Cardiomyocyte expression of PPARgamma leads to cardiac dysfunction in mice

Three forms of PPARs are expressed in the heart. In animal models, PPARgamma agonist treatment improves lipotoxic cardiomyopathy; however, PPARgamma agonist treatment of humans is associated with peripheral edema and increased heart failure. To directly assess effects of increased PPARgamma on heart function, we created transgenic mice expressing PPARgamma1 in the heart via the cardiac alpha-myosin heavy chain (alpha-MHC) promoter. PPARgamma1-transgenic mice had increased cardiac expression of fatty acid oxidation genes and increased lipoprotein triglyceride (TG) uptake. Unlike in cardiac PPARalpha-transgenic mice, heart glucose transporter 4 (GLUT4) mRNA expression and glucose uptake were not decreased. PPARgamma1-transgenic mice developed a dilated cardiomyopathy associated with increased lipid and glycogen stores, distorted architecture of the mitochondrial inner matrix, and disrupted cristae. Thus, while PPARgamma agonists appear to have multiple beneficial effects, their direct actions on the myocardium have the potential to lead to deterioration in heart function.     

Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries

This article provides an update on the global cancer burden using the GLOBOCAN 2020 estimates of cancer incidence and mortality produced by the International Agency for Research on Cancer. Worldwide, an estimated 19.3 million new cancer cases (18.1 million excluding nonmelanoma skin cancer) and almost 10.0 million cancer deaths (9.9 million excluding nonmelanoma skin cancer) occurred in 2020. Female breast cancer has surpassed lung cancer as the most commonly diagnosed cancer, with an estimated 2.3 million new cases (11.7%), followed by lung (11.4%), colorectal (10.0 %), prostate (7.3%), and stomach (5.6%) cancers. Lung cancer remained the leading cause of cancer death, with an estimated 1.8 million deaths (18%), followed by colorectal (9.4%), liver (8.3%), stomach (7.7%), and female breast (6.9%) cancers. Overall incidence was from 2-fold to 3-fold higher in transitioned versus transitioning countries for both sexes, whereas mortality varied <2-fold for men and little for women. Death rates for female breast and cervical cancers, however, were considerably higher in transitioning versus transitioned countries (15.0 vs 12.8 per 100,000 and 12.4 vs 5.2 per 100,000, respectively). The global cancer burden is expected to be 28.4 million cases in 2040, a 47% rise from 2020, with a larger increase in transitioning (64% to 95%) versus transitioned (32% to 56%) countries due to demographic changes, although this may be further exacerbated by increasing risk factors associated with globalization and a growing economy. Efforts to build a sustainable infrastructure for the dissemination of cancer prevention measures and provision of cancer care in transitioning countries is critical for global cancer control.     

急性百草枯中毒大鼠肺组织MMP-2和TIMP-1的基因表达

目的 利用实时荧光定量PCR法测定急性百草枯中毒大鼠肺组织中基质金属蛋白酶-2(MMP-2)、基质金属蛋白酶组织因子抑制剂-1(TIMP-1)基因的表达,探讨其在急性百草枯中毒所致的大鼠急性肺损伤及纤维化中的作用.方法 80只SD大鼠,随机分为对照组(n:8)、染毒组(n:72);对照组一次性腹腔注射与染毒组等体积的生理盐水,染毒组一次性腹腔注射百草枯溶液(18mg/kg)染毒;分别于1、3、5、7、14、28 d光镜下观察两组大鼠的肺组织病理变化,同时利用实时荧光定量PCR法动态测定MMP-2、TIMP-1的mRNA表达量.结果 与对照组相比,染毒组大鼠早期主要表现为肺脏的急性炎症反应,肺水肿和出血明显,染毒5 d后观察到肺纤维化变化,第28天纤维化最明显;染毒组肺组织中的MMP-2的mRNA表达较对照组从第1天开始即明显增强,第7天达到高峰,为对照组的2.83倍,以后逐渐下降,但28 d时仍高于对照组,差异无统计学意义(P<0.01);TIMP-1的mRNA表达第1天也明显高于对照组,逐渐增强至14 d达到峰值,为对照组的7.28倍,后开始缓慢下降,28 d时仍明显高于对照组(P<0.01).结论 MMP-2、TIMP-1在急性百草枯中毒所致的急性肺损伤中起了重要的作用,同时大鼠的肺纤维化进程与MMPs/TIMPs的基因表达比例失调有很大的关系.     

Changes in blood counts after the administration of granulocyte-colony- stimulating factor and the collection of peripheral blood stem cells from healthy donors

BACKGROUND: After the collection of granulocyte-colony-stimulating factor (G-CSF)-mobilized peripheral blood stem cells from healthy donors, the donor platelet counts fall. However, the magnitude and duration of this decrease are not known. STUDY DESIGN AND METHODS: Sixty healthy people were given G-CSF (5, 7.5, or 10 micrograms/kg/day) for 5 days (Days 1–5), and 1 peripheral blood stem cell component was collected on Day 6. The platelet count, white cell count, absolute neutrophil count, hematocrit, and red cell count were measured before administration of G-CSF (Day 0), before collection of peripheral blood stem cells on Day 6, and on Days 8, 10, 13, 16, and 20. RESULTS: The platelet count fell from 261 +/? 47 × 10(9) cells per L on Day 0 to 159 +/? 30 × 10(9) cells per L on Day 8 (p < 0.0001) and reached its lowest level on Day 10 (146 +/? 30 × 10(9)/L; p < 0.001). Compared to Day 0 levels, the platelet count was lower on Day 13 (185 +/? 49 × 10(9)/L, p < 0.001), was the same on Day 16 (270 +/? 53 × 10(9)/L), and was greater on Day 20 (333 +/? 60 × 10(9)/L, p < 0.0001). The white cell count returned to pretreatment values on Day 13, and the absolute neutrophil count returned to pretreatment values on Day 10 (Day 0 white cell count = 6.05 +/? 1.59 × 10(9)/L and Day 0 absolute neutrophil count = 3.97 +/? 1.52 × 10(9)/L). On Day 20, both were less than pretreatment values (white cell count = 5.14 +/? 1.24 × 10(9)/L, p = 0.0007 and absolute neutrophil count = 3.20 +/? 1.24 × 10(9)/L, p = 0.0036). The red cell counts on Day 16 (4.52 +/? 0.41 × 10(12)/L) and Day 20 (4.42 +/? 0.39 × 10(12)/L) were less than Day 0 values (4.73 +/? 0.43 × 10(12)/L, p = 0.008 and p < 0.0001, respectively). The hematocrit on Day 20 (39.2 +/? 3.2%) was also less than that on Day 0 (41.2 +/? 4.8%; p = 0.01). The changes in these blood counts were not affected by the dose of the G-CSF. CONCLUSION: After stimulation with granulocyte-colony-stimulating factor and the collection or peripheral blood stem cells, the platelet counts in normal donors were decreased for at least 7 days (Days 6–13). Two weeks after collection of peripheral blood stem cells (Day 20), platelet production was increased, but the production of neutrophils and red cells was decreased. If two or more peripheral blood stem cell components are collected, then the platelet count should be measured after the second and subsequent collections. Further studies on the long-term effect of G-CSF on blood counts are needed.     

Identification of rare variants in the hLIMD1 gene in breast cancer

The hLIMD1 gene is located at chromosome 3p21 and was identified as a putative tumor suppressor gene using an elimination test assay. Chromosome 3p21 loci are frequently deleted in a number of cancers, including breast. The 3p21.3 locus harbors a number of tumor suppressor candidates, including LIMD1, a member of the ZYXIN family of genes. LIMD1 directly interacts with RB and is thought to play a role in suppressing tumor growth. To investigate whether mutations in the LIMD1 gene could potentially be involved in breast cancer, we used single-stranded conformation polymorphism analysis on DNA from 235 breast cancers and 95 controls. We identified four novel coding region alterations, including two amino acid substitutions at positions 255 and 302. The two remaining novel variants were found at amino acid positions 246 and 647 and encoded silent alterations. The rare Ser255Arg variant was identified in only sporadic breast tumors (2/165 tumors). Some ZYXIN proteins are phosphorylated by serine/threonine kinases, and the Ser255Arg change is located in a region phosphorylated on serine residues. Together, the data suggest that this variant may warrant further characterization.     

Rapid identification of bacterially contaminated platelets using reagent strips: glucose and pH analysis as markers of bacterial metabolism

