[Adefovir Dipivoxil-induced Fanconi's Syndrome and Osteomalacia Following Multiple Bone Fractures in a Patient with Chronic Hepatitis B].

We herein present the case of a 66-year-old Japanese man with Fanconi's syndrome. He had been receiving adefovir dipivoxil (ADV) for the treatment of entecavir (ETV)-resistant chronic hepatitis B (CHB) for four years in his 8-year treatment of hepatocellular carcinoma (HCC), but was referred to our hospital after increased levels of bone pain in his ribs, knees, and ankles. Renal dysfunction, hypophosphatemia, and increased levels of bone alkaline phosphatase were found by a hematology test after admission for treatment of HCC. Radiography and 99m Tc-labeled hydroxymethylene diphosphonate (HMDP) scintigraphy revealed multiple insufficiency fractures in the ribs, knees, ankles, and heels. After switching from ADV to tenofovir disoproxil fumarate (TDF) and treatment with calcitriol and sodium dihydrogenphosphate, the patient's serum phosphate levels slightly increased and renal dysfunction did not improve, but after six months his clinical symptoms disappeared. To detect and prevent adverse effects from ADV, physicians and pharmacists should carefully monitor renal function and serum phosphate levels in patients with hepatitis B virus (HBV) treated for a long time with ADV.

[Consideration of the interaction of anti-diabetes agents].

While taking anti-diabetes agents, in combination with drugs that attenuate the hypoglycemic action or drug, or that enhance the hypoglycemic action, it is necessary to pay attention to hypoglycemia and fluctuations in blood glucose levels. Furthermore, a coadministration of two or more anti-diabetes agents including newly coming drugs, especially used in combination with insulin formulations or insulin secretagogues should be closely monitored and may need to reduce the dose.

[Usefulness of group work as a teaching strategy for long-term practical training in the 6-year pharmaceutical education].

At the initiation of long-term practical training in the 6-year pharmaceutical education, there are many issues to be solved. For example, it is necessary for teaching pharmacists, who are in charge of both staffing and teaching pharmacy students, to manage their workload with other staff pharmacists. To overcome this situation and to improve the motivation of teaching pharmacists towards student practical training, we twice held group work (GW) sessions for teaching pharmacists, and then evaluated whether such training was effective for their understanding of the Model Core Curriculum for Practical Training and for promoting a higher level of motivation. During the two-day GW discussions, teaching pharmacists, who work daily in the dispensing area, were separated into two groups to discuss teaching skills. A questionnaire survey was completed by participants before and after each GW session. According to the survey, more than 90% of the pharmacists had a higher motivation level for practical training after the sessions. Particularly in the second GW training, the response rate of "being actively involved" improved from 40% to 70%. Furthermore, "The Educational Evaluation Testing" was conducted, which confirmed the increased participant comprehension. The median scores of the comprehensive exams significantly (p<0.01) improved in twice GW, respectively. Therefore, we conclude that GW sessions are a useful tool for both improving professional knowledge about the Model Core Curriculum and motivating teaching pharmacists involved in the practical training of students. We hope that this exercise will lead to higher student motivation and satisfaction during their practical training.

[Pharmacists contribute to the safety of medicines].

Pharmacists have a professional obligation in medicine. As a member of a medical team to provide a safe medication, it is important that they be involved with drug safety in mind. Currently a pharmacist in a business operating with a focus on traditional dispensing and drug administration also functions with a focus on patient care and the provision of drug information. It is important that a pharmacist has a risk management approach to medicine. Together with the institutions responsible for drug safety, he must be cognizant of published reports to prevent serious adverse drug reactions as well as taking part in post-marketing surveillance. Management of safety information for high-risk pharmaceutical drugs, also falls to the pharmacist. Thus he must have knowledge of the skill required for the job of each member of the health care team. Recent newly added responsibilities are: advice in planning patient treatment, checking vital signs and the prescription brought to him to fill. In short a pharmacist working in the medical field must, above all, respect and assure safety to the patients he serves.

Protective effect against Parkinson's disease-related insults through the activation of XBP1.

