Acquisition of resistance to antitumor alkylating agent ACNU: a possible target of positron emission tomography monitoring

Early detection of tumor response to chemotherapy is of great importance for appropriate treatment of tumors. In this study, characteristics of two positron emission tomography (PET) tracers, [(18)F]2-fluoro-2-deoxy-D-glucose (FDG) and[(18)F]3'-fluoro-3'-deoxy-thymidine (FLT), in the early detection of tumor cell response as well as tolerance development to chemotherapy was compared using rat C6 glioma cells and 1-(4-amino-2-methyl-5-pyrimidinyl)-methyl-3-(2-chloroethyl)-3-nitrosoureahydrochloride (ACNU). ACNU is an alkylating agent known to induce drug resistance through expression of O(6)-methylguanine-deoxyribonucleic acid methyl transferase (O(6)-MGMT). We established an ACNU-resistant C6 glioma cell line (C6/ACNU) and investigated the effect of ACNU on the uptake of FLT and FDG. In C6 cells, DNA synthesis presented as [(3)H]thymidine ([(3)H]Thd) incorporation into DNA was quickly suppressed by ACNU. In C6/ACNU cells, the suppression was recovered promptly, indicating that DNA alkylation occurs initially but highly expressed O(6)-MGMT repairs DNA, leading to the recovery of DNA synthesis. The patterns of FLT uptake in C6 and C6/ACNU were difficult to distinguish in the very early stage of the treatment, though it was reported that FLT uptake well correlated with proliferation in certain conditions. FDG uptake showed different patterns between the resistant and control cells, with significantly decreased uptake in C6 cells and unchanged uptake in C6/ACNU cells at 18-24 h after the treatment. Though difficult to be directly translated into clinical situation, the present study will provide a base to develop an appropriate protocol to assess tumor response to treatment by PET and to design effective treatment plans.     

Degree of Trauma Differs for Major Osteoporotic Fracture Events in Older Men Versus Older Women

To examine the degree of trauma in major osteoporotic fractures (MOF) in men versus women, we used data from 15,698 adults aged ≥65 years enrolled in the Osteoporotic Fractures in Men (MrOS) study (5994 men) and the Study of Osteoporotic Fractures (SOF) (9704 women). Participants were contacted tri‐annually to ascertain incident fractures, which were confirmed by radiographic reports and coded according to degree of self‐reported trauma. Trauma was classified as low (fall from ≤ standing height; fall on stairs, steps, or curb; minimal trauma other than fall [coughing, turning over]); moderate (collisions with objects during normal activity without associated fall); or high (fall from > standing height; severe trauma [motor vehicle accident, assault]). MOF included hip, clinical vertebral, wrist, and humerus fractures. Mean fracture follow‐up was 9.1 years in SOF and 8.7 years in MrOS. A total of 14.6% of the MOF in men versus 6.3% of the MOF in women were classified as high trauma (p < 0.001); men versus women more often experienced fractures resulting from severe trauma as well as from fall > standing height. High‐trauma fractures were more significantly common in men versus women at the hip (p = 0.002) and wrist (p < 0.001) but not at the spine or humerus. Among participants with MOF, the odds ratio of a fracture related to high‐trauma fracture among men versus women was 3.12 (95% confidence interval [CI] 1.70–5.71) after adjustment for traditional risk factors. Findings were similar in analyses limited to participants with hip fractures (odds ratio [OR] = 3.34, 95% CI 1.04–10.67) and those with wrist fracture (OR = 5.68, 95% CI 2.03–15.85). Among community‐dwelling older adults, MOF are more likely to be related to high trauma in men than in women. These findings are not explained by sex differences in conventional risk factors and may reflect a greater propensity among men to engage in risky behavior. © 2015 American Society for Bone and Mineral Research.     

An evaluation of bubble-CPAP in a neonatal unit in a developing country: effective respiratory support that can be applied by nurses

