Potentially inappropriate medications in elderly Japanese patients: effects of pharmacists' assessment and intervention based on Screening Tool of Older Persons' Potentially Inappropriate Prescriptions criteria ver.2.

WHAT IS KNOWN AND OBJECTIVES: The Screening Tool of Older Persons' Potentially Inappropriate Prescriptions (stopp) criteria were updated in 2014 (stopp criteria ver.2), but few studies have evaluated the usefulness of stopp criteria in elderly patients. This prospective observational study evaluated the prevalence of potentially inappropriate medications (PIMs), and the efficacy of hospital pharmacists' assessment and intervention based on stopp criteria ver.2. METHODS: The study was conducted at three medical units of Kobe University Hospital between April 2015 and March 2016. Pharmacists assessed and detected PIMs based on stopp criteria ver.2 and considered the patient's intention to change the prescription at the time of admission of each patient. If the pharmacists judged that benefits outweighed risks of prescription change and the patients consented to change the medications, they recommended the doctor to change the prescription. If there was a risk of exacerbation of disease by the change of medications and the pharmacists judged it to be difficult to adjust medications during hospitalization or the patients did not consent to change the medications, they did not recommend to change it. The pharmacists and the doctors discussed and finally decided whether to change the PIMs or not. The number of patients prescribed PIMs, the number and contents of PIMs, and the number of medications changed after pharmacists' intervention were calculated. RESULTS: Totally, 822 new inpatients aged ≥65 years prescribed ≥1 daily medicine were included. Their median (interquartile range) age was 75·0 (71·0-80·0) years, and 54·9% were male. According to the criteria, 346 patients (42·1%) were prescribed ≥1 PIMs. Patients prescribed PIMs took significantly more medications than others: 10·0 (7·0-13·0) vs. 6·0 (4·0-9·0), P < 0·001. The total number of PIMs was 651%, 47·6% of which (n = 310) were recommended the doctors to change, and 292 of 651 PIMs (44·9%) were finally discontinued/changed after pharmacists' assessment and intervention. PIMs related to benzodiazepines, including Z-drugs, were most frequent, with a detailed classifications as follows (changed/total): (i) benzodiazepines for 4 or more weeks (75/205), (ii) drugs that predictably increase the risk of falls in older people (benzodiazepines) (30/67) and (iii) drugs that predictably increase the risk of falls in older people (hypnotic Z-drugs) (15/31). CONCLUSION: Over 40% elderly patients were prescribed PIMs, and pharmacists' assessments and interventions based on stopp criteria ver.2 were useful in detecting and correcting prescription of PIMs.

Development of an improved RT-PCR for specific detection of spring viraemia of carp virus.

Spring viraemia of carp (SVC) is a rhabdovirus infection, which has a significant economic impact in pond cultures of carp in Europe and western Independent States of the former Soviet Union. The causative agent of SVC, spring viraemia of carp virus (SVCV), has been divided into four subgroups, Ia, Ib, Ic and Id, on the basis of glycoprotein (G) protein gene sequences. In this study, a new primer set was designed from a G gene sequence of SVCV to identify the four subtypes of SVCV by reverse transcription polymerase chain reaction (RT-PCR). The specific PCR products of 369 bp were amplified from 15 SVCV isolates of all four subtypes. However, pike fry rhabdovirus (PFRV), which is antigenically related to SVCV, and other viruses antigenically related to SVCV and PFRV were not amplified. The four subtypes of SVCV were specifically amplified by the RT-PCR. Furthermore, the detection limit of the RT-PCR was 7.1 × 10(2) copies/reaction, and it was not influenced by the addition of RNA extracted from fish tissues. The RT-PCR will be applied not only to RNA extracted from viral suspensions, but also from fish tissue. It will contribute to rapid identification of SVCV in fish with clinical signs of SVC.

Examination of the effect of changing to azilsartan from candesartan in renal transplant patients.

