Maternal multivitamin intake and orofacial clefts in offspring: Japan Environment and Children's Study (JECS) cohort study

Objectives: Orofacial clefts are common birth defects with a lack of strong evidence regarding their association with maternal nutrition. We aimed to determine whether a relationship exists between maternal nutrient or multivitamin intake and orofacial clefts. Design: This is a prospective, population-based nationwide cohort study. Setting: The study was conducted in 15 regional centres, consisting of local administrative units and study areas. Participants: A total of 98 787 eligible mother–child pairs of the Japan Environment and Children’s Study were included. Intervention: Exposures were maternal nutrition and the use of supplemental multivitamins in mothers. Primary and secondary outcome measures: Outcomes were the occurrence of any orofacial cleft at birth. Multinomial logistic regression analyses were used to evaluate the association between maternal multivitamin intake and the incidence of orofacial clefts. Results: Of the 98 787 children, 69 (0.07%) were diagnosed with cleft lip alone, 113 (0.11%) were diagnosed with cleft lip and palate, and 52 (0.05%) were diagnosed with cleft palate within 1 month after birth. Regarding the total orofacial cleft outcome, statistically significant point estimates of relative risk ratios (RR) were determined for multivitamin intake before pregnancy (RR=1.71; 95% CI 1.06 to 2.77) and during the first trimester (RR=2.00; 95% CI 1.18 to 3.37), but the association was not significant for multivitamin intake after the first trimester (RR=1.34; 95% CI 0.59 to 3.01). Maternal micronutrient intake via food was not associated with the incidence of orofacial clefts in offspring. Conclusions: Intake of multivitamin supplements shortly before conception or during the first trimester of pregnancy was found to be associated with an increased incidence of orofacial clefts at birth. Pregnant women and those intending to become pregnant should be advised of the potential risks of multivitamin supplementation

Life Cycle of the Soybean Aphid Aphis glycines Matsumura, in Japan

The soybean aphid Aphis glycines MATSUMURA is the main sap-sucking pest on soybeans Glycine max. In Japan, it is distributed from Hokkaido to Kyushu (Sakai, 1949); abroad, it is found in Korea, China, Taiwan, Thailand, Malay (Paik, 1965), the Phillipines (Takahashi, 1966), and India (Raychaudhuri et al., 1980). In addition to soybeans, wild Glycine species are known to be a secondary host. Matsumura reported this aphid species on soybean (1917a) and in the same year recorded that its eggs over-wintered on plants belonging to the wild pea family (1917b). Shindo (1928, 1932) originally identified Kitsunenomago Justicia procumbens and purplish amaranth Amaranthus blitum as primary hosts, but later retracted and reported that the eggs over-winter in the roots of the Japanese chaff flower Acyranthes japonica (1941). However, Sakai (1949, 1950a, b) showed in greenhouse studies that this aphid does not over-winter in the chaff flower, and concluded that the species found on chaff flower was actually Aphis justiciae SHINJI which Shindo (1928) considered to be the same as Aphis glycines. While the controversy in Japan about the primary host remained unresolved, in China it was reported by Wang et al. (1962) that the eggs over-wintered in the Dahurian buckthorn Rhamnus davurica of the buckthorn family. Zhang and Zhong (1982) subsequently established that several of the 15 species in the genus Rhamnus found in China were primary hosts. In the reports from China, only the body color and the number of secondary sensilla of the third antennal segment of gynopara were reported, and no mention was made of the morphs on the primary host. Since 1981, our field surveys and greenhouse studies have focused on the life cycle and morphs on primary hosts in the genus Rhamnus, the results of which are reported here.Originating text in Japanese.Citation: Takahashi, Shigeru, Inaizumi, Mitsumaru, Kawakami, Koji. (1993). Life Cycle of the Soybean Aphid Aphis glycines Matsumura, in Japan. Japanese Journal of Applied Entomology and Zoology, 37, 207-212

Tadalafil use is associated with a lower incidence of Type 2 diabetes in men with benign prostatic hyperplasia: A population-based cohort study

BACKGROUND: Tadalafil, commonly prescribed for benign prostatic hyperplasia (BPH), may benefit patients with Type 2 diabetes mellitus (T2DM) for glycemic markers and complications. However, the association between the long-term use of tadalafil and the incidence of T2DM has not been investigated. METHODS: We emulated a target trial of tadalafil use (5 mg/day) and the risk of T2DM using a population-based claims database in Japan. Patients who initiated tadalafil or alpha-blockers for BPH and had no history of diabetes diagnosis, no dispensing of glucose-lowering drugs, and no history of hemoglobin A1c levels of ≥6.5% (47–48 mmol/mol) were included. The primary outcome was the incidence of T2DM. Pooled logistic regression was used to estimate adjusted risk ratios (RRs) and 5-year cumulative incidence differences (CIDs). RESULTS: A total of 5180 participants initiated tadalafil treatment and were compared with 20, 049 patients who initiated alpha-blockers. The median follow-up time for each arm was 27.2 months (interquartile range [IQR], 12.0–47.9) in tadalafil users and 31.3 months (IQR, 13.7–57.2) in alpha-blocker users. The incidence rates of T2DM in tadalafil and alpha-blocker users were 5.4 (95% confidence interval [CI], 4.0–7.2) and 8.8 (95% CI, 7.8–9.8) per 1000-person years, respectively. Initiation of tadalafil was associated with a reduced risk of T2DM (RR, 0.47; 95% CI, 0.39–0.62; 5-year CID, −0.031; 95% CI, −0.040 to −0.019). CONCLUSION: The incidence of T2DM was lower in men with BPH treated with tadalafil than in those treated with alpha-blockers. Thus, tadalafil may be more beneficial than alpha-blockers in preventing T2DM

