Germline gain-of-function MMP11 variant results in an aggressive form of colorectal cancer

Matrix metalloproteinase-11 (MMP11) is an enzyme with proteolytic activity against matrix and nonmatrix proteins. Although most MMPs are secreted as inactive proenzymes and are later activated extracellularly, MMP11 is activated intracellularly by furin within the constitutive secretory pathway. It is a key factor in physiological tissue remodeling and its alteration may play an important role in the progression of epithelial malignancies and other diseases. TCGA colon and colorectal adenocarcinoma data showed that upregulation of MMP11 expression correlates with tumorigenesis and malignancy. Here, we provide evidence that a germline variant in the MMP11 gene (NM_005940: c.232C>T; p.(Pro78Ser)), identified by whole exome sequencing, can increase the tumorigenic properties of colorectal cancer (CRC) cells. P78S is located in the prodomain region, which is responsible for blocking MMP11's protease activity. This variant was detected in the proband and all the cancer-affected family members analyzed, while it was not detected in healthy relatives. In silico analyses predict that P78S could have an impact on the activation of the enzyme. Furthermore, our in vitro analyses show that the expression of P78S in HCT116 cells increases tumor cell invasion and proliferation. In summary, our results show that this variant could modify the structure of the MMP11 prodomain, producing a premature or uncontrolled activation of the enzyme that may contribute to an early CRC onset in these patients. The study of this gene in other CRC cases will provide further information about its role in CRC development, which might improve patient treatment in the future.     

Extubación ultra fast-track vs. convencional tras cirugía cardiaca en un centro de referencia cardiovascular en Colombia. Estudio longitudinal

Introduction

The fast track / ultra-fast-track protocols are techniques used to optimise the patient care process and a quick recovery after cardiac surgery. They are one of the mainstays of efficient practice. With their use, the length of hospital and intensive care unit (ICU) stays are reduced, with a direct impact on costs and the quality of the health service.

Thyrotrophin-Releasing Hormone Raises Cytosolic Free Calcium Concentration in Human Adenomatous Somatotrophs and Corticotrophs; Comparison with in vivo Responsiveness to Thyrotrophin-Releasing Hormone in Patients with Acromegaly or Cushing's Disease

The effect of thyrotrophin-releasing hormone (TRH) on intracellular free Ca²⁺ concentration, [Ca²⁺)i, was investigated with the fluorescent dye fura-2 in cell suspensions obtained from 13 human growth hormone-secreting adenomas and 6 adrenocorticotrophin-secreting adenomas. Preoperatively, 9 out of 13 acromegalic patients showed a positive growth hormone response to TRH administration while none of the 6 patients with Cushing's disease had a plasma adrenocorticotrophin increase after TRH injection. In all the growth hormone-secreting adenomas the addition of TRH (100 nM) caused a significant rise in [Ca²⁺]i (from a resting level of 133±40 (±SD) to a value of 284±119 nM at 100 nM TRH, n = 42; P<0.001). The transient induced by TRH was found to have a dual origin, one due to Ca²⁺ mobilization from intracellular stores which was maintained in presence of EGTA (3mM) and verapamil (10 μM) and a plateau phase due to Ca²⁺ influx from the extracellular media. Somatostatin (0.1 μM) lowered both resting [Ca²⁺]i and TRH-induced transients. The effect of gonadotrophin-releasing hormone on [Ca²⁺]i was evaluated on cell suspensions obtained from 6 growth hormone-secreting adenomas. Gonadotrophin-releasing hormone (100 nM) caused a marked rise in [Ca²⁺]i (from 179±25 to 283±15nM) on the cell suspension obtained from the only in vivo responsive adenoma while it was ineffective in the remaining 5. Although TRH was ineffective in modifying plasma adrenocorticotrophin levels in all patients with Cushing's disease, in 5 out of 6 tumors the addition of 100 nM TRH caused a significant rise in [Ca²⁺]i (from 102.5 ± 36 to 163±66 nM, n = 22; P < 0.005). However, the effect of TRH on [Ca²⁺]i was significantly lower than that caused by arginine vasopressin, a physