Vexed surgeons, perplexed patients, and breast cancers which may not be cancer

In situ cancer of the breast is being diagnosed with increasing frequency due to the widespread use of mammography and heightened awareness of these lesions among pathologists. Treatment of these preinvasive cancers is controversial in light of recent data supporting breast-conserving therapy for small invasive cancers. Therapy for in situ breast cancer is discussed with attention to known risk factors for recurrence and breast cancer-related mortality. The controversies surrounding treatment of ductal and lobular carcinoma in situ compel the conscientious oncologist to seek fully informed consent and to respect the individual patient's feelings about cosmesis and breast cancer risk. Hopefully, prospective randomized studies such as the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-17 trial will relieve the oncology community of much of its confusion about the natural history and optimal therapy for these diseases.     

体外膜肺氧合技术支持治疗期间患者血乳酸浓度及其预后

目的:探讨体外膜肺氧合支持治疗患者血乳酸浓度的变化和预后。方法:于2004-12/2006-09在中国医学科学院阜外心血管病医院因脱离体外循环困难的心脏外科术后患者、扩张性心肌病和冠状动脉粥样硬化性心脏病发生心源性休克的患者共40例进行了体外膜肺氧合支持治疗,按年龄和存活预后分为4组:成人存活组、成人死亡组、儿童存活组、儿童死亡组。分析4组的治疗效果,分别抽取各组患者体外膜肺氧合建立时、体外膜肺氧合运转6h、运转中间时点、停机前6h、停机时的血乳酸浓度。结果:①体外膜肺氧合支持治疗患者40例,成人组26例,20例脱机,16例生存,10例死亡,脱机率76.9%,生存率61.5%;儿童组14例,7例脱机,5例生存,9例死亡,脱机率50.0%,生存率35.0%。②成人或儿童存活组的乳酸浓度都与死亡组有明显差别,存活组血乳酸浓度明显低于死亡组,其中建立和运转6h、中间时点的差异有显著性意义(P<0.05),其余2个时点的差异有非常显著性意义(P<0.001)。组内与建立时比较,中间时点、停止前6h、停止时差异均有显著性意义(P<0.001),血乳酸浓度逐渐降低。结论:经体外膜肺氧合支持治疗的患者,血乳酸浓度明显下降,脱机时血乳酸仍高的患者预后不良。     

血管内皮细胞生长因子和c-Fos在单基因遗传自然发病型糖尿病小鼠颌下腺中的表达

目的:观察血管内皮细胞生长因子和c-Fos蛋白在db/db自发性糖尿病小鼠颌下腺的表达,及其与糖尿病病程和颌下腺形态学改变的关系。方法:实验于2004-05在承德医学院中心实验室和承德医学院附属医院病理科完成。取3,4,6,8,10月龄db/db(单基因遗传自然发病型)糖尿病小鼠颌下腺(实验组)及相应月龄的db/ m正常小鼠颌下腺(对照组),采用SP免疫组化染色,观察颌下腺血管内皮细胞生长因子、c-Fos阳性表达的变化。结果:①颌下腺血管内皮细胞生长因子阳性细胞数目:实验组3,4,6,8,10月龄高于相应对照组[(11.8±3.35),(17.4±2.61),(20.6±1.92),(26.8±4.85),(28.0±4.22)个/视野;(6.6±0.89),(11.8±1.64),(16.2±3.27),(16.4±3.97),(17.6±1.82)个/视野,P<0.05,0.01],且呈逐渐增加趋势。②颌下腺c-Fos阳性细胞数目:实验组3,4,6月龄低于相应对照组[(6.4±0.65),(7.8±0.84),(7.9±0.65)个/视野;(12.2±0.84),(11.4±0.55),(10.8±0.84)个/视野,P<0.01]。③糖尿病病程的延长,实验组下颌下腺的实质细胞有明显形态学改变,其中腺泡萎缩明显,细胞排列紊乱。结论:①血管内皮细胞生长因子表达在db/db糖尿病小鼠颌下腺中随病程延长表达增加,与糖尿病病程呈正相关。②db/db糖尿病状态下颌下腺实质发生萎缩性形态学变化,颌下腺细胞表达c-Fos蛋白明显降低,可能与其密切相关。     

Is programming of glucocorticoid receptor expression by prenatal dexamethasone in the rat secondary to metabolic derangement in adulthood?