Designed hybrid TPR peptide targeting Hsp90 as a novel anticancer agent

<p>Abstract</p> <p>Background</p> <p>Despite an ever-improving understanding of the molecular biology of cancer, the treatment of most cancers has not changed dramatically in the past three decades and drugs that do not discriminate between tumor cells and normal tissues remain the mainstays of anticancer therapy. Since Hsp90 is typically involved in cell proliferation and survival, this is thought to play a key role in cancer, and Hsp90 has attracted considerable interest in recent years as a potential therapeutic target.</p> <p>Methods</p> <p>We focused on the interaction of Hsp90 with its cofactor protein p60/Hop, and engineered a cell-permeable peptidomimetic, termed "hybrid Antp-TPR peptide", modeled on the binding interface between the molecular chaperone Hsp90 and the TPR2A domain of Hop.</p> <p>Results</p> <p>It was demonstrated that this designed hybrid Antp-TPR peptide inhibited the interaction of Hsp90 with the TPR2A domain, inducing cell death of breast, pancreatic, renal, lung, prostate, and gastric cancer cell lines <it>in vitro</it>. In contrast, Antp-TPR peptide did not affect the viability of normal cells. Moreover, analysis <it>in vivo </it>revealed that Antp-TPR peptide displayed a significant antitumor activity in a xenograft model of human pancreatic cancer in mice.</p> <p>Conclusion</p> <p>These results indicate that Antp-TPR peptide would provide a potent and selective anticancer therapy to cancer patients.</p

Impact of health insurance coverage forHelicobacter pylorigastritis on the trends in eradication therapy in Japan: retrospective observational study and simulation study based on real-world data

Objectives: To explore the prevalence of Helicobacter pylori infection in Japan and the trends of its eradication therapy before and after the changes of the insurance coverage policy, first started in 2000, and expanded to cover H. pylori-positive gastritis in 2013. The impacts that the changes brought were estimated. Methods: In this retrospective observational study and simulation study based on health insurance claims data, product sales data and relevant studies, individuals who received triple therapy (amoxicillin, clarithromycin, proton-pump inhibitors or potassium-competitive acid blockers) were defined as the first-time patients for H. pylori eradication in two Japanese health insurance claims databases (from approximately 1.6 million and 10.5 million individuals). Each sales data of eradication packages and examination kits were used to estimate the number of H. pylori-eradicated individuals nationwide. The prevalence of H. pylori infection, including the future rate, was predicted using previous studies and the estimated population trend by a national institute. Cases completed prior to the policy change on insurance coverage were simulated to estimate what would have happened had there been no change in the policy. Results: The numbers of patients first received eradication therapy were 81 119 and 170 993 from two databases. The nationwide estimated number of patients successfully eradicated was approximately 650 000 per year between 2001 and 2012, whereas it rapidly rose to 1 380-000 per year in 2013. The estimated prevalence of infection in 2050 is 5%, this rate was estimated to be 28% and 22% if the policy changes had not occurred in 2000 and 2013, respectively. Conclusions: The impact of policy changes for H. pylori eradication therapy on the prevalence of infection was shown. The results suggest that insurance coverage expansion may also reduce the prevalence in other countries with a high prevalence of H. pylori infection if the reinfection is low

Targeted Anticancer Immunotoxins and Cytotoxic Agents with Direct Killing Moieties

Despite the progress of the bioinformatics approach to characterize cell-surface antigens and receptors on tumor cells, it remains difficult to generate novel cancer vaccines or neutralizing monoclonal antibody therapeutics. Among targeted cancer therapeutics, biologicals with targetable antibodies or ligands conjugated or fused to toxins or chemicals for direct cell-killing ability have been developed over the last 2 decades. These conjugated or fused chimeric proteins are termed immunotoxins or cytotoxic agents. Two agents, DAB389IL-2 (ONTAKTM) targeting the interleukin-2 receptor and CD33-calicheamicin (Mylotarg®), have been approved by the FDA for cutaneous T-cell lymphoma (CTCL) and relapsed acute myeloid leukemia (AML), respectively. Such targetable agents, including RFB4(dsFv)-PE38 (BL22), IL13-PE38QQR, and Tf-CRM107, are being tested in clinical trials. Several agents using unique technology such as a cleavable adapter or immunoliposomes with antibodies are also in the preclinical stage. This review summarizes the generation, mechanism, and development of these agents. In addition, possible future directions of this therapeutic approach are discussed

