Cost utility analysis of pharmacist counseling care for breast cancer chemotherapy outpatients.

Chemotherapy for cancer is increasingly implemented in the outpatient setting. Pharmacists contribute to cancer treatment by conducting counseling during outpatient chemotherapy visits. They provide guidance on drug treatment, side effects, and side effect countermeasures on every visit. However, there have been few economic evaluations of pharmacist involvement in outpatient chemotherapy. Therefore, we performed a cost utility analysis. We assigned usual care (control) and pharmacist counseling to two groups of 19 patients receiving outpatient chemotherapy for breast cancer at Gifu Municipal hospital. Quality of life was measured at three timepoints before and during chemotherapy treatment using the EuroQol 5 dimension instrument (EQ-5D). EQ-5D values across the timepoints were 0.831, 0.757, and 0.791 for the control group, and 0.882, 0.883, and 0.921 for the pharmacist counseling group. The additional cost in the pharmacist counseling group was 2,227 yen per counseling session. The change in quality-adjusted life years (QALY) was a maximum of -0.021±0.186 in the control group and 0.007±0.199 in the pharmacist counseling group. The maximum cost for one QALY was 1,360,558 yen (≈12,460 US dollars). Pharmacists' counseling in outpatient cancer chemotherapy for breast cancer patients had an acceptable incremental cost-effect ratio, contributing to improved patient quality of life without significant additional expenditure to healthcare.

The TriAGe+ Score for Vertigo or Dizziness: A Diagnostic Model for Stroke in the Emergency Department.

BACKGROUND: Vertigo or dizziness is a common occurrence, but it remains a challenging symptom when encountered in the emergency department (ED). A diagnostic score for stroke with high accuracy is therefore required. METHODS: A single-center observational study (498 patients) was conducted. The predictor variables were derived from a multivariate logistic regression analysis with Akaike information criterion. The outcome was the occurrence of stroke. We evaluated the utility of a new diagnostic score (TriAGe+) and compared it with the ABCD2 score. RESULTS: The cohorts included 498 patients (147 with stroke [29.4%]). Eight variables were included: triggers, atrial fibrillation, male gender, blood pressure ≥140/90 mm Hg, brainstem or cerebellar dysfunction, focal weakness or speech impairment, dizziness, and no history of vertigo or dizziness or labyrinth or vestibular disease. We derived the TriAGe+ score from these variables. In the cohort, the prevalence of stroke increased significantly using the diagnostic score: 5.9% for a score of 0-4; 9.1% for 5-7; 24.7% for 8-9; and 57.3% for 10-17. At a cutoff value of 10 points, the sensitivity of the score was 77.5%, the specificity was 72.1%, and the positive likelihood ratio was 3.2. When the cutoff was defined as 5 points, the score obtained a high sensitivity (96.6%) with a good negative likelihood ratio (.15). The new score outperformed the ABCD2 score for the occurrence of stroke (C statistic, .818 versus .726; P < .001). CONCLUSIONS: The TriAGe+ score can identify the occurrence of stroke in patients with vertigo or dizziness presenting to the ED.

Quantitative Analyses of Hepatic OATP-Mediated Interactions Between Statins and Inhibitors Using PBPK Modeling With a Parameter Optimization Method.

This study aimed to construct a widely applicable method for quantitative analyses of drug-drug interactions (DDIs) caused by the inhibition of hepatic organic anion transporting polypeptides (OATPs) using physiologically based pharmacokinetic (PBPK) modeling. Models were constructed for pitavastatin, fluvastatin, and pravastatin as substrates and cyclosporin A (CsA) and rifampicin (RIF) as inhibitors, where enterohepatic circulations (EHC) of statins were incorporated. By fitting to clinical data, parameters that described absorption, hepatic elimination, and EHC processes were optimized, and the extent of these DDIs was explained satisfactorily. Similar in vivo inhibition constant (Ki ) values of each inhibitor against OATPs were obtained, regardless of the substrates. Estimated Ki values of CsA were comparable to reported in vitro values with the preincubation of CsA, while those of RIF were smaller than reported in vitro values (coincubation). In conclusion, this study proposes a method to optimize in vivo PBPK parameters in hepatic uptake transporter-mediated DDIs.