OBJECTIVE: Glucocorticoids may contribute to the association between retarded growth in utero and insulin resistance in adulthood. Administration of dexamethasone (dex) to pregnant rats results in low birth weight offspring, which develop glucose intolerance, hyperinsulinaemia and hypercorticosteronaemia. This may be explained by tIssue-specific differences in expression of glucocorticoid receptors (GR) in adult offspring: GR is increased in visceral fat and liver, and decreased in hippocampus and soleus muscle. However, cause and effect between altered GR expression, hypercorticosteronaemia, and hyperinsulinaemia remains to be established. DESIGN AND METHODS: Rats were treated with dex (100 microg/kg per day) or saline during the third week of pregnancy. In 5-8-Month-old male offspring, GR expression in insulin target tIssues was quantified by RNase protection assay in rats that were adrenalectomised (ADX group), sham operated (SHAM group), or adrenalectomised with supra-physiological corticosterone replacement (CORT group) (n=7-8 per group), and in rats treated orally with vehicle, metformin (43 mg/kg per day) or rosiglitazone (1 mg/kg per day), after 3 weeks. RESULTS: Manipulation of corticosterone concentration did not affect GR mRNA in skeletal muscle or adipose. In liver, sham-operated animals showed lower GR mRNA, but there was no difference between adrenalectomised and hypercorticosteronaemic animals (SHAM 0.11+/-0.01 ratio to beta-actin, vs ADX 0.22+/-0.02, CORT 0.23+/-0.02, (values expressed as means+/-s.e.m.), P<0.001). Rosiglitazone reduced GR mRNA by approximately 30% in liver of dex- and saline-treated offspring (P<0.05), but had no effect on GR in adipose and skeletal muscle. Metformin abolished the 38% up-regulation of liver GR mRNA induced by antenatal dex and also reduced GR mRNA preferentially in muscle of dex-treated animals (0.14+/-0.01 vs 0.10+/-0.01; P=0.03). CONCLUSIONS: We conclude that neither hypercorticosteronaemia nor hyperinsulinaemia are sufficient to cause the changes in GR expression in dex-programmed rats, implying that these changes may be primary in determining the programmed insulin resistant phenotype. Normalisation of GR expression by metformin may be important in the mode of action of this anti-diabetic agent and may be especially useful to reverse-programmed up-regulation of GR.     

High-throughput preparation of hexagonally ordered mesoporous silica and gadolinosilicate nanoparticles for use as MRI contrast agents

The development of biomedical nanoparticulate materials for use in diagnostics is a delicate balance between performance, particle size, shape, and stability. To identify materials that satisfy all of the criteria it is useful to employ automated high-throughput (HT) techniques for the study of these materials. The structure and performance of surfactant templated mesoporous silica is very sensitive to a wide number of variables. Variables, such as the concentration of the structure-directing agent, the cosolvent and dopant ions and also the temperature and concentration of quenching all have an influence on the structure, surface chemistry, and therefore, the performance of the mesoporous silica nanoparticles generated. Using an automated robotic synthetic platform, a technique has been developed for the high-throughput preparation of mesoporous silica and gadolinium-doped silicate (gadoliniosilicate) nanoparticulate MRI contrast agents. Twelve identical repeats of both the mesoporous silica and gadolinosilicate were synthesized to investigate the reproducibility of the HT technique. Very good reproducibility in the production of the mesoporous silica and the gadolinosilcate materials was obtained using the developed method. The performance of the gadolinosilicate materials was comparable as a T(1) agent to the commercial MRI contrast agents. This HT methodology is highly reproducible and an effective tool that can be translated to the discovery of any sol-gel derived nanomaterial.     

Prenatal Programming of Metabolic Syndrome in the Common Marmoset Is Associated With Increased Expression of 11��-Hydroxysteroid Dehydrogenase Type 1

OBJECTIVE

Recent studies in humans and animal models of obesity have shown increased adipose tissue activity of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which amplifies local tissue glucocorticoid concentrations. The reasons for this 11β-HSD1 dysregulation are unknown. Here, we tested whether 11β-HSD1 expression, like the metabolic syndrome, is “programmed” by prenatal environmental events in a nonhuman primate model, the common marmoset monkey.

RESEARCH DESIGN AND METHODS

We used a “fetal programming” paradigm where brief antenatal exposure to glucocorticoids leads to the metabolic syndrome in the offspring. Pregnant marmosets were given the synthetic glucocorticoid dexamethasone orally for 1 week in either early or late gestation, or they were given vehicle. Tissue 11β-HSD1 and glucocorticoid receptor mRNA expression were examined in the offspring at 4 and 24 months of age.