Initiating SGLT2 inhibitor therapy to improve renal outcomes for persons with diabetes eligible for an intensified glucose-lowering regimen: hypothetical intervention using parametric g-formula modeling

[Introduction] Sodium–glucose cotransporter 2 (SGLT2) inhibitors are now recommended in guidelines for persons with type 2 diabetes mellitus (T2DM) and at risk of advanced kidney disease as part of the glucose-lowering regimen. [Research design and methods] To explore the optimal threshold at which to initiate SGLT2 inhibitor therapy, we conducted an observational study analyzed under a counterfactual framework. This study used the electronic healthcare database in Japan, comprising data from approximately 20 million patients at approximately 160 medical institutions. Persons with T2DM with an estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73 m2 in April 2014 were eligible. The primary end point was the composite of renal deterioration (>40% decline in eGFR) and the development of eGFR<30 mL/min/1.73 m2. We estimated the risk of the composite end point occurring over 77 months in different scenarios, such as early or delayed intervention with SGLT2 inhibitors for uncontrolled diabetes at different hemoglobin A1c (HbA1c) thresholds. The parametric g-formula was used to estimate the risk of the composite end point, adjusting for time-fixed and time-varying confounders. [Results] We analyzed data from 36 237 persons (149 346 person-years observation), of whom 4679 started SGLT2 inhibitor therapy (9470 person-years observation). Overall, initiating SGLT2 inhibitor therapy was associated with a 77-month risk reduction in the end point by 1.3–3.7%. The largest risk reduction was observed within 3 months of initiation once the HbA1c level exceeded 6.5% (risk reduction of 3.7% (95% CI 1.6% to 6.7%)) compared with a threshold of 7.0% or higher. [Conclusions] Our analyses favored early intervention with SGLT2 inhibitors to reduce the renal end point, even for persons with moderately controlled HbA1c levels. Our findings also suggest caution against clinical inertia in the care of diabetes

Prevalence, recognition and management of chronic kidney disease in Japan: population-based estimate using a healthcare database with routine health checkup data

[Background] We aimed to update information on the prevalence of chronic kidney disease (CKD) in Japan. We also explored whether CKD was properly recognized and managed. [Methods] We used data from annual health checkups in 2017, compiling records for 5 million persons. These included laboratory results and were linked to healthcare utilization records via personal identifiers. CKD was defined as an estimated glomerular filtration rate 95% sought medical services and 64.6% received laboratory tests within 180 days of the checkup. However, the diagnostic code suggestive of CKD was recorded in only 23.2% of patients and prescriptions for DM and HT were found in 31.2% (1590/5096) and 36.7% (8081/22 019) of comorbid persons, respectively. [Conclusions] The prevalence of CKD in Japan has increased over the past decade. However, recognition of CKD is likely suboptimal and there is room to improve the management of comorbid DM and HT

A novel transferrin receptor-targeted hybrid peptide disintegrates cancer cell membrane to induce rapid killing of cancer cells

BACKGROUND: Transferrin receptor (TfR) is a cell membrane-associated glycoprotein involved in the cellular uptake of iron and the regulation of cell growth. Recent studies have shown the elevated expression levels of TfR on cancer cells compared with normal cells. The elevated expression levels of this receptor in malignancies, which is the accessible extracellular protein, can be a fascinating target for the treatment of cancer. We have recently designed novel type of immunotoxin, termed "hybrid peptide", which is chemically synthesized and is composed of target-binding peptide and lytic peptide containing cationic-rich amino acids components that disintegrates the cell membrane for the cancer cell killing. The lytic peptide is newly designed to induce rapid killing of cancer cells due to conformational change. In this study, we designed TfR binding peptide connected with this novel lytic peptide and assessed the cytotoxic activity in vitro and in vivo. METHODS: In vitro: We assessed the cytotoxicity of TfR-lytic hybrid peptide for 12 cancer and 2 normal cell lines. The specificity for TfR is demonstrated by competitive assay using TfR antibody and siRNA. In addition, we performed analysis of confocal fluorescence microscopy and apoptosis assay by Annexin-V binding, caspase activity, and JC-1 staining to assess the change in mitochondria membrane potential. In vivo: TfR-lytic was administered intravenously in an athymic mice model with MDA-MB-231 cells. After three weeks tumor sections were histologically analyzed. RESULTS: The TfR-lytic hybrid peptide showed cytotoxic activity in 12 cancer cell lines, with IC(50 )values as low as 4.0-9.3 μM. Normal cells were less sensitive to this molecule, with IC(50 )values > 50 μM. Competition assay using TfR antibody and knockdown of this receptor by siRNA confirmed the specificity of the TfR-lytic hybrid peptide. In addition, it was revealed that this molecule can disintegrate the cell membrane of T47D cancer cells just in 10 min, to effectively kill these cells and induce approximately 80% apoptotic cell death but not in normal cells. The intravenous administration of TfR-lytic peptide in the athymic mice model significantly inhibited tumor progression. CONCLUSIONS: TfR-lytic peptide might provide a potent and selective anticancer therapy for patients