Determining Optimal Intervals for In-Person Visits During Video-Based Telemedicine Among Patients With Hypertension: Cluster Randomized Controlled Trial.

BACKGROUND: Introducing telemedicine in outpatient treatment may improve patient satisfaction and convenience. However, the optimal in-person visit interval for video-based telemedicine among patients with hypertension remains unreported in Japan. OBJECTIVE: We determined the optimal in-person visit interval for video-based telemedicine among patients with hypertension. METHODS: This was a cluster randomized controlled noninferiority trial. The target sites were 8 clinics in Japan that had a telemedicine system, and the target patients were individuals with essential hypertension. Among patients receiving video-based telemedicine, those who underwent in-person visits at 6-month intervals were included in the intervention group, and those who underwent in-person visits at 3-month intervals were included in the control group. The follow-up period of the participants was 6 months. The primary end point of the study was the change in systolic blood pressure, and the secondary end points were the rate of treatment continuation after 6 months, patient satisfaction, health economic evaluation, and safety evaluation. RESULTS: Overall, 64 patients were enrolled. Their mean age was 54.5 (SD 10.3) years, and 60.9% (39/64) of patients were male. For the primary end point, the odds ratio for the estimated difference in the change in systolic blood pressure between the 2 groups was 1.18 (90% CI -3.68 to 6.04). Notably, the criteria for noninferiority were met. Patient satisfaction was higher in the intervention group than in the control group. Furthermore, the indirect costs indicated that lost productivity was significantly lesser in the intervention group than in the control group. Moreover, the treatment continuation rate did not differ between the intervention and control groups, and there were no adverse events in either group. CONCLUSIONS: Blood pressure control status and safety did not differ between the intervention and control groups. In-person visits at 6-month intervals may cause a societal cost reduction and improve patient satisfaction during video-based telemedicine. TRIAL REGISTRATION: UMIN Clinical Trials Registry (UMIN-CTR) UMIN000040953; https://tinyurl.com/2p8devm9.

[Recurrent episodes of hypothermia as a sequela of human herpesvirus 6 encephalitis following cord blood transplantation for acute myeloid leukemia].

A 46-year-old female patient underwent a cord blood transplantation (conditioning regimen: fludarabine/busulfan4/melphalan80; graft-versus-host disease (GVHD) prophylaxis: tacrolimus + mycophenolate mofetil) for acute myeloid leukemia (AML) with her 1st hematological complete response to induction therapy (idarubicin 3 days+cytarabine 7 days). She lost her consciousness due to human herpesvirus 6 (HHV-6) encephalitis on day 31, and therefore, we increased the foscarnet dosage (from 120 mg/kg to 180 mg/kg). Her consciousness level improved after treatment. However, 8 hours of sudden hypothermia occurred with hyperhidrosis, hypertension, and subsequent hyperglycemia on day 34. Her condition did not improve even after administration of anticonvulsant, steroid pulse, or intravenous immunoglobulin. A total of 75 attacks were observed until she was discharged on day 471. She has not shown chronic GVHD or relapsed AML since then. However, HHV-6 caused prolonged damage to her hypothalamus as observed through magnetic resonance imaging (MRI) and single-photon emission computed tomography (SPECT) using 99mTc ethyl cysteinate dimer even when the virus was not detected from her cerebrospinal fluid. This damage can be responsible for the hypothermia attacks. This is the first case report of prolonged series of hypothermia attacks for over a year as a sequela of HHV-6 encephalitis after a cord blood transplantation for AML.

Impact of sodium glucose cotransporter 2 inhibitor on histological features and glucose metabolism of non-alcoholic fatty liver disease complicated by diabetes mellitus.

AIM: The aim of this study was to investigate the therapeutic potential of sodium glucose cotransporter 2 inhibitor (SGLT2I) as an effective therapeutic option for non-alcoholic fatty liver disease (NAFLD). METHODS: In this prospective study, nine patients with NAFLD complicated by type 2 diabetes mellitus (DM), were introduced to the regimen of canagliflozin 100 mg once daily for 24 weeks and were evaluated by liver histology at pretreatment and at 24 weeks after the start of treatment. The primary outcome was histological improvement, defined as a decrease in NAFLD activity score of one point or more without worsening in fibrosis stage. Glucose metabolism was evaluated based on the meal tolerance test. The usefulness of extracellular and exosome microRNA-122 (miR-122) as early predictors of histological improvement was investigated. RESULTS: All of the nine patients achieved histological improvement. Scores of steatosis, lobular inflammation, ballooning, and fibrosis stage decreased by 78%, 33%, 22%, and 33% at 24 weeks compared to the pretreatment, respectively. Six patients showed improvement in insulin resistance, and the other three patients showed partial improvement of insulin secretion function. Six patients, who showed a decrease in both extracellular and exosome miR-122 ratios (the ratio of miR-122 levels at 1 day after treatment to that at baseline), showed histological improvement. Furthermore, one patient, who showed a decrease in exosome miR-122 ratios regardless of the increase in extracellular miR-122 ratios, also showed decreases in NAFLD activity score and fibrosis stage. CONCLUSION: A prospective study showed that SGLT2I for NAFLD complicated by DM improved histological features in connection with glucose metabolism. This trial was registered as clinical trial UMIN000018166.

Effects of a sodium-glucose cotransporter 2 inhibitor in nonalcoholic fatty liver disease complicated by diabetes mellitus: Preliminary prospective study based on serial liver biopsies.

A prospective study based on serial liver biopsies was performed to investigate the efficacy of sodium-glucose cotransporter 2 inhibitor for nonalcoholic fatty liver disease complicated with type 2 diabetes mellitus. Conclusion: Treatment for 24 weeks resulted in improvement in histopathologic features in all 5 patients. (Hepatology Communications 2017;1:46-52).

Single nucleotide polymorphisms of vascular endothelial growth factor gene intron 2 are markers for early progression of diabetic retinopathy in Japanese with type 1 diabetes.

BACKGROUND: Few studies investigated the relationship between single nucleotide polymorphisms (SNPs) of vascular endothelial growth factor (VEGF) gene and time to the development and progression of diabetic retinopathy. METHODS: Eight SNPs of VEGF gene were typed using TaqMan assays in 175 Japanese patients with type 1 diabetes. Fundi were evaluated longitudinally. The overall mean HbA1c value was calculated to assess long-term glycemic control. RESULTS: Cumulative incidence of severe nonproliferative diabetic retinopathy (NPDR) differed among genotypes in rs833070 and rs2146323, both of which located in intron 2. Homozygotes for the minor alleles of rs833070, rs2146323, and rs699947, which were in strong linkage disequilibrium, showed earlier progression to severe NPDR than those with other genotypes (p = 0.010, p = 0.011, and p = 0.031, respectively). Cox proportional hazards analysis showed that homozygosity for the minor allele of rs833070 or rs2146323 was marginally insignificant as risk factor for severe NPDR, but significant after the mean HbA1c value was deleted from the model [hazard ratio (95% confidence interval): 1.67 (1.01-2.54), p = 0.047 and 1.67 (1.01-2.74), p = 0.047, respectively]. CONCLUSIONS: Certain SNPs in intron 2 of the VEGF gene are associated with early progression of retinopathy in Japanese patients with type 1 diabetes, though their contributions were weakened by glycemic exposure.

Rate of beta-cell destruction in type 1 diabetes influences the development of diabetic retinopathy: protective effect of residual beta-cell function for more than 10 years.

CONTEXT: Although residual beta-cell function delays the onset and progression of diabetic retinopathy in patients with type 1 diabetes, the rate of beta-cell destruction is variable. OBJECTIVE: The aim of the study was to clarify the influence of the rate of beta-cell destruction on the development and progression of diabetic retinopathy in type 1 diabetes. DESIGN: We performed a historical cohort study regarding residual beta-cell function and retinopathy. SETTING: The study was conducted in the outpatient clinic of a general hospital. PATIENTS: A total of 254 patients with type 1 diabetes participated. MAIN OUTCOME MEASURES: Serum C-peptide and fundus findings were evaluated longitudinally. RESULTS: The cumulative incidence of mild nonproliferative diabetic retinopathy was higher in the patients without detectable beta-cell function than in those with residual beta-cell function at 20, 15, and 10 yr after the onset of diabetes (P = 0.013, P = 0.006, and P = 0.048, respectively), but not at 5 yr after the onset (P = 0.84). There were higher mean glycosylated hemoglobin values during the entire follow-up period in the patients without detectable beta-cell function at 20 and 15 yr after the onset of diabetes (P = 0.030 and P = 0.042, respectively). Positivity for HLA-A24 and -DQA1 03, as well as the acute onset of diabetes, was associated with early beta-cell loss and also with early development of diabetic retinopathy. Cox proportional hazards analysis showed that undetectable beta-cell function at 20, 15, or 10 yr after the onset of diabetes was an independent risk factor for the development of diabetic retinopathy. CONCLUSIONS: Undetectable beta-cell function within 10 yr of the onset of type 1 diabetes is associated with the earlier occurrence of diabetic retinopathy.