BACKGROUND: One in every 1000 units of platelets is bacterially contaminated, which puts patients at risk for transfusion-associated sepsis and death. However, there is currently no screening test in place to detect contaminated units. The use of commercially available multiple-reagent urine dipsticks for this purpose was evaluated. STUDY DESIGN AND METHODS: Platelet concentrates were inoculated with either sterile saline or suspensions of Staphylococcus aureus, Staphylococcus epidermidis, Bacillus cereus, Klebsiella pneumoniae, or Serratia marcescens to a final concentration of 50 colony-forming units (CFU) per mL. The platelets were analyzed daily by the use of multiple- reagent strips, quantitative culture, and glucometry. RESULTS: B cereus grew rapidly, reaching 10(7) CFU per mL 1 day after inoculation, while S. epidermidis grew slowly, achieving similar concentration 4 to 6 days after inoculation. Two of 10 dipstick reagents, glucose and pH, proved useful in detecting bacteria. Both were lower in bacterially contaminated units than in controls. Glucose data obtained from automated analyzers validated the dipstick data. All organisms were detected at concentrations > or = 10(7) CFU per mL, and S. aureus and K. pneumoniae were detected in the range of 10(3) to 10(5) CFU per mL. CONCLUSION: The multiple-reagent test used had a sensitivity and specificity of 95 percent (> or = 10(7) CFU/mL) and 98 to 100 percent, respectively. These data indicate that urine dipsticks can be used to rapidly and inexpensively detect bacterial contamination in platelet concentrates, which potentially will reduce morbidity and mortality at minimal cost.     

Transfusion of red cells is associated with increased incidence of bacterial infection after colorectal surgery: a prospective study

BACKGROUND: Several studies suggest that perioperative blood transfusion is a major independent risk factor for postoperative bacterial infections. Transfusion-induced immunosuppression is thought to mediate this effect. STUDY DESIGN AND METHODS: In a randomized clinical trial comprising 697 patients with colorectal cancer, the relationship between two types of red cell components (buffy coat- depleted packed red cells and white cell-reduced [filtered] packed red cells) and postoperative bacterial infections was analyzed. RESULTS: Both types of red cells appeared to be associated with a greater incidence of postoperative infection than was no transfusion (39 vs. 24%, p < 0.01). A dose-response relationship could be demonstrated: the corrected relative risk was 1.6 for 1 to 3 units of red cells and 3.6 for more than 3 units. Multivariate analyses identified the transfusion of red cells and tumor location as the only significant independent risk factors for postoperative bacterial infection. CONCLUSION: Because allogeneic white cells, plasma, microaggregates, citrate, and platelets could be ruled out as risk factors for transfusion-associated postoperative infections, it is hypothesized that the transfusion of red cells is a potentially detrimental factor that transiently impairs the clearance of bacteria by phagocytic cells.     

Abnormal antioxidant vitamin and carotenoid status in chronic renal failure

Oxidative modification of plasma lipoproteins increases their atherogenicity. Nutritive antioxidants, including carotenoids, can prevent such lipoperoxidation and may protect against atherosclerosis. Plasma retinol, ascorbate, alpha-tocopherol and four carotenoids (lutein, lycopene, alpha-carotene and beta-carotene) were measured using HPLC in 45 patients with chronic renal failure (CRF) and in 21 controls. Plasma retinol was significantly increased in patients with CRF (conservative therapy mean of 3.7 mumol/l vs. 1.9 mumol/l; p < 0.001). Plasma lycopene was significantly lower in patients with CRF (healthy mean 0.44 mumol/l vs. conservative therapy mean 0.27 mumol/l and haemodialysis mean of 0.17 mumol/l; p < 0.001), a finding that persisted even after adjusting for plasma cholesterol. Low circulating antioxidant lycopene levels may contribute to an already impaired antioxidant defence system in patients with CRF. The process of haemodialysis further compromises antioxidant defences, principally by removing water-soluble ascorbate and urate, but does not appear to affect circulating carotenoid concentrations.      

Self Chest Clapping: Patients'' Views and the Effects on Oxygen Saturation

The literature suggests that self chest clapping (SCC) does not enhance rate of sputum clearance if combined with the active cycle of breathing techniques (ACBT), but many patients find SCC beneficial and continue to use it. Previous studies have examined the effects of assisted chest clapping on oxygen saturation (SaO₂), but what would be the effects of SCC on SaO₂? It was important to establish any possible detrimental effects from its use and to explore the views of patients using it as part of their treatment.

The SaO₂ was measured in 20 clinically stable patients with cystic fibrosis during their physiotherapy (the ACBT with SCC in a gravity assisted position) and all patients completed a short anonymous questionnaire to obtain their views on SCC. Patient characteristics of lung function, arterial blood gases, response to bronchodilator therapy, 24-hour sputum weight and exercise ability were recorded, within 48 hours of participation within the study, to identify a possible relationship between these and a change in SaO₂.

In the group as a whole there was a statistically significant mean fall in SaO₂ with SCC (p = 0.026). However, this fall was never greater than 4.4%. In some patients a fall in SaO₂ was recorded with SCC, but in others there was an increase. There was no correlation between the variables measured and a fall in SaO₂ with SCC. The patients using SCC had strong views and beliefs about why they did so.