Double mutations in klotho and osteoprotegerin gene loci rescued osteopetrotic phenotype

Klotho gene mutant mice (klotho mice, also called kl/kl) exhibit osteopetrosis in the metaphysis of femora and tibiae and die within 3 months. We previously showed by semiquantitative RT-PCR that osteoprotegerin (opg) expression levels in klotho mice were about 2-fold higher than those in wild-type mice in the bone marrow, spleen, and lung. To examine whether the high osteoprotegerin expression levels account for the osteopetrotic phenotype in the klotho homozygous mutant mice in vivo, we made double mutant mice by crossing klotho mutant and osteoprotegerin-deficient mice. Micro computed tomography analysis in the two-dimensional sagittal planes of the metaphyses and cross-sections of femoral midshaft revealed that the abnormally high fractional trabecular bone volume in klotho homozygous mice (kl/kl; 29.71%), which was about 4-fold higher compared with that of wild-type [klotho (+/+) opg (+/+)] mice (7.81%), was rescued by the coexistence of heterozygous mutation in opg gene locus (+/-; 8.36%). Single heterozygous mutation in the opg gene locus alone (without klotho mutation) did not show phenotype (trabecular bone volume, 5.84%; not significantly different from wild type). High levels of osteoprotegerin mRNA expression in the bone marrow in klotho mutant mice were reduced by the heterozygous mutation in the opg gene locus. Furthermore, high osteoprotegerin protein levels in klotho mutant mice were also reduced by the heterozygous mutations in opg gene locus. Thus, elevated levels of osteoprotegerin in mutant mice contribute at least in part to reveal the osteopetrotic phenotype in klotho mice.     

Perforation and Tumor Formation of the Intestine in Primary Amyloidosis

We report a case of primary amyloidosis with repeated bowel perforations. This patient also had localized amyloid deposition creating a tumorous region mimicking malignancy in the rectum. Perforation of the intestine is common in systemic amyloidosis. The ischemic change due to amyloid infiltration into the vessel wall may lead to perforation of the affected bowel. Amyloid tumors occur more often in localized amyloid than in systemic amyloidosis. Macroscopically, it is difficult to distinguish amyloid tumor of the intestine from neoplasia.     

Quantification of circulating varicella zoster virus-DNA for the early diagnosis of visceral varicella

Varicella zoster virus (VZV)-DNA was quantified in peripheral blood of 2 patients with visceral varicella due to endogenous reactivation. An 18-year-old male contracted varicella following the courses of chemotherapy for T cell lymphoma. Another 18-year-old male suffered from varicella 16 months after the complete engraftment of hematopoietic stem cell transplantation. Both patients had past VZV infection, but no recent contact with the disease. Paralytic ileus and ascites preceded the skin lesions. Quantitative real-time polymerase chain reaction revealed >200 copies of VZV per 1 ml of whole blood before or at the time when cropping vesicles emerged. The viral load reflected their prolonged clinical courses. Similar levels of VZV-DNA were detected in primary varicella patients, but not in herpes zoster patients or immunocompromised children without varicella or zoster. Quantitative monitoring of circulating VZV-DNA may be useful for the diagnosis and assessing the treatment response of visceral varicella in immunocompromized hosts.     

Predictors of hyperglycaemic individuals who do not follow up with physicians after screening in Japan: A cohort study

Aims

Although people screened as being hyperglycaemic often fail to follow up with physicians for clinical assessment, epidemiologic findings on the frequency and predictors of not following up (hereafter, “no follow-up”) are lacking. The purpose of this study was to examine the no follow-up rate with physicians after screening for diabetes and predictors of no follow-up.

Methods

We assessed cases of no follow-up with physicians within six months after screening based on medical claims data from employee-based social health insurance programs in Japan, for people aged 20 to 68 years from 2005 to 2010.

Results

Among 3878 screened participants with hyperglycaemia, 2527 (65%) did not follow up with their physicians within six months after screening. Multiple logistic regression analysis revealed that younger age and lower blood glucose level predicted no follow-up among both men and women, while lower body mass index and negative proteinuria also predicted no follow-up among men. Treatment for dyslipidaemia facilitated follow-up among both genders, and treatment for hypertension or depression facilitated follow-up among men.

Conclusions

Approximately two thirds of individuals screened as having hyperglycaemia did not follow up with their physicians within six months after screening. Predictors of no follow-up were younger age and milder hyperglycaemia. Being on treatment for co-morbidities tended to facilitate follow-up.     

Low-dose radioiodine therapy for patients with intermediate- to high-risk differentiated thyroid cancer

Annals of Nuclear Medicine - The efficacy of low-dose radioiodine therapy (RIT) for intermediate-risk or high-risk differentiated thyroid cancer (DTC) patients is controversial. Because of the...     