PDZ adaptor protein PDZK2 stimulates transport activity of organic cation/carnitine transporter OCTN2 by modulating cell surface expression.

A part of the organic cation transporter families (OCT3, OCTN1, and OCTN2) has recently been identified to physically interact with PDZ (PSD95, Dlg, and ZO1) domain-containing proteins, although the physiological relevance of such interaction has not yet been fully examined. Here we have examined the stimulatory effect of PDZK2 [also named NaPi-Cap2 and intestinal and kidney-enriched PDZ protein (IKEPP)] on those cation transporters. In HEK293 cells, coexpression with PDZK2 increased the uptake of carnitine by OCTN2 with minimal effect on its substrate recognition specificity, but not for transport activity of OCT3 or OCTN1. The stimulatory effect of PDZK2 on OCTN2 was compatible with an approximately 2 times increase in transport capacity and can be accounted for by the increase in cell surface expression of OCTN2. Coexpression of PDZK2 did not affect carnitine transport activity of OCTN2 with deletion of the last four amino acids, which were found to be important for the interaction, suggesting involvement of physical interaction of the two proteins in the increase of cell surface expression of OCTN2. In mouse kidney, colocalization of PDZK2 and OCTN2 occurred predominantly in the region that was close to, but not the same as, the surface of apical membranes where OCTN2 alone was observed, suggesting the existence of OCTN2 in the subapical compartment that interacts with PDZK2. The present data have thus proposed an "intracellular pool" for OCTN2 that may be relevant to the stabilization of cell surface expression of OCTN2, thereby increasing transport activity for carnitine.

Regulation of drug transporters by PDZ adaptor proteins and nuclear receptors.

Drug transporters have been suggested to be involved in various aspects of pharmacokinetics. Identification and characterization of drug transporters have given us a scientific basis for understanding drug disposition, as well as the molecular mechanisms of drug interaction and inter-individual/inter-species differences. On the other hand, regulatory mechanisms of drug transporters are still poorly understood, and information is limited to induction and down-regulation of drug transporters by various microsomal enzyme inducers. Little is known about the molecular machinery that directly interacts with the drug transporters. As a first step to clarify such molecular mechanisms, recent studies have identified PDZ (PSD-95/Discs-large/ZO-1) domain-containing proteins that directly interact with the so-called PDZ binding motif located at the C-terminus of drug transporters. Some of the PDZ proteins have been suggested to regulate transporters via at least two pathways, i.e. stabilization at the cell-surface and direct modulation of transporter function. Therefore, it is possible that membrane transport of therapeutic agents is not only governed by the drug transporters themselves, but also indirectly by PDZ proteins. The PDZ proteins are classified as a family, the members of which are thought to have distinct, but also redundant physiological roles. The purpose of this review article is to summarize the available knowledge on protein interactions and functional modulation of drug transporters.

Chorea and Broca aphasia induced by diabetic ketoacidosis in a type 1 diabetic patient diagnosed as Moyamoya disease.

We here report one case of hemichorea and Broca aphasia occurred with diabetic ketoacidosis. A 20-year-old woman with type 1 diabetes mellitus had experienced diabetic ketoacidosis fourth time after the onset of diabetes. At the third ketoacidotic episode, the patient was admitted to our hospital for the first time to show hemichorea of the left extremities. Brain computed tomography (CT) demonstrated a high-density area in the right caudate head and low-density area in the right putamen. Magnetic resonance angiography (MRA) demonstrated a stenosis at the root of the bilateral middle and anterior cerebral arteries. The hemichorea disappeared within 3 days. At the fourth ketoacidotic episode, not hemichorea but unconsciousness was there for 2 days even after ketoacidosis disappeared. After the unconscious state, Broca aphasia was demonstrated for 15 days. The cerebral angiography showed a finding compatible to Moyamoya disease. These findings support that chorea and Broca aphasia induced by diabetic ketoacidosis was developed in addition to blood vessel abnormalities such as Moyamoya disease. We suggest that poorly controlled diabetic patients with hemichorea should undergo cerebral angiography.

Na+/H+ exchanger 3 affects transport property of H+/oligopeptide transporter 1.