Effects of fatigue from sleep deprivation on experimental periodontitis in rats.

BACKGROUND AND OBJECTIVE: Factors such as vascularization of the periodontium, inflammatory reactions and immune response affect the oral environment and ecology, decreasing host resistance and promoting the development of symptoms and the advancement of periodontal disease. Fatigue also influences the hypothalamic-pituitary-adrenal axis and reports relate it to systemic resistance. The aim of this study was to evaluate whether fatigue is a modifying factor for periodontal disease in rats. MATERIAL AND METHODS: We divided 24 3-wk-old male Sprague-Dawley rats randomly into the following four groups: control; fatigue (deep sleep deprivation for 7 d); infection (rats inoculated with carboxymethyl cellulose containing periodontopathic bacteria); and compound (combined fatigue and infection conditions). Weight, serum corticosterone levels, serum albumin levels, interleukin-1ß and tumor necrosis factor-α expression levels and distance from the cement-enamel junction to the alveolar bone crest were measured at baseline, and on the 36th (before sleep deprivation), 43rd (immediately after sleep deprivation) and 57th d (end of experiment). RESULTS: Immediately after sleep deprivation and at the end of the experiment, weight gain in the fatigue and compound groups was significantly lower than in controls (p < 0.05). Immediately after sleep deprivation, serum corticosterone levels were significantly higher in the fatigue and compound groups than in controls (p < 0.05). Moreover, serum albumin levels were significantly lower in the fatigue and compound groups than in controls (p < 0.05). Immediately after sleep deprivation, gene expression of interleukin-1ß was significantly higher in the infection and compound groups than in controls (p < 0.05). Moreover, gene expression of tumor necrosis factor-α was significantly higher in the compound group than in controls (p < 0.05). At the end of the experiment, the distance from the cement-enamel junction to the alveolar bone crest was significantly higher in the infection and compound groups than in controls (p < 0.05). Moreover, the distance was significantly higher in the compound group than in the infection group. CONCLUSIONS: Fatigue worsened systemic health in rats and increased gingival inflammation and alveolar bone loss in experimental periodontitis. In conclusion, our results suggest that fatigue is a modifying factor for periodontal disease in rats.

Utility of patch testing for patients with drug eruption.

BACKGROUND: Patch testing is less dangerous than oral provocation testing for identification of the causative drug for patients with drug eruption; however, its usefulness for such identification is controversial. AIM: To clarify the rates of positive patch testing for patients with drug eruption, classified by causative drugs and clinical features. METHODS: We analysed results during the period 1990-2010 for 444 patients (151 men, 293 women; mean ± SD age 49.9 ± 18.6 years) who were tested for drug eruption. In the patient group, there were 309 people (69.1%) with maculopapular eruption and 31 (6.9%) with severe drug eruption. The test materials were applied to the back and left for 2 days under occlusion, then results were assessed by the International Contact Dermatitis Research Group (ICDRG) scoring system 3 days after application. Reactions of + to +++ were regarded as positive. RESULTS: Of the 444 patients, 100 (22.4%) had a positive patch test result to a suspected drug. Positive rates were 23.6% and 20.0% for maculopapular eruption and fixed drug eruption, respectively. The class of materials to which most patients reacted positively was contrast medium (n = 53; 41.1%), followed by drugs acting on the central nervous system (n = 18; 28.6%). In the latter group, 16 of the 18 patients were positive to antiepileptics. CONCLUSIONS: Positive rates depend on the causative drug rather than the clinical features of the drug eruption. Patch testing is useful when contrast medium or antiepileptics are suspected to be the causative drugs. However, standardization of patch test materials and method of reading is needed, as well as guidelines regarding when testing should be performed. Although patch testing for drug eruption has significant potential, it requires further validation.