Pharmacokinetics and tissue distribution of 3,4‐diaminopyridine in rats

Lambert‐Eaton myasthenic syndrome (LEMS) is characterized by muscle weakness, amyotrophy, easy fatigability, and depressed tendon reflexes. 3,4‐Diaminopyridine (3,4‐DAP) is the recommended therapy for the treatment of LEMS. However, estimations of 3,4‐DAP pharmacokinetics in human and animals, such as rats, are rarely reported because 3,4‐DAP is an orphan drug for the treatment of a very rare disease (LEMS). In particular, little is known about its tissue distribution. Therefore, the pharmacokinetics of 3,4‐DAP were studied, with particular focus on tissue distribution, in rats. After intravenous administration of 3,4‐DAP to rats, the half‐life of 3,4‐DAP was 15.9 ± 3.9 min and the volume of distribution at steady‐state was 2.8 ± 0.7 L/kg. The tissue‐to‐plasma partition coefficient (Kp) was high in the kidney, heart, and muscle. In addition, with increased steady state plasma concentration (Css), a tendency toward increased Kp was found in most tissues. In the muscle, a likely target region of 3,4‐DAP in LEMS patients, the Kp was higher than in the plasma. Furthermore, more than 68% of 3,4‐DAP was distributed to the muscle as determined by the ratio of 3,4‐DAP distribution calculated from the apparent volumes of distribution. Hence, 3,4‐DAP may provide for more effective and long‐lasting effects.     

Rationale and design of “Can Very Low Dose Rivaroxaban (VLDR) in addition to dual antiplatelet therapy improve thrombotic status in acute coronary syndrome (VaLiDate-R)” study

Impaired endogenous fibrinolysis is novel biomarker that can identify patients with ACS at increased cardiovascular risk. The addition of Very Low Dose Rivaroxaban (VLDR) to dual antiplatelet therapy has been shown to reduce cardiovascular events but at a cost of increased bleeding and is therefore not suitable for all-comers. Targeted additional pharmacotherapy with VLDR to improve endogenous fibrinolysis may improve outcomes in high-risk patients, whilst avoiding unnecessary bleeding in low-risk individuals. The VaLiDate-R study (ClinicalTrials.gov Identifier: NCT03775746, EudraCT: 2018-003299-11) is an investigator-initiated, randomised, open-label, single centre trial comparing the effect of 3 antithrombotic regimens on endogenous fibrinolysis in 150 patients with ACS. Subjects whose screening blood test shows impaired fibrinolytic status (lysis time?>?2000s), will be randomised to one of 3 treatment arms in a 1:1:1 ratio: clopidogrel 75 mg daily (Group 1); clopidogrel 75 mg daily plus rivaroxaban 2.5 mg twice daily (Group 2); ticagrelor 90 mg twice daily (Group 3), in addition to aspirin 75 mg daily. Rivaroxaban will be given for 30 days. Fibrinolytic status will be assessed during admission and at 2, 4 and 8 weeks. The primary outcome measure is the change in fibrinolysis time from admission to 4 weeks follow-up, using the Global Thrombosis Test. If VLDR can improve endogenous fibrinolysis in ACS, future large-scale studies would be required to assess whether targeted use of VLDR in patients with ACS and impaired fibrinolysis can translate into improved clinical outcomes, with reduction in major adverse cardiovascular events in this high-risk cohort.

     

Elective antireflux surgery in the US: an analysis of national trends in utilization and inpatient outcomes from 2005 to 2010

Background

Previous research suggested that antireflux surgery reached its peak volume in the US more than a decade ago. Factors such as changes in population demographics and improvements in surgical outcomes may have reversed this decline. We sought to examine national trends in the management of antireflux surgery patients and identify patient and hospital characteristics associated with postoperative complications.

Methods

We analyzed data from the Nationwide Inpatient Sample to identify adults with gastroesophageal reflux disease or esophagitis who underwent elective antireflux surgery between 2005 and 2010. Patient and hospital characteristics were analyzed. A multivariate logistic regression model was used to identify characteristics associated with an increased risk of postoperative complications following laparoscopic antireflux surgery.

Results

The volume of elective antireflux surgery remained relatively stable between 2005 (n = 15,819) and 2010 (n = 18,780). The percentage of patients older than 64 years of age increased from 21.1 % in 2005 to 30.9 % in 2010 (p < 0.01), while the percentage with a Charlson score over 2 more than doubled (1.2–2.7 %; p < 0.01). Inpatient complication rates (6.3 vs. 6.6 %; p = 0.21) and mortality (0.08 vs. 0.21; p = 0.72) were unchanged. On multivariate analysis, patients older than 79 years were three times as likely to develop a complication (odds ratio [OR] 3.1; 95 % CI 2.1–4.5) as were patients with a Charlson score over 2 (OR 3.1; 95 % CI 2.2–4.3).

Conclusions

Today’s antireflux surgery patient population is a higher-risk cohort, but complication rates have remained stable and inpatient mortality has declined more than 50 % over the past decade. Given these findings, additional research is needed to understand why antireflux surgery is underutilized, with a decline of more than two-thirds since its peak in 1999.