BACKGROUND: Azilsartan, an angiotensin receptor blocker (ARB), was administered to renal transplant recipients to investigate the safety and antihypertensive effect in addition to its ARB-characteristic organ-protective effect. METHODS: The subjects were 20 patients (18 males, 2 females; baseline serum creatinine 2.39 ± 1.33 mg/dL) responding poorly to candesartan, who suffered albuminuria (>0.3 g/g creatinine) and hypertension (>140/90 mm Hg) following renal transplantation. Three months after candesartan was switched to azilsartan 20 mg/d, blood pressure, creatinine-corrected urinary albumin excretion, urinary L-type acid binding protein, urinary 8-hydroxydeoxyguano-sine, serum creatinine, and estimated glomerular filtration rate were evaluated. Thirteen patients received cyclosporine (65.0%) and 7 received tacrolimus (35.0%). Another hypertensive (calcium antagonist) agent was combined in 7 (35.0%). RESULTS: Systolic blood pressure significantly decreased from 139.5 mm Hg (baseline) from 128.7 mm Hg (at 3 months), whereas no significant changes were observed for diastolic blood pressure. The percentage of patients achieving the target level of antihypertensive effect (blood pressure < 130/80 mm Hg) significantly improved from 30.0% (baseline) to 70.0% (at 3 months). No significant changes were observed in renal graft function, oxidative stress marker level, or biochemical examination findings. CONCLUSION: Sufficient antihypertensive effect was demonstrated soon after switching to azilsartan. However, no significant change was found in renal damage markers. Long-term study must be conducted to confirm the protective effect azilsartan on the transplanted kidney, as found with candesartan. The safety of azilsartan was demonstrated. If the transplanted kidney protection is demonstrated, this drug is expected to contribute to the improved long-term prognosis of renal transplant recipients.

Nicotine increases the resistance of lung cancer cells to cisplatin through enhancing Bcl-2 stability.

BACKGROUND: Nicotine is able to activate mitogenic signalling pathways, which promote cell growth or survival as well as increase chemoresistance of cancer cells. However, the underlying mechanisms are not fully understood. METHODS: In this study, we used immunoblotting and immunoprecipitation methods to test the ubiquitination and degradation of Bcl-2 affected by nicotine in lung cancer cells. Apoptotic assay was also used to measure the antagonising effect of nicotine on cisplatin-mediated cytotoxicity. RESULTS: We demonstrated that the addition of nicotine greatly attenuated Bcl-2 ubiquitination and degradation, which further desensitised lung cancer cells to cisplatin-induced cytotoxicity. In this process, Bcl-2 was persistently phosphorylated in the cells cotreated with nicotine and cisplatin. Furthermore, Akt was proven to be responsible for sustained activation of Bcl-2 by nicotine, which further antagonised cisplatin-mediated apoptotic signalling. CONCLUSIONS: Our study suggested that nicotine activates its downstream signalling to interfere with the ubiquitination process and prevent Bcl-2 from being degraded in lung cancer cells, resulting in the increase of chemoresistance.

Development of a compact thermal lithium atom beam source for measurements of electron velocity distribution function anisotropy in electron cyclotron resonance plasmas.

The anisotropy of the electron velocity distribution function (EVDF) in plasmas can be deduced from the polarization of emissions induced by anisotropic electron-impact excitation. In this paper, we develop a compact thermal lithium atom beam source for spatially resolved measurements of the EVDF anisotropy in electron cyclotron resonance (ECR) plasmas. The beam system is designed such that the ejected beam has a slab shape, and the beam direction is variable. The divergence and flux of the beam are evaluated by experiments and calculations. The developed beam system is installed in an ECR plasma device with a cusp magnetic field, and the LiI 2s-2p emission (670.8 nm) is observed in low-pressure helium plasma. The two-dimensional distributions of the degree and direction of the polarization in the LiI emission are measured by a polarization imaging system. The evaluated polarization distribution suggests the spatial variation of the EVDF anisotropy.

Thrombus-targeted perfluorocarbon-containing liposomal bubbles for enhancement of ultrasonic thrombolysis: in vitro and in vivo study.