Plumping fluid added to storage medium increases twofold the functional life span of fowl spermatozoa in vitro at 4°C.

1. The objective of this study was to examine whether addition of plumping fluid (PF) to Lake's solution (LS) for storage of fowl spermatozoa in vitro at 4°C can prolong survival and improve the quality of spermatozoa. 2. In experiment 1, aliquots of spermatozoa were stored in vitro in LS alone and LS containing 10%, 25%, 50% and 75% (v:v) PF for 0.5, 24, 48, 72, 96 and 120 h at 4°C. After the end of each storage period, spermatozoa were evaluated for their viability, mobility and penetrability. Viability was determined using SYBR-14 and propidium iodide (PI) staining. Mobility was assessed using an Accudenz assay. Penetrability was assessed using spermatozoa-inner perivitelline layer (IPL) interaction assay. 3. In experiment 2, aliquots of spermatozoa were stored in vitro in LS alone and LS containing 25% and 50% (v:v) PF for 0.5, 24, 48 and 72 h at 4°C, and then fertility of the spermatozoa was evaluated using intravaginal artificial insemination (AI) in hens. 4. Storage of spermatozoa in LS alone resulted in loss of viability, mobility, penetrability and fertility within 48 h. In contrast, no loss of viability and penetrability was observed for the spermatozoa stored for 48, 96, 72 and 48 h in LS containing 10%, 25%, 50% and 75% (v:v) PF, respectively. In particular, fertilising capacity was not lost for the spermatozoa stored in the presence of 25% or 50% PF in LS for 48 and 24 h, respectively. 5. In conclusion, these findings demonstrated that in vitro exposure of fowl spermatozoa to PF during hypothermic storage in LS prolonged spermatozoa survival. A 25% (v:v) level of inclusion of PF in LS may be effective for the improvement of viability, penetrability and fertilising ability of the stored spermatozoa.

Acrosome reaction of fowl sperm: evidence for shedding of the acrosomal cap in intact form to release acrosomal enzyme.

The aim of this study was to determine the site of enzyme release from the acrosome and the fate of the acrosomal cap during the process of acrosome reaction (AR) in fowl sperm. Gelatin substrate coverslips with halos were subjected to scanning electron microscopy to determine the site from which acrosomal proteolytic enzyme was released to form a halo around the acrosome of individual sperm. Aliquots of sperm treated with solubilized inner perivitelline layer (IPL) containing 5 mmol CaCl(2) were simultaneously subjected to fluorescent staining with fluorescein isothiocyanate-labeled peanut agglutinin and scanning electron microscopy to evaluate AR of sperm and to examine the status of the acrosomal region, respectively. Inside the halos, a gelatin-free (proteolyzed gelatin) layer was found extending some distance around the acrosome of sperm. All of the sperm showing the formation of halos on gelatin had a single circular opening around their subacrosomal rod at the base of the acrosomal cap. Interaction of sperm with solubilized IPL in the presence of 5 mmol CaCl(2) resulted in 41.4 ± 1.8% of the sperm to undergo AR, as evaluated by fluorescein isothiocyanate-labeled peanut agglutinin. Similarly, as observed using scanning electron microscopy, 38.2 ± 2.3% of the sperm treated with solubilized IPL plus 5 mmol CaCl(2) had exposed subacrosomal rod. In all sperm examined, no sign of disruption of the acrosomal membrane was found in the apical region of the acrosome. Rather, the acrosomal caps were found intact detached from the acrosomal region of the sperm, indicating that AR of fowl sperm resulted in the intact removal of the acrosomal cap. Based on these experimental observations, we suggest that the process of AR in fowl sperm is unique; the release of the acrosomal proteolytic enzyme may occur through a single circular opening formed at the base of the acrosomal cap and the acrosomal cap is detached in intact form from the posterior acrosomal region of the sperm.