To describe the implementation of bubble-CPAP in a referral hospital in a developing country and to investigate: the feasibility of nurses implementing bubble-CPAP and the impact of bubble-CPAP on need for mechanical ventilation and mortality. Retrospective evaluation of prospectively collected data from two time periods: 18 months before and 18 months after the introduction of bubble-CPAP. The introduction of bubble-CPAP was associated with a 50 per cent reduction in the need for mechanical ventilation; from 113 of 1,106 (10.2 per cent) prior to bubble-CPAP to 70 of 1,382 (5.1%) after introduction of CPAP (chi2, p<0.001). In the 18 months prior to bubble-CPAP there were 79 deaths (case fatality of 7.1 per cent). In the 18 months after bubble-CPAP there were 74 deaths (CF 5.4 per cent), relative risk: 0.75 (0.55-1.02, chi2, p=0.065). Nurses could safely apply bubble-CPAP after 1-2 months of on-the-job training. Equipment for Bubble-CPAP cost 15 per cent of the cost of the cheapest mechanical ventilator. The introduction of bubble-CPAP substantially reduced the need for mechanical ventilation, with no difference in mortality. In models of neonatal care for resource-limited countries, bubble-CPAP may be the first type of ventilatory support that is recommended. Its low cost and safety when administered by nurses makes it ideal for this purpose. Bubble-CPAP has the potential for being available at even lower cost than the current commercially available bubble systems used in this study.     

Temporal stability of urinary cadmium in samples collected several years apart in a population of older persons

Objectives

There is growing evidence that urine cadmium is a temporally stable biomarker indicative of long-term cadmium exposure; however questions remain with regard to generalizability to older persons, the impact of changes in smoking behavior, and the degree of temporal stability when repeat sample collection spans years instead of weeks or months.

Histopathological studies of microtubule disassembling agent-induced myocardial lesions in rats

Microtubule disassembling agents (MDAs) such as colchicine (COL) and vincristine sulfate (VCR) are known to be cardiotoxic. However, few attempts have been made to histopathologically examine cardiac lesions induced by MDAs. In this study, we endeavored to induce myocardial injury in rats by administering MDAs and to clarify the morphological features of these myocardial lesions. Male rats were intravenously administered COL (1.00 or 1.25 mg/kg for 2 days at single daily doses) or VCR (0.50 or 0.75 mg/kg for 2 days at single daily doses). The day after administration, hearts were excised and examined histopathologically, immunohistochemically and electron microscopically. Degeneration and necrosis of myocardial cells with vacuolation were observed in rats administered COL at 1.25 mg/kg or VCR at 0.75 mg/kg. Electron microscopic examination revealed vacuoles in swollen mitochondria. Moreover, there were cells showing pyknosis and karyorrhexis in the interstitium. TUNEL and immunohistochemical staining for endothelial cells and electron microscopic examination identified the apoptotic cells in the interstitium to be vascular endothelial cells. These vascular endothelial lesions were induced by lower doses of MDAs than were myocardial lesions. Furthermore, common sites of cardiac lesions induced by MDAs had almost the same distribution as areas positive for pimonidazole, a marker of hypoxia. These findings indicate that MDAs occasionally damage mitochondria in myocardial cells, and suggest that these changes involve microcirculatory dysfunction induced by endothelial cell injury.     

Triglyceride level and soft drink consumption predict nonalcoholic fatty liver disease in nonobese male adolescents

Aim

Differential metabolic risk factors of nonalcoholic fatty liver disease (NAFLD) in nonobese male adolescents were analyzed examining relationships between NAFLD and clinical parameters of metabolic syndrome, including exercise and soft drink consumption, in male adolescents.

Methods

In total, 134 male university students (nonobese, n = 78; obese, n = 56) who underwent the first-year health checkup were divided into the NAFLD and non-NAFLD groups based on abdominal ultrasonography (AUS) findings. Relationships between NAFLD and metabolic parameters, including body mass index (BMI) and AUS score, were examined in nonobese students.

Results

Metabolic factors associated with hypertension, abdominal fat, liver damage, dyslipidemia, and impaired glucose tolerance were significantly less common in nonobese students than in obese students. The aforementioned factors and soft drink consumption were significantly more common in the NAFLD group than in the non-NAFLD group. The univariate and multivariate analyses of nonobese students showed that the triglyceride level (odds ratio [OR], 1.06; 95% confidence interval [CI], 1.01–1.10, p = 0.001) was higher and soft drink consumption (OR, 36.8; 95% CI, 3.69–368, p < 0.001) was more common in the NAFLD group than the non-NAFLD group.

Conclusions

Triglyceride level and soft drink consumption could aid in the detection of NAFLD in nonobese male adolescents. Our findings could provide useful information related to NAFLD and metabolic syndrome in nonobese adolescents.     