RESULTS

Prenatal dexamethasone administration, selectively during late gestation, resulted in early and persistent elevations in 11β-HSD1 mRNA expression and activity in the liver, pancreas, and subcutaneous—but not visceral—fat. The increase in 11β-HSD1 occurred before animals developed obesity or overt features of the metabolic syndrome. In contrast to rodents, in utero dexamethasone exposure did not alter glucocorticoid receptor expression in metabolic tissues in marmosets.

CONCLUSIONS

These data suggest that long-term upregulation of 11β-HSD1 in metabolically active tissues may follow prenatal “stress” hormone exposure and indicates a novel mechanism for fetal origins of adult obesity and the metabolic syndrome.The metabolic syndrome and its component features (central obesity, insulin resistance/type 2 diabetes, hypertension, dyslipidemia) have been causally linked to early life events as marked by low birth weight and other features of an adverse intrauterine environment (1,2). Two major etiological hypotheses of the “developmental origins” effects have been proposed: malnutrition and glucocorticoid overexposure (3,4). These mechanisms of “programming” may be linked because maternal undernutrition increases maternal glucocorticoid concentrations and reduces the placental enzymatic barrier to maternal glucocorticoids in rats, thus increasing fetal glucocorticoid exposure (5). Moreover, maternal glucocorticoid administration reduces food intake in rodents (6).The processes that link intrauterine insults and later risk of the metabolic syndrome are not yet understood. The metabolic syndrome resembles the rare Cushing''s syndrome of circulating glucocorticoid excess, but in uncomplicated metabolic syndrome, plasma cortisol levels are not raised, spawning the suggestion that increased tissue sensitivity to glucocorticoid action may be important in its pathogenesis (7). In the major metabolic organs, tissue sensitivity and exposure to glucocorticoids are determined by the density of intracellular glucocorticoid receptors and the activity of the microsomal enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) which catalyzes the regeneration of active cortisol (corticosterone in rodents) from inert cortisone (11-dehydrocorticosterone) (7). 11β-HSD1 is highly expressed in liver and adipose tissue, where glucocorticoids reduce insulin sensitivity and action (7).In obese humans and in monogenic obesity in rodents, there is a selective increase in 11β-HSD1 mRNA and activity in adipose tissues (8–10). Increased 11β-HSD1 in liver is found in other causes of metabolic syndrome, such as myotonic dystrophy (11). Transgenic overexpression of 11β-HSD1 selectively in adipose tissue in mice recapitulates all the major features of metabolic syndrome without changes in circulating steroid levels (12), whereas overexpression of 11β-HSD1 in liver alone produces an attenuated syndrome with insulin resistance, dyslipidemia, and hypertension, but not hyperglycemia or obesity (13). Conversely, 11β-HSD1 knockout mice are insulin sensitized and resist metabolic syndrome with dietary obesity (14).However, genetic variation in the HSD1B1 gene does not associate with obesity (15), suggesting the cause of increased 11β-HSD1 in adipose tissue in obesity is environmentally determined. Although many factors may upregulate 11β-HSD1 in the short term, attempts to chronically induce 11β-HSD1 in adipose tissue by nongenetic approaches have been unsuccessful. In particular, high-fat diets in rodents downregulate 11β-HSD1 in adipose tissue (16), although this does not appear to occur in humans (17), underlining the importance of relevant models of the human situation.Here, we have explored the early life antecedents of metabolic syndrome and especially 11β-HSD1 expression in metabolic tissues in a nonhuman primate model (the common marmoset monkey) of fetal programming.     

Infant morbidity, mortality, and breast milk immunologic profiles among breast-feeding HIV-infected and HIV-uninfected women in Botswana