Limit on neutrinoless ßß decay of 136Xe from the first phase of KamLAND-Zen and comparison with the positive claim in 76Ge.

We present results from the first phase of the KamLAND-Zen double-beta decay experiment, corresponding to an exposure of 89.5 kg yr of (136)Xe. We obtain a lower limit for the neutrinoless double-beta decay half-life of T(1/2)(0ν)>1.9×10(25) yr at 90% C.L. The combined results from KamLAND-Zen and EXO-200 give T(1/2)(0ν)>3.4×10(25) yr at 90% C.L., which corresponds to a Majorana neutrino mass limit of <(120-250) meV based on a representative range of available matrix element calculations. Using those calculations, this result excludes the Majorana neutrino mass range expected from the neutrinoless double-beta decay detection claim in (76)Ge, reported by a part of the Heidelberg-Moscow Collaboration, at more than 97.5% C.L.

Maturational changes in the survivability and fertility of fowl sperm during their passage through the male reproductive tract.

The objective of this study was to examine whether domestic fowl (Gallus domesticus) sperm undergo maturation in their capacity for survival and fertilization in the male reproductive tract. Sperm collected from the testis, epididymis and the proximal, middle and distal vas deferens were simultaneously stored in vitro in minimum essential medium (MEM) at 39°C for 0, 3 and 6h, and at 4°C for 24 and 48h. Sperm membrane integrity was measured using the dual fluorescent stain SYBR-14/propidium iodide (PI). Aliquots of sperm from the various sites were subjected to artificial insemination (AI) into the uteri of hens to assess the duration of sperm survival in the oviduct and to determine the fertility status of the sperm. Testicular sperm exhibited a very low capacity to survive under in vitro liquid storage conditions, irrespective of the storage temperature used, and in the oviduct, and they had a low ability to fertilize the ovum. On the contrary, sperm from the distal vas deferens had a higher survival rate during in vitro storage periods, a longer life span in the oviduct, and high fertility. Survival and fertilizing capacity of the sperm recovered from the testes increased gradually (P<0.05) from the testes to the distal vas deferens. In conclusion, we suggest that fowl sperm may undergo functional maturation through a process of gradual changes in their survival and fertilization capacities during their passage through the successive parts of the male reproductive tract.

Maturational changes in motility, acrosomal proteolytic activity, and penetrability of the inner perivitelline layer of fowl sperm, during their passage through the male genital tract.

The objective was to examine, in vitro, the motility, acrosomal proteolytic activity (APA), and penetrating ability of fowl sperm recovered from the testis and epididymis, as well as the proximal, middle, and distal vas deferens, to assess the potential fertilizing ability of sperm as a function of maturation. A motile sperm separation technique was used to estimate sperm motility with Accudenz, a gelatin slide technique was used to measure the diameter of the halo around the acrosome of individual sperm as an indication of APA, and a sperm-inner perivitelline layer (IPL) interaction assay was done to estimate the number of hole formations as an indication of sperm penetration into the IPL. Sperm in the testis exhibited the least motility, produced the smallest halos, and created the least number of holes per 0.25 mm(2). Motility, diameter of the halo, and number of holes increased gradually (P < 0.05) from the epididymis to the distal vas deferens and were markedly different (P < 0.05) between testicular and deferent duct sperm. Based on these in vitro experimental findings, we inferred that fowl sperm undergo a gradual process of maturational changes in motility, APA, and penetrability as a means of acquiring potential fertility during their passage throughout the male genital tract.

mRNA induces RANTES production in trophoblast cells via TLR3 only when delivered intracellularly using lipid membrane encapsulation.