BACKGROUND: External low-frequency ultrasound (USD) in combination with microbubbles has been reported to recanalize thrombotically occluded arteries in animal models. OBJECTIVE: The purpose of this study was to examine the enhancing effect of thrombus-targeted bubble liposomes (BLs) developed for fresh thrombus imaging during ultrasonic thrombolysis. METHODS: In vitro: after the administration of thrombus-targeted BLs or non-targeted BLs, the clot was exposed to low-frequency (27 kHz) USD for 5 min. In vivo: Rabbit iliofemoral arteries were thrombotically occluded, and an intravenous injection of either targeted BLs (n = 22) or non-targeted BLs (n = 22) was delivered. External low-frequency USD (low intensity, 1.4 W cm(-2) , to 12 arteries, and high intensity, 4.0 W cm(-2) , to 10 arteries, for both the targeted BL group and the non-targeted BL group) was applied to the thrombotically occluded arteries for 60 min. In another 10 rabbits, recombinant tissue-type plasminogen activator (rt-PA) was intravenously administered. RESULTS: In vitro: the weight reduction rate of the clot with targeted BLs was significantly higher than that of the clot with non-targeted BLs. In vivo: TIMI grade 3 flow was present in a significantly higher number of rabbits with USD and targeted BLs than rabbits with USD and non-targeted BLs, or with rt-PA monotherapy. High-intensity USD exposure with targeted BLs achieved arterial recanalization in 90% of arteries, and the time to reperfusion was shorter than with rt-PA treatment (targeted BLs, 16.7 ± 5.0 min; rt-PA, 41.3 ± 14.4 min). CONCLUSIONS: Thrombus-targeted BLs developed for USD thrombus imaging enhance ultrasonic disruption of thrombus both in vitro and in vivo.

Long-term renoprotective effect of candesartan in renal transplant patients.

BACKGROUND: The renoprotective effects of angiotensin II type 1 receptor blockers (ARBs) have been demonstrated in a number of clinical studies, but there are few evaluations of long-term ARB treatment. We measured blood pressure, urine protein, and estimated glomerular filtration rate (eGFR) among patients under long-term (up to 9 years) treatment with candesartan cilexetil to evaluate its safety and effectiveness to protect renal graft function. METHODS: This study of 41 patients (31 male and 10 female) who presented with proteinuria and hypertension (blood pressure >140/90 mm Hg) after receiving a renal graft. Their serum creatinine level at baseline was 1.51 ± 0.53 mg/dL. Cyclosporine or tacrolimus were concomitantly prescribed for 18 (43.9%) and 22 (53.7%) subjects, respectively. The ARB treatment period was ≥12 months (up to 9 years, mean 4.8 years). Combination with other antihypertensive drugs (calcium antagonists) was necessary in 14/41 subjects (34.1%). RESULTS: Significant declines in blood pressure were observed during the treatment period; blood pressure reduction target (blood pressure <130/80 mm Hg) was met in 56.1% for systolic and 68.3% for diastolic pressure. No significant increase in serum creatinine level or eGFR was observed. Urinary protein was reduced to negative or marginal in 63.4% of the subjects, demonstrating a significant decrease. CONCLUSIONS: Candesartan cilexetil was considered to be safe even for long-term treatment in renal transplant patients, and effective to protect renal graft function.

Laparoscopic donor nephrectomy: single-center experience.

OBJECTIVE: Laparoscopic living donor nephrectomy (LLDN) has become the standard procedure for renal transplantation. This technique is considered less invasive for the donor, allowing lower postoperative analgesic requirements and a faster return to daily activities. In Japan, 1123 renal transplantation were performed in 2009. And, almost 83% were living related procedures. The aim of this study was a retrospective assessment of the safety and outcomes of LLDN on renal transplantations. MATERIAL AND METHODS: We retrospectively analyzed the intraoperative data and surgical complications for 21 patients who underwent retroperitoneoscopic living donor nephrectomy between June 2009 and March 2011. RESULTS: LLDN was successfully completed in all patients, without conversion to open surgery. Mean operative time was 243.5 ± 46.0 minutes with an average blood loss of 46.0 ± 46.1 mL. Warm ischemic time was 2.1 ± 0.62 minutes. Hospital stay was 11.1 ± 2.7 days. There were no major donor complications. One patient presented a wound infection responding to conservative treatment. CONCLUSIONS: LLDN is a safe effective procedure. The vascular stapler is useful to manage the renal vessels.

