous system radiation necrosis caused by conventional radiotherapy. The region showing such radiation necrosis was within the area irradiated with approximately 15-20Gy or more by SLRS; however, dense viable tumor cells remained in the periphery that was irradiated with less than 15Gy. In a comparative immunohistochemical study of the tumors before and after SLRS, neither MIB-1 and p53 labeling indices nor immunoreactivity for GFAP represented any persistent tendencies. There were very few TUNEL-positive cells in either tumor before and after SLRS. These results showed that radiosurgery for malignant gliomas leads to earlier radiation necrosis than conventional radiation and that it is useful in eradicating tumor cells in the center of the target. However, some viable tumor cells may remain in the periphery irradiated with an insufficient dose for cell death and may be partly transformed in character by DNA damage due to radiation. Proton magnetic resonance spectroscopy (MRS) was suggested to characterize the radiation response in radiosurgery tumor targets for correlation with histological findings.

Improvement of automated detection method of lacunar infarcts in brain MR images.

The detection of asymptomatic lacunar infarcts on magnetic resonance (MR) images are important tasks for radiologists to ensure the prevention of sever cerebral infarction. However, their accurate identification is often difficult task. Therefore, the purpose of this study is to develop a computer-aided diagnosis scheme for the detection of lacunar infarcts. Our database consisted of 1,143 T1- and 1,143 T2-weighted images obtained from 132 patients. We first segmented the cerebral region in the T1- weighted image by using a region growing technique. For identifying the initial lacunar infarcts candidates, white top-hat transform and multiple-phase binarization were then applied to the T2- weighted image. For eliminating false positives (FPs), we determined 12 features, i.e., the locations x and y, density differences in the T1- and T2- weighted images, nodular components (NC), and nodular & linear components (NLC) from a scale 1 to 4. The NCs and NLCs were obtained using filter bank technique. The rule-based scheme and a neural network with 12 features were employed as the first step for eliminating FPs. The modular classifier was then used for eliminating three typical sources of FPs. As a result, the sensitivity of the detection of lacunar infarcts was 96.8% with 0.30 FP per image. Our computerized scheme would assist radiologists in identifying lacunar infarcts on MR images.

Automated classification of cerebral arteries in MRA images and its application to maximum intensity projection.

Detection of unruptured aneurysms is a major task in magnetic resonance angiography (MRA). However, it is difficult for radiologists to detect small aneurysms on the maximum intensity projection (MIP) images because adjacent vessels may overlap with the aneurysms. Therefore, we proposed a method for making a new MIP image, the SelMIP image, with the interested vessels only, as opposed to all vessels, by manually selecting a cerebral artery from a list of cerebral arteries recognized automatically. By using our new SelMIP viewing technique, the selected vessel regions can also be observed from various directions and would further facilitate the radiologists in detecting small aneurysms. For automated classification of cerebral arteries, two 3D images, a target image and a reference image, are compared. Image registration is performed using the global matching and feature correspondence techniques. Segmentation of vessels in the target image is performed using the thresholding and region growing techniques. The segmented vessel regions were classified into eight cerebral arteries by calculating the Euclidean distance between a voxel in the target image and each of the voxels in the labeled eight vessel regions in the reference image. In applying the automated cerebral arteries recognization algorithm to thirteen MRA studies, results of 10 MRA studies were evaluated as clinically acceptable. Our new viewing technique would be useful in assisting radiologists for detection of aneurysms and for reducing the interpretation time.

Anti-inflammatory effects of angiotensin II AT1 receptor antagonism prevent stress-induced gastric injury.

Stress reduces gastric blood flow and produces acute gastric mucosal lesions. We studied the role of angiotensin II in gastric blood flow and gastric ulceration during stress. Spontaneously hypertensive rats were pretreated for 14 days with the AT1 receptor antagonist candesartan before cold-restraint stress. AT1 receptors were localized in the endothelium of arteries in the gastric mucosa and in all gastric layers. AT1 blockade increased gastric blood flow by 40-50%, prevented gastric ulcer formation by 70-80% after cold-restraint stress, reduced the increase in adrenomedullary epinephrine and tyrosine hydroxylase mRNA without preventing the stress-induced increase in adrenal corticosterone, decreased the stress-induced expression of TNF-alpha and that of the adhesion protein ICAM-1 in arterial endothelium, decreased the neutrophil infiltration in the gastric mucosa, and decreased the gastric content of PGE2. AT1 receptor blockers prevent stress-induced ulcerations by a combination of gastric blood flow protection, decreased sympathoadrenal activation, and anti-inflammatory effects (with reduction in TNF-alpha and ICAM-1 expression leading to reduced neutrophil infiltration) while maintaining the protective glucocorticoid effects and PGE2 release. Angiotensin II has a crucial role, through stimulation of AT1 receptors, in the production and progression of stress-induced gastric injury, and AT1 receptor antagonists could be of therapeutic benefit.