BACKGROUND: Infants of human immunodeficiency virus (HIV)-infected women have high mortality, but the immunologic integrity and protection afforded by the breast milk of HIV-infected women is unknown. METHODS: We determined morbidity and mortality by 24 months among breast-fed infants of 588 HIV-infected and 137 HIV-uninfected women followed-up in a clinical trial in Botswana. A matched case-control study compared clinical, behavioral, and breast milk immunologic parameters among 120 HIV-infected women by infant outcome. Breast milk factors were also compared between HIV-infected and HIV-uninfected women. RESULTS: Twenty-four-month mortality was 29.5% among HIV-infected infants, 6.7% among HIV-exposed uninfected infants, and 1.6% among HIV-unexposed infants. No differences were detected in breast milk immunologic profiles of HIV-infected women whose infants were either ill or well. Discontinuation of breast-feeding was the strongest predictor of illness (P<.001). Levels in breast milk of pathogen-specific immunoglobulin (Ig) G and IgA to Haemophilus influenzae, Campylobacter jejuni, Helicobacter pylori, Streptococcus pneumoniae, and innate immune factors were not lower among HIV-infected women than among HIV-uninfected women. CONCLUSIONS: Mortality was higher among HIV-infected and HIV-exposed infants than among HIV-unexposed infants. However, the immunologic profiles of breast milk among HIV-infected women were intact, and discontinuation of breast-feeding was the primary risk for infant morbidity. Thus, the breast milk of HIV-infected women may confer protection against common infant pathogens. TRIAL REGISTRATION: (ClinicalTrials.Gov) identifiers: NCT00197691 and NCT00197652.     

The impact of childhood epilepsy on quality of life: a qualitative investigation using focus group methods to obtain children's perspectives on living with epilepsy

As children's perceptions of their quality of life are unique, it is essential to elicit their concerns directly rather than from proxy informants. This study therefore aimed to investigate the impact of childhood epilepsy on quality of life directly from the child's perspective. Focus group techniques and qualitative analysis were utilized. Twenty-two children between 7 years 4 months and 12 years 6 months of age (11 females, 11 males) were stratified by age (7-8, 9-10, 11-12 years) into five focus groups. Data were transcribed and analyzed using grounded theory techniques to generate themes and categories. Themes were presented using the children's language. Two major themes were identified, "things to do with growing up" and "things to do with epilepsy," with five and four subthemes, respectively. No significant age-related differences were found. A conceptual model illustrates these findings, and comparisons are made to previous research with adolescents using similar methodology.     

Inhibition of mitochondrial translation as a therapeutic strategy for human acute myeloid leukemia

To identify FDA-approved agents targeting leukemic cells, we performed a chemical screen on two human leukemic cell lines and identified the antimicrobial tigecycline. A genome-wide screen in yeast identified mitochondrial translation inhibition as the mechanism of tigecycline-mediated lethality. Tigecycline selectively killed leukemia stem and progenitor cells compared to their normal counterparts and also showed antileukemic activity in mouse models of human leukemia. ShRNA-mediated knockdown of EF-Tu mitochondrial translation factor in leukemic cells reproduced the antileukemia activity of tigecycline. These effects were derivative of mitochondrial biogenesis that, together with an increased basal oxygen consumption, proved to be enhanced in AML versus normal hematopoietic cells and were also important for their difference in tigecycline sensitivity.     

Astrocytes, but not olfactory ensheathing cells or Schwann cells, promote myelination of CNS axons in vitro

We have examined the interaction between olfactory ensheathing cells (OECs), Schwann cells (SC), oligodendrocytes, and CNS axons using cultures generated from embryonic rat spinal cord. Oligodendrocyte process extension and myelination in these cultures was poor if the cells were plated on OECs or SCs. Myelin internodes and nodes of Ranvier formed frequently if these cultures were plated onto monolayers of neurosphere-derived astrocytes (NsAs). In the myelinated fibers generated on NsAs, Nav channels, caspr, and neurofascin molecules were correctly assembled at the nodes of Ranvier. The density of neurites, survival, and antigenic differentiation of oligodendrocytes was similar on OEC and NsAs monolayers. However, on OEC monolayers, despite a transient increase in the number of endogenous oligodendrocytes, there was a decrease in oligodendrocyte process extension and axonal ensheathment when compared with cultures plated on NsAs monolayers. To determine if these changes were due to axonal or glial factors, spinal cord oligodendrocytes were plated onto monolayers of OECs, NsAs, and poly-L-lysine in the absence of neurons. In these cultures, process extension and myelin-like membrane formation by oligodendrocytes was improved on monolayers of OEC. This suggests that inhibition of process extension is mediated via cross-talk between OECs and neurites. In cultures containing axons plated on OEC monolayers, oligodendrocyte process formation, axonal ensheathment, and myelination occurred albeit lower if the cultures were supplemented with NsAs conditioned medium. These data suggest OECs can permit neurite extension and oligodendrocyte proliferation, but lack secreted factor(s) and possible cell-cell contact that is necessary for oligodendrocyte process extension and myelination.