Saturated and Unsaturated Bone Marrow Lipids Have Distinct Effects on Bone Density and Fracture Risk in Older Adults

Greater bone marrow adiposity (BMAT) is associated with lower bone mineral density (BMD) and vertebral fractures; less is known about BMAT composition and bone. We studied BMAT composition and bone outcomes in 465 participants from the Age Gene/Environment Susceptibility (AGES)-Reykjavik study. BMAT saturation and unsaturation, measured with magnetic resonance spectroscopy, were defined as the ratio of saturated (1.3 ppm peak) or unsaturated (5.3 ppm peak) lipid to total marrow contents, respectively. At baseline and follow-up visits, spine and hip BMD were assessed with quantitative computed tomography (QCT) and dual-energy X-ray absorptiometry (DXA) and vertebral fractures were identified with DXA. Incident clinical fractures were identified through medical records for up to 8.8 years of follow-up. Associations between BMAT composition and BMD, bone loss, and fractures were evaluated in adjusted regression models. At baseline, mean ± standard deviation (SD) participant age was 81.7 ± 4.3 years, mean BMAT unsaturation was 3.5% ± 1.0%, and mean saturation was 46.3% ± 7.2% in the full cohort (47.7% women). Each SD increase in BMAT saturation was associated with lower trabecular BMD: −23.6% (spine) and −13.0% (total hip) (all p < 0.0001). Conversely, BMAT unsaturation (per SD increase) was associated with higher trabecular BMD: +17.5% (spine) and +11.5% (total hip) (all p < 0.001). BMAT saturation (per SD increase) was associated with greater risk for prevalent (odds ratio [OR] 1.46; 95% confidence interval [CI], 1.11–1.92) and incident (OR 1.55; 95% CI, 1.03–2.34) vertebral fracture. BMAT unsaturation (per SD increase) was associated with lower risk for incident vertebral fracture (OR 0.58; 95% CI, 0.38–0.89). In gender stratified analyses, BMAT saturation and unsaturation had opposite associations with incident clinical fracture among men. In general, saturated marrow lipids were associated with worse skeletal outcomes, whereas unsaturated lipids were associated with better outcomes. We recommend that future studies of marrow fat and skeletal health report measurements of saturated and unsaturated marrow lipids, rather than total marrow fat content alone. © 2022 American Society for Bone and Mineral Research (ASBMR).     

Arterial switch operation for transposition of the great arteries, with special reference to left ventricular function

Between June 1984 and September 1987, 48 patients underwent Lecompte's modification of the arterial switch operation for transposition of the great arteries, including transposition with intact ventricular septum with preparatory pulmonary artery banding (n = 18), with patent ductus arteriosus (n = 11), with dynamic left ventricular outflow tract obstruction (n = 4), and transposition with ventricular septal defect (n = 15). Ages ranged from 12 days to 36 months (mean 8 months) and weights ranged from 2.7 to 12.8 kg (mean 5.7 kg). Two deaths occurred, yielding an operative mortality rate of 4.2%. Preparatory pulmonary artery banding resulted in an increase to 65 +/- 5 mm Hg in the left ventricular afterload. Linear regression of the optimum circumference of the band (Y, millimeters) against left ventricular end-diastolic volume (X, milliliters) yielded the following formula: Y = 0.23X + 19.7 (r = 0.885, p less than 0.001). Influence of left ventricular mass on cardiac function after anatomic correction was evaluated. The total amount of dopamine used after repair in patients in whom the left ventricular mass was less than 60% of normal was significantly larger than that in patients with a left ventricular mass greater than or equal to 60% of normal (p less than 0.002). The left ventricular end-diastolic volume in patients with a left ventricular mass less than 60% of normal increased significantly 2 months after operation (p less than 0.05), whereas it decreased in patients with a left ventricular mass greater than 60% of normal (p less than 0.01). We believe it is safe to perform this procedure in patients in whom the left ventricular mass is larger than 60% of normal. Most newborn infants with simple transposition can undergo correction between 10 and 20 days of life if the ductus arteriosus is kept patent with prostaglandin E1 and the left ventricle is thereby loaded. Preparatory pulmonary artery banding, when necessary, will be satisfactory if the left ventricular pressure is greater than 65 mm Hg and/or the left ventricular/right ventricular pressure ratio is greater than 0.8.     

Role of the vitreous in branch retinal vein occlusion

We analyzed the vitreous findings in 62 patients (62 eyes) with major branch retinal vein occlusion to determine whether vitreous examination was useful in predicting the development of retinal or disk neovascularization, or both. In 18 eyes with no or partial posterior vitreous detachment and large areas of capillary nonperfusion (5 disk diameters or more), ten eyes (55.6%) eventually developed neovascularization. Only three of the remaining 44 eyes (6.8%) developed neovascularization. The probability of this development was greater in eyes with no partial posterior vitreous detachment at the initial vitreous examination (P = .0177, Cox's regression analysis), and in those with large areas of nonperfusion (P = .0097, Cox's regression analysis).