BACKGROUND: Trophoblasts express Toll-like receptor 3 (TLR3). The artificial TLR3 ligand, PolyI:C, induces an inflammatory response in trophoblasts but an endogenous ligand has not been identified. Notably, inflammatory disorders of pregnancy are associated with increased circulating placenta-derived mRNA. Endogenous degraded, uncapped mRNA is recognized by TLR3 in other cell lines. OBJECTIVE: We tested the hypothesis that plasma-derived mRNA induces an inflammatory response in a trophoblast cell line via TLR3. METHODS: Experiments were performed in the human first trimester extravillous trophoblast cell line HTR-8/SV neo. Plasma-derived mRNA was amplified using modified template switching and final in vitro transcription. We compared free mRNA (which favors cell surface interaction) to liposomally encapsulated mRNA (which favors intracellular mRNA delivery). We tested for the specific requirement of TLR3 signaling using siRNA. We tested for involvement of the canonical signaling pathway downstream of TLR3 by measuring NF-κB and IFN regulatory factor transcriptional activity using firefly-luciferase constructs. RESULTS: Free mRNA did not induce RANTES production. In contrast, liposomal mRNA resulted in marked induction of RANTES production (non-stimulated control 3.4 ± 0.6 pg/mL, liposomal mRNA 169.7 ± 26.2 pg/mL, p < 0.001), and this RANTES production was abolished by siRNA for TLR3. Downstream of TLR3, liposomal mRNA-induced dose-response NF-κB and IFN regulatory factor transcriptional activity, and IFN beta production. CONCLUSION: Plasma-derived 5' uncapped mRNA delivered intracellularly signals to induce NF-κB activation and increase RANTES production via TLR3.

N-glycosylation of zona glycoproteins during meiotic maturation is involved in sperm-zona pellucida interactions of porcine oocytes.

The objective was to determine whether N-glycosylation of zona pellucida (ZP) glycoproteins occurred during meiotic maturation of porcine oocytes, and whether this had a role in fertilization. In the first of three experiments, carbohydrate residues in the ZP of in vitro matured porcine oocytes were blocked with various lectins and the influence of such blocking on sperm-ZP interactions was studied. The second experiment used a lectin-binding assay to determine whether the number of GlcNAc residues in ZP was changed by N-glycosylation during in vitro maturation (IVM) of porcine oocytes. The last experiment determined the effects of tunicamycin, a specific N-glycosylation inhibitor, for various intervals during IVM, on sperm-ZP interactions in porcine oocytes. The primary findings were that: 1) N-glycosylation of GlcNAc residues in porcine ZP occurred during the first 24 h of IVM; and 2) such glycosylation was indispensible for sperm-ZP interactions, e.g., number of sperm bound to ZP, acrosome-reacted sperm, sperm penetration rate, and level of polyspermy (P < 0.05). However, blocking N-glycosylation by tunicamycin treatment during IVM did not adversely influence the progression of oocytes to meiotic metaphase II and male pronucleus formation, indicating that this glycosylation was involved only in the initial stages of fertilization. We inferred that the increase in terminal GlcNAc residues in ZP glycoprotein through new N-glycosylation during the first 24 h of meiotic maturation played a critical role in porcine ZP acquiring the capacity to accept sperm.

Toll-like receptor-3 stimulation upregulates sFLT-1 production by trophoblast cells.

BACKGROUND: Preeclampsia is characterized by a systemic inflammatory response involving cytokines, chemokines, and anti-angiogenic factors such as sFLT-1. In many other inflammatory diseases related responses are triggered by toll-like receptor (TLR) stimulation. Therefore, we tested the hypothesis that TLR stimulation of a trophoblast cell line induces inflammatory mediator production and, in particular, production of the preeclampsia-related anti-angiogenic factor sFLT-1. METHODS: We stimulated human first trimester extravillous trophoblast cells (HTR-8/SV neo cell line) with a variety of TLR ligands and measured downstream NF-kappaB and IRF signaling, inflammatory mediator (RANTES), and sFLT-1 mRNA expression and protein production. RESULTS: Of all TLR ligands, we found that TLR3 ligation with polyI:C resulted in the biggest response with 5.6-fold increased signaling via NF-kappaB and 5.8-fold increased signaling via IRF. RANTES mRNA expression increased 2900 fold and protein production increased 1600 fold in response to TLR3 ligation. sFLT-1 mRNA expression increased 1.7-fold and protein production increased 3.1-fold in response to TLR3 ligation. Inhibitors of the NF-kappaB and IRF signaling pathway decreased TLR3 ligation-induced sFLT-1 protein production by 31.8% and 24.9%, respectively. CONCLUSION: We conclude that trophoblast cells respond to TLR3 ligation by signaling through both NF-kappaB and IRF pathways resulting in expression of inflammatory mediators and, in particular, the preeclampsia-related anti-angiogenic factor sFLT-1.