Oligopeptide transporter PEPT1 is thought to be involved in the intestinal absorption and renal reabsorption of peptides and therapeutic agents. The driving force of PEPT1 is H+ gradient, a part of which is supplied by Na+/H+ exchanger (NHE) expressed on the apical surface of the epithelium although molecular identification of NHE has not yet been fully clarified. Here we examined the effect of NHE3 coexpression on the function of PEPT1 to support the hypothesis that NHE3 regulates PEPT1 function by supplying its driving force. HEK293 cells expressing PEPT1 alone exhibited Na+-independent but pH-dependent uptake of glycylsarcosine (GlySar), whereas those coexpress PEPT1 and NHE3 showed an increase in GlySar uptake and conferred Na+-dependence on the uptake of GlySar. The increase in GlySar transport by PEPT1 depended on the expression level of NHE3 and was found at various levels of PEPT1 expression. Kinetic analysis of GlySar uptake in HEK293 cells expressing both PEPT1 and NHE3 or those expressing PEPT1 alone revealed an approximately 3 times increase in the transport capacity in the presence of NHE3, as normalized by PEPT1 mRNA expression. Confocal microscopy indicated that both PEPT1 and NHE3 are colocalized on the cell-surface of HEK293 cells. Thus, the present findings are the first to specify that NHE3 exerts post-transcriptional stimulation of PEPT1-mediated transport and can affect cellular uptake of the substrates by PEPT1 expressed on apical membranes in the body.

PDZK1 directly regulates the function of organic cation/carnitine transporter OCTN2.

Urinary excretion of cationic xenobiotics is believed to be mediated by organic cation transporter (OCT and OCTN) families expressed on both basolateral and brush-border membranes of renal tubules, although the molecular mechanisms for targeting of these transporters to each membrane are poorly understood. Here, to examine the regulatory mechanisms for cell-surface expression and function of these transporters, we evaluated the interaction of these transporters with several PDZ proteins. A pull-down study using recombinant C-terminal proteins of OCTs and OCTNs identified a specific interaction of apical transporters OCTN1 and OCTN2, but not basolateral transporters OCT1 and OCT2, with PDZK1, intestinal and kidney-enriched PDZ protein, and Na+/H+ exchanger regulatory factor 2 (also called E3KARP, SIP-1, or TKA-1). Both yeast two-hybrid and pull-down studies suggested a requirement of the last four amino acids in OCTN1 and OCTN2 for the interaction. The interaction of PDZK1 with the C terminus of OCTN2 was also confirmed in a pull-down study using kidney brush-border membrane vesicles. Immunohistochemical analysis revealed that both PDZK1 and OCTN2 are colocalized in brush-border membranes of the kidney. Finally, double transfection of OCTN2 with PDZK1 stimulated the uptake by OCTN2 of its endogenous substrate carnitine, and this increase could be accounted for by the 6-fold increase in transport capacity. Such an increase was not observed for OCTN2 with deletion of the last four amino acids. Biotinylation study of surface proteins revealed minimal effect of PDZK1 on cell-surface expression of OCTN2. The present findings are the first to identify PDZK1 as a functional regulator of OCTN2 through direct interaction with the C terminus.

Screening of the interaction between xenobiotic transporters and PDZ proteins.

PURPOSE: Xenobiotic transporters have been proposed to be involved in membrane penetration of various therapeutic agents. As little information is available on molecular mechanism of their functional regulation, we have attempted to clarify the protein-protein interactions of such transporters as a first step to identify their regulators. METHODS: Yeast two-hybrid screening was performed to examine the interaction between carboxylic terminus of various xenobiotic transporters and PDZ (PSD95, D1g and ZO1) domain-containing proteins. The interaction and functional regulation were also evaluated in pull-down, immunoprecipitation and transport studies. RESULTS: Specific interaction with PDZ proteins was identified for several xenobiotic transporters including PEPT1, PEPT2, OCT3, OCTN1, OCTN2, OAT4, OATP-A, OATP-D, and OATP-F. The potent interaction was observed between PEPT2 and PDZK1, and deletion of the last four amino acids of the PEPT2 C-terminus almost completely abrogated such interaction. Recombinant PEPT2 C-terminus fusion protein can bind to purified His6-tagged PDZK1, confirming the involvement of two of four PDZ domains within PDZK1 in the interaction. Alanine-scanning mutation in PEPT2 revealed the presence of a consensus sequence (-T-X-L) that is responsible for the PDZK1 interaction. Transfection of PDZK1 increased the uptake of glycylsarcosine by PEPT2, whereas such stimulation was not observed for PEPT2 with the last four amino acids deleted. CONCLUSIONS: These results first identified the interaction between PDZ proteins and the cytosolic tail of various xenobiotic transporters. PDZK1 directly interacts with PEPT2, exerting functional regulation of its transporting activity. The current findings imply the localization of PEPT2 within a protein network constructed from PDZK1 and other transporter proteins.