Comparative genomic analysis using microarray demonstrates a strong correlation between the presence of the 80-kilobase pathogenicity island and pathogenicity in Kanagawa phenomenon-positive Vibrio parahaemolyticus strains

Vibrio parahaemolyticus is a gram-negative marine bacterium. A limited population of the organisms causes acute gastroenteritis in humans. Almost all of the clinical V. parahaemolyticus isolates exhibit beta-type hemolysis on Wagatsuma agar, known as the Kanagawa phenomenon (KP). KP is induced by the thermostable direct hemolysin produced by the organism and has been considered a crucial marker to distinguish pathogenic strains from nonpathogenic ones. Since 1996, so-called “pandemic clones,” the majority of which belong to serotype O3:K6, have caused worldwide outbreaks of gastroenteritis. In this study, we used a DNA microarray constructed based on the genome sequence of a pandemic V. parahaemolyticus strain, RIMD2210633, to examine the genomic composition of 22 strains of V. parahaemolyticus, including both pathogenic (pandemic and nonpandemic) and nonpathogenic strains. More than 86% of the RIMD2210633 genes were conserved in all of the strains tested. Many variably present genes formed gene clusters on the genome of RIMD2210633 and were probably acquired through lateral gene transfer. At least 65 genes over 11 loci were specifically present in the pandemic strains compared with any of the nonpandemic strains, suggesting that the difference between pandemic and nonpandemic strains is not due to a simple genetic event. Only the genes in the 80-kb pathogenicity island (Vp-PAI) on chromosome II, including two tdh genes and a set of genes for the type III secretion system, were detected only in the KP-positive pathogenic strains. These results strongly suggest that acquisition of this Vp-PAI was crucial for the emergence of V. parahaemolyticus strains that are pathogenic for humans.     

Calcium-stimulated ATPase of dog submandibular gland

A Ca^2?-stimulated ATPase present in a microsomal fraction prepared from canine submandibular glands was investigated. The Ca²⁺ concentration for half maximal activation of the enzyme was about 0.3 mM. Addition of Mg²⁺ to incubation media containing Ca²⁺ decreased the ATPase activity. The presence of neither Na⁺ nor K⁺ is required for Ca²⁺-activation of the enzyme. Also, Ca²⁺ will not substitute for Mg²⁺ in the Mg²⁺-dependent (Na⁺ + K⁺)-ATPase reaction. The Ca²⁺-activation was not appreciably affected by ouabain (10^?4M), but was inhibited by about 50 per cent by 5 × 10^?3M ethacrynic acid. These studies provide a possible enzymatic basis for the calcium uptake by salivary gland microsomes that has been reported by other workers.     

A medical school-based program to encourage native Hawaiians to choose medical careers.

Native Hawaiians are highly underrepresented in the field of medicine, both nationally and in Hawaii. Since 1991, the Native Hawaiian Center of Excellence (funded by the Bureau of Health Professions) at the John A. Burns School of Medicine in Honolulu has developed programs to encourage Native Hawaiians to enter and complete medical school. In this article, the authors focus on a revised version of a six-week summer enrichment program for high school students developed by the Center in 1995 and funded by the Hawaii State Department of Education and the federal government. The authors trace the difficulties in attracting Native Hawaiian students and how these difficulties were overcome. They show that once Native Hawaiians have entered the academically rigorous, culturally rich program, their academic and career ambitions have been kindled, and some are planning careers in medicine. The history of the program illustrates that a committed medical school and dedicated individuals in the community, with the support of the federal and state governments, can increase interest among underrepresented students in medical and other health professions careers. Eventually, when such students graduate, there is a likelihood that some of them will go back to serve the health needs of their communities.     

Real World Treatment Practices for Chronic Lymphocytic Leukemia in Japan: An Observational Database Research Study (CLIMBER-DBR)

There are limited real-world data on the treatment practices and healthcare resource utilization associated with chronic lymphocytic leukemia (CLL) in Japan. In this study (CLIMBER-DBR), we performed retrospective analyses of the Japanese Medical Data Vision database, and extracted data for 2562 patients with newly diagnosed CLL (CLL-1 cohort) and 930 patients receiving CLL treatment (CLL-2 cohort) registered between March 1, 2013 and February 28, 2018. The median follow-up in the CLL-1 cohort was 721 (quartile 1–3: 363–1267) days and the median time to initial (first-line) treatment was 1331 (quartile 1–3: 189–not reached) days. In the CLL-2 cohort, the most frequently used regimens were fludarabine alone (17.7%), cyclophosphamide alone (13.7%), and bendamustine/rituximab (8.2%). The median (quartile 1–3) times to second-line and third-line treatments were 1066 (273–not reached) and 1795 (631–not reached) days, respectively. The CLIMBER-DBR was the first database research study to assess current treatment practices for CLL in Japan, where the treatment patterns were driven by the approval/reimbursement status of drugs in the study period. Our study provides an important benchmark for future studies of CLL in Japan.     