Cytomegalovirus infection after prophylactic valganciclovir therapy post-kidney transplantation: case reports.

This report describes three patients who developed cytomegalovirus infection 4 months after high-risk donor+/recipient-(D+/R-) kidney transplantation, despite treatment with valgancyclovir (VGCV) for 3 months at low dose (450 mg/d).

Encephalomyelitis associated with microsporidian infection in farmed greater amberjack, Seriola dumerili (Risso).

An outbreak of a disease characterized by a peculiar spiral movement in farmed greater amberjack, Seriola dumerili (Risso), occurred in Kagoshima Prefecture, Japan, in May 2008, immediately after importing the fish from China. Although neither bacteria nor viruses were detected in routine diagnostic tests, histopathological observations of the affected fish revealed severe inflammation in the tegmentum of the brain including the medulla oblongata and the anterior part of the spinal cord. In addition, a microsporidian parasite was observed in the nerve cell bodies or axons in the inflamed tissues. We identified a microsporidian small subunit rRNA gene (SSU rDNA) from the lesion, and the sequence showed 96.1% identity with that of Spraguea lophii. Subsequent in situ hybridization using probes presumably specific to the SSU rRNA confirmed that the parasite observed in histopathology harboured the identified SSU rRNA. Apparently degenerated microsporidian cells or spores were also frequently observed in tissue sections. Thus, the disease was most probably caused by the infection of a hitherto unknown microsporidian parasite that has a genetic affinity to the genus Spraguea, in the central nervous system of the amberjack.

Development of multiwavelength-range fine-resolution spectrometer for hydrogen emissions and its application to large helical device periphery plasmas.

We developed a spectrometer specialized for simultaneous observation of the hydrogen Balmer-alpha, -beta, -gamma lines and the Fulcher-alpha v(')=v(")=2 rovibronic transition band. The spectrometer was optimized for the light input coupled by nine optical fibers having 400 microm core diameters. The spectral resolutions were 0.02-0.03 nm for these wavelength ranges at the entrance slit width of 20 microm. The polarization resolved spectra of these emissions from the peripheral region of large helical device (LHD) plasmas were measured simultaneously and showed the polarization dependence coming from the magnetic field in the LHD plasma.

Genetic heterogeneity of betanodaviruses in juvenile production trials of Pacific bluefin tuna, Thunnus orientalis (Temminck & Schlegel).

Pacific bluefin tuna, Thunnus orientalis (Temminck & Schlegel), is one of the most important commercially exploited fish species in the world, and juvenile production techniques have been developed for its culture and stock enhancement in Japan. However, recent juvenile production has often failed because of the occurrence of viral nervous necrosis caused by betanodaviruses. In this study, we examined the genetic variability of betanodaviruses detected in the diseased juveniles to understand the transmission of the disease in a tuna hatchery. A total of 94 nucleotide sequences of betanodavirus (partial sequence of the coat protein gene, RNA2) were obtained from fish samples by reverse-transcriptase polymerase chain reaction amplification and 13 haplotypes were recognized among the sequences. The haplotype distributions in the viral populations from the diseased juveniles were related to the broodstocks from which the juveniles originated, suggesting that vertical transmission had occurred in the hatchery. The statistical parsimony network of viral haplotypes suggests that the nucleotide substitutions among the samples were accumulated in a recent population growth.

Clear cell adenocarcinoma of the uterine cervix arising from a background of cervical endometriosis.

The radiological findings of cervical clear cell adenocarcinoma (CCA) have not been described previously. Here, we present MR findings of this neoplasm that included mixed solid and cystic components with eccentric solid components. These are similar to the MR features of ovarian CCA. Endometriosis was also noted in the uterine cervix. Coexistence of CCA and endometriosis at the cervix suggests that the pathogenesis may be similar to that of ovarian CCA.

Efficacy of carvedilol for ischemia/reperfusion-induced oxidative renal injury in rats.