The accumulation of misfolded and unfolded proteins in endoplasmic reticulum (ER) induces ER stress, activating the unfolded protein response (UPR). Recent evidence has suggested the relationship between UPR and dopaminergic neuronal cell death in Parkinson's disease (PD); however, it remains unclear whether it makes sense to modulate UPR, to mitigate the progression of PD. In this study, we investigated a role of the IRE1 alpha-XBP1 pathway in the survival of dopaminergic cells, under stress induced by PD-related insults. The exogenous expression of the active-form XBP1 (XBP1s) protein had protective effects against cell death induced by 1-methyl-4-phenylpyridinium (MPP+) and proteasome inhibitors. Moreover, adenoviral XBP1s expression significantly suppressed the degeneration of dopaminergic neurons in the mouse model of PD, as induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). These results demonstrate that the enhancement of XBP1 could be a novel PD therapeutic strategy.

A combination of HNF-4 and Foxo1 is required for reciprocal transcriptional regulation of glucokinase and glucose-6-phosphatase genes in response to fasting and feeding.

Glucokinase (GK) and glucose-6-phosphatase (G6Pase) regulate rate-limiting reactions in the physiologically opposed metabolic cascades, glycolysis and gluconeogenesis, respectively. Expression of these genes is conversely regulated in the liver in response to fasting and feeding. We explored the mechanism of transcriptional regulation of these genes by nutritional condition and found that reciprocal function of HNF-4 and Foxo1 plays an important role in this process. In the GK gene regulation, Foxo1 represses HNF-4-potentiated transcription of the gene, whereas it synergizes with HNF-4 in activating the G6Pase gene transcription. These opposite actions of Foxo1 concomitantly take place in the cells under no insulin stimulus, and such gene-specific action was promoter context-dependent. Interestingly, HNF-4-binding elements (HBEs) in the GK and G6Pase promoters were required both for the insulin-stimulated GK gene activation and insulin-mediated G6Pase gene repression. Indeed, mouse in vivo imaging showed that mutating the HBEs in the GK and G6Pase promoters significantly impaired their reactivity to the nutritional states, even in the presence of intact Foxo1-binding sites (insulin response sequences). Thus, in the physiological response of the GK and G6Pase genes to fasting/feeding conditions, Foxo1 distinctly decodes the promoter context of these genes and differently modulates the function of HBE, which then leads to opposite outcomes of gene transcription.

The prepattern transcription factor Irx2, a target of the FGF8/MAP kinase cascade, is involved in cerebellum formation.

The cerebellum develops from the rhombic lip of the rostral hindbrain and is organized by fibroblast growth factor 8 (FGF8) expressed by the isthmus. Here we report characterization of Irx2, a member of the Iroquois (Iro) and Irx class of homeobox genes, that is expressed in the presumptive cerebellum. When Irx2 is misexpressed with Fgf8a in the chick midbrain, the midbrain develops into cerebellum in conjunction with repression of Otx2 and induction of Gbx2. During this event, signaling by the FGF8 and mitogen-activated protein (MAP) kinase cascade modulates the activity of Irx2 by phosphorylation. Our data identify a link between the isthmic organizer and Irx2, thereby shedding light on the roles of Iro and Irx genes, which are conserved in both vertebrates and invertebrates.

The canonical Wnt pathway directly regulates NRSF/REST expression in chick spinal cord.

Neural precursor cells actively proliferate in the ventricular zone to self-renew the stem cell population, and in parallel, maintain their undifferentiated state. This progenitor pool generates postmitotic cells that migrate to the mantle layer and differentiate into mature neurons. The growth of these stem cells is strictly controlled by the canonical Wnt signaling cascade, in part mediated by the direct regulation of Cyclin D1, a critical regulator of cell cycle progression. Here, we report that the canonical Wnt pathway directly controls the expression of NRSF/REST. The Wnt-activated beta-catenin/TCF complex up-regulates this gene through a conserved element found in its exon 1a, a critical result obtained by a novel in ovo transcriptional assay. Hence, our data show that the canonical Wnt signaling cascade directly regulates the NRSF/REST and Cyclin D1 genes, thereby controlling the progenitor cells. In addition, we show that our in ovo transcription assay is a powerful way to analyze gene regulation in a natural in vivo context.