Identification of binding sites for anti-aquaporin 4 antibodies in patients with neuromyelitis optica.

OBJECTIVE: Anti-aquaporin 4 antibodies (AQP4-Ab) are specifically detected in patients with neuromyelitis optica. To investigate the role of AQP4-Ab, we examined the antibody binding epitope using human and mouse mutant AQP4. METHODS: We constructed human and mouse amino acid substitution AQP4 mutants and compared the reactivity with wild-form of human, mouse and rat AQP4. RESULTS: The decreased intensity of AQP4-Ab staining with mouse AQP4 was recovered to that of human AQP4 with the mouse mutant A228E for 9 of the 10 sera. CONCLUSIONS: The third extracellular loop of AQP4 is considered to be the major epitope for AQP4-Ab in NMO.

A support system for context awareness in a group home using sound cues.

OBJECTIVES: In a group home, caregivers should be aware of the inhabitant's real-time situation. The aim of our study is to facilitate the awareness of an inhabitant's situation by means of enhanced sound cues. METHODS: We propose an audio notification system that indicates the real-time situation of persons in a group home environment using sound cues instead of visual surveillance. The notification system comprises a prediction and a notification function. The prediction function estimates a person's real-time situation using a Bayesian network and sensed information; the notification function informs recipients of the predicted situation and the confidence level of the prediction by means of sound cues. We use natural sounds as sound cues. RESULTS: As a first step to examine our system in a group home, we conducted operation and performance tests of each unit under a simple test environment. The correct prediction of the subject's situation is approximately 90%; further, it is shown that the sound cues should be selected according to their environmental dependence. CONCLUSIONS: The results show that the method is useful for monitoring persons. As future study, we will conduct a field test on an implemented system and improve it for practical use in a group home.

Evaluation of post-procedure changes in aneurysmal lumen following detachable coil-placement using multi-planar reconstruction of high-field (3.0T) magnetic resonance angiography.

BACKGROUND: Placement of detachable coil(s) for intracranial aneurysms has become one of the standard methods of management. Although detailed analysis of post-procedure changes in aneurysmal lumen is essential, technical difficulties often limit such evaluation. Development of higher magnetic field systems is steadily widening clinical usage of magnetic resonance imaging (MRI) primarily due to its significantly higher signal to noise ratio. OBJECTIVE: In this study, we evaluated a multi-planar reconstruction (MPR) technique of magnetic resonance angiography (MRA) on a 3.0T system in an attempt to develop a routine method of post-procedure evaluation following detachable coil placement. METHODS: Eleven patients with an intracranial aneurysm following placement of a Guglielmi detachable coil (GDC) participated in the study. Time of flight (TOF) magnetic resonance angiography (MRA) was obtained immediately after, and up to two years after coil embolisation utilising a GE 3.0T system. Data was analysed using standard maximum intensity projection (MIP) as well as the MPR technique and the results were compared to conventional catheter angiography. RESULTS: The study demonstrated that, compared to MIP, MPR can provide further information of alteration in aneurysm lumen, especially in analysis of: 1) jet of blood flow, 2) thrombus formation, 3) neck remnant or re-filling of blood, 4) location and shape of coils including compaction, and 5) coil protrusion into the parent artery. CONCLUSIONS: Combined MPR/MIP analysis of high-field MRA appears to be a powerful non-invasive method for evaluating GDC-treatment that can potentially replace conventional catheter angiography in many clinical situations.