In renal transplantation, ischemia/reperfusion (I/R) injury is related to production of reactive oxygen species. In addition to its antihypertensive action due to nonselective beta-adrenergic blocking activity, carvedilol has potent antioxidant activity. This study was designed to investigate the effects of carvedilol on I/R injury in rats. On postoperative days 2 and 4, serum creatinine levels were higher among the control and the metoprolol treatment groups compared with the carvedilol treatment group (P < .005). However, there were no significant differences on postoperative day 7. In conclusion, increased antioxidant modulation by carvedilol attenuated renal I/R injury.

Arterial stiffness after successful renal transplantation.

Cardiovascular disease is a major barrier to the long-term survival of transplant recipients. The aim of this study was to determine whether successful renal transplantation improves the arterial stiffness resulting from chronic renal failure. This study involved a group of 9 recipients (23-56 years) who underwent successful renal transplantation at our clinic. The brachial-ankle pulse wave velocity and--intima-media thickness of the bilateral common carotid arteries were measured in each patient before and 1 year after successful renal transplantation. One year after renal transplantation, the 9 patients showed a mean serum creatinine level of 1.41 mg/dL. Assessment of arterial stiffness in this group revealed that the mean brachial-ankle pulse wave velocity was reduced after renal transplantation, but there was no reduction in the mean intima-media thickness of the bilateral common carotid arteries. There was a significant correlation between the variance ratios of pulse wave velocity and median blood pressure. The more effective blood pressure control provided by renal transplantation may functionally improve arterial stiffness. However, organic arterial stiffness remained unchanged 1 year after transplantation.

Effects of bisphosphonate on the mandible of rats in the growing phase with steroid-induced osteoporosis.

AIM: The objective of this study was to investigate the effects of bisphosphonate on the mandible of rats in the growing phase with steroid-induced osteoporosis, and to estimate the biomechanical response in the mandibular bone. MATERIALS AND METHODS: Eight-week-old male Wistar rats (n = 50) were assigned to a 6-week control (Co-6) group, 6-week steroid (St) group, 9-week control (Co-9) group, 9-week steroid + standard diet (StSD) group, or 9-week steroid + standard diet + bisphosphonate (StSDBp) group. The mandibular bone was evaluated by two-dimensional bone density measurement (PDS-15), three-dimensional pQCT, and quantitative analysis of Ca, P, Mg, and Zn using a sequential high frequency plasma spectrometer (ICPS-8000). RESULTS: In PDS-15 analysis, the bone density converted to aluminum equivalent was higher in StSDBp group when compared with the StSD group, and no significant difference was observed in bone density between St group and Co-6 group. In pQCT analysis, trabecular bone density and mineral content were significantly higher, while all other bone parameters were significantly lower in St group when compared with the Co-6 group. The densities of trabecular and cortical bones, mineral content and cross-sectional area of cortical bone, and non-invasive stress strain index with reference to x and yaxes were higher in StSDBp group than in StSD group. In quantitative analyses, Ca and P were markedly higher in StSDBp group than in StSD group, while there were no differences in Mg and Zn. CONCLUSION: Bisphosphonate treatment increases trabecular and cortical bone parameters in the mandible of growing rats with steroid-induced osteoporosis.

Deficiency of tenascin-C attenuates liver fibrosis in immune-mediated chronic hepatitis in mice.

Tenascin-C (TNC), an extracellular matrix glycoprotein, is upregulated in chronic liver disease. Here, we investigated the contribution of TNC to liver fibrogenesis by comparing immune-mediated hepatitis in wild-type (WT) and TNC-null (TNKO) mice. Eight-week-old BALB/c mice received weekly intravenous injections of concanavalin A to induce hepatitis, and were sacrificed one week after the 3rd, 6th, 9th, and 12th injections. In WT livers, immunohistochemical staining revealed a gradual increase in TNC deposition. TNC mRNA levels also increased sequentially and peaked after the 9th injection. Collagen deposition, stained with picrosirius red, was significantly less intense in TNKO mice than in WT mice, and procollagen I and III transcripts were significantly upregulated in WT mice compared with TNKO mice. Inflammatory infiltrates were most prominent after the 3rd-6th injections in both groups and were less intense in TNKO mice than in WT mice. Interferon-gamma, tumour necrosis factor-alpha, and interleukin-4 mRNA levels were significantly higher in WT mice than in TNKO mice, while activated hepatic stellate cells (HSCs) and myofibroblasts, a cellular source of TNC and procollagens, were more common in WT livers. Transforming growth factor (TGF)-beta1 mRNA expression was significantly upregulated in WT mice, but not in TNKO mice. In conclusion, TNC can promote liver fibrogenesis through enhancement of inflammatory response with cytokine upregulation, HSC recruitment, and TGF-beta expression during progression of hepatitis to fibrosis.