Medical education in paradise: another facet of Hawaii

Hawaii is synonymous with paradise in the minds of many. Few know that it is also an environment where high quality medical education is thriving. This paper outlines medical education initiatives beginning with native Hawaiian healers of centuries ago, and continuing to present-day efforts to support top-notch multicultural United States medical education across the continuum of training. The undergraduate medical education program has as its core community-based problem-based learning. The community basis of training is continued in graduate medical education, with resident doctors in the various programs rotating through different clinical experiences at various hospitals and clinics. Continuing medical education is provided by nationally accredited entities, within the local context. Educational outreach activities extend into primary and secondary schools, homeless shelters, neighbouring islands, and to countries throughout the Pacific. Challenges facing the medical education community in Hawaii are similar to those faced elsewhere and include incorporating more technology to improve efficiency, strengthening the vertical integration of the training continuum, better meeting the needs of the state, and paying for it all. Readers are invited to join in addressing these challenges to further the realisation of medical education in paradise as a paradise of medical education.     

A phase 1/2 study of carfilzomib in Japanese patients with relapsed and/or refractory multiple myeloma

We conducted a phase 1/2 study of single‐agent carfilzomib in Japanese patients with relapsed/refractory multiple myeloma. Safety, pharmacokinetics and pharmacodynamics of carfilzomib were examined in phase 1. The primary endpoint in phase 2 was the overall response rate (ORR). Carfilzomib was administered in a twice‐weekly, consecutive‐day dosing schedule. In Phase 1, doses of 15 or 20 mg/m² were administered on this schedule or 20 mg/m² on Days 1 and 2 of Cycle 1 and then 27 mg/m² in the 20/27 mg/m² cohort. Patients had a median of five prior therapies, including bortezomib and an immunomodulatory agent. The dose level did not reach the maximum tolerated dose. The most common adverse events were haematological. Notably, carfilzomib either induced new hypertension (n = 4) or aggravated previously existing hypertension (n = 6) in 10 of 50 patients. Four of the eight patients who previously experienced peripheral neuropathy (PN) experienced a recurrence with carfilzomib use, but no new cases of PN occurred. The ORR of the 20/27 mg/m² 40 patient cohort was similar to that in the pivotal US study. The dose was efficacious and tolerable in heavily pre‐treated Japanese patients; however, meticulous control of hypertension may be necessary for further carfilzomib use.     

Comparison of elemental concentrations in the acinar cells of the human labial salivary gland.

Two types of acinar cells were observed in human labial glands by conventional and analytical electron microscopic and light microscopic techniques. The predominant type contained large and prominent secretory granules that were strongly mucicarmine and PAS (with and without diastase) positive. The second type contained small, lacy, secretory granules, and these cells were faintly positive with these stains. The elemental contents of the two types of granules were measured by analytical electron microscopy using digital mapping and spot analysis applied to freeze-dried cryosections prepared from gland slices incubated in vitro under non-stimulated conditions. The large secretory granules had significantly higher Ca, S and Mg concentrations and significantly lower Cl and K concentrations than the small granules. The difference in elemental contents probably reflects differences in the content of secretory macromolecules. Specifically, the S content is thought to reflect the anionic properties of the secretory macromolecules, while the levels of divalent cations are thought to be determined by electroneutrality requirements for macromolecular folding and storage. No differences were found in nuclear or cytoplasmic elemental concentrations between the two cell types.     

Constipation Is a Frequent Problem Associated with Vascular Complications in Patients with Type 2 Diabetes: A Cross-sectional Study

Objective Diabetes is recognized as an underlying disease of constipation. However, the prevalence of constipation varies according to the diagnostic criteria applied. We investigated the prevalence of constipation based on the new guideline for constipation in Japanese patients with type 2 diabetes and examined the relationship with the clinical background, including diabetic vascular complications. Methods Questionnaire surveys including items concerning the diagnosis and treatment status of constipation were administered to 410 patients with type 2 diabetes. Results Although 29% of the patients considered that they had experienced constipation (self-judged), only 14% had consulted a physician about constipation. The prevalence of chronic constipation based on the guideline was 26%. After including laxative users, constipation was finally found in 36%. Despite the use of laxatives (n=81), 51% of the patients were still diagnosed with chronic constipation. Patients with constipation (chronic constipation or laxative use) were significantly older and had a longer duration of diabetes than those without constipation. The body mass index (BMI) of patients with constipation (24.9±3.8 kg/m²) was significantly lower than that of those without constipation (26.3±4.6 kg/m²). Diabetic neuropathy (49% vs. 32%) and coronary heart disease (CHD) (27% vs. 13%) were significantly more frequent in the patients with constipation than in those without constipation. A multivariate logistic regression analysis revealed that gender, BMI, diabetic neuropathy, insulin use, and CHD were significantly associated with constipation. Conclusion An accurate diagnosis of constipation is desirable in patients with type 2 diabetes because constipation is independently associated with CHD.     

Graft versus host disease-related secretory immunoglobulin A deficiency in bone marrow transplant recipients. Findings in labial saliva

Graft versus host disease-dependent decreases in salivary IgA levels were sought in labial gland saliva samples from bone marrow transplant recipients. Transplantation-associated, irradiation-related effects were also present, but these could be avoided if analyses were performed at 1 year or later after transplantation. Sampling of minor gland saliva eliminated the possibility of contamination with IgA-rich serum transudates arising from gingival or mucosal pathways which obscured results from previous studies using whole saliva samples. Patients with active extensive clinical disease had significantly depressed levels of salivary IgA. Since labial saliva is a principal source of total salivary IgA, the present findings may explain why patients with graft versus host disease are susceptible to infection via the sinobronchial portal.