Creatol, an oxidative product of creatinine in kidney transplant patients, as a useful determinant of renal function: a preliminary study.

Creatol (CTL, 5-hydroxycreatinine) is a creatinine (Cr) oxidative metabolite, which was originally isolated from the urine of patients with chronic renal failure, representing a candidate for a uremic toxin. The effectiveness of CTL as an indicator of oxidative stress after kidney transplantation has not been reported. Therefore, we examined the relation between the change in oxidative stress (using CTL) in renal transplant patients and their change in renal function (using Cr). The serum Cr and serum and urine CTL were examined in five renal transplant patients. Serum CTL closely correlated with serum Cr. Serum CTL also correlated with urine CTL, but in some cases there was a time lag. Both the ratio of CTL/(Cr) and serum CTL observed in patient 2 were slow to improve after transplantation. The process through which oxidative stress was reduced was shown by the index of renal damage correlated with kidney function oxidative stress (using serum CTL) after transplantation. Our data suggested that CTL/Cr may be a good indicator of graft prognosis.

Can monitoring of serum 8-OHdG level for 2 hours after renal transplantation predict prognosis of the graft?

8-Hydroxy-2'-deoxyguanosine (8-OHdG) is an oxidant of deoxyguanosine, a base in the construction of DNA. We examined the extent of DNA damage to the graft through oxidative stress after renal transplantation. Seven renal transplant patients were enrolled in this study. Before reperfusion of the grafts, the level of serum 8-OHdG was measured using enzyme-linked immunosorbent assay. No relationship was found between the level of serum 8-OHdG just before reperfusion and the postoperative course. In all cases, the level of serum 8-OHdG increased after reperfusion and decreased within 2 hours. In six cases, it remained almost the same as the preoperative level. A faster rate of decrease from the first peak of serum 8-OHdG was associated with a lower nadir serum creatinine and reduced occurrence of acute rejection. This study suggested that immediate calming of the oxidative stress following reperfusion may potentially have a positive influence on graft prognosis. In addition, biomarkers of oxidative stress may predict graft prognosis.

Caspase-dependent cell death involved in brain damage after acute subdural hematoma in rats.

Traumatic brain injury is associated with acute subdural hematoma (ASDH) that worsens outcome. Although early removal of blood can reduce mortality, patients still die or remain disabled after surgery and additional treatments are needed. The blood mass and extravasated blood induce pathomechanisms such as high intracranial pressure (ICP), ischemia, apoptosis and inflammation which lead to acute as well as delayed cell death. Only little is known about the basis of delayed cell death in this type of injury. Thus, the purpose of the study was to investigate to which extent caspase-dependent intracellular processes are involved in the lesion development after ASDH in rats. A volume of 300microL blood was infused into the subdural space under monitoring of ICP and tissue oxygen concentration. To asses delayed cell death mechanisms, DNA fragmentation was measured 1, 2, 4 and 7 days after ASDH by TUNEL staining, and the effect of the pan-caspase inhibitor zVADfmk on lesion volume was assessed 7 days post-ASDH. A peak of TUNEL-positive cells was found in the injured cortex at day 2 after blood infusion (53.4+/-11.6 cells/mm(2)). zVADfmk (160ng), applied by intracerebroventricular injection before ASDH, reduced lesion volume significantly by more than 50% (vehicle: 23.79+/-7.62mm(3); zVADfmk: 9.06+/-4.08). The data show for the first time that apoptotic processes are evident following ASDH and that caspase-dependent mechanisms play a crucial role in the lesion development caused by the blood effect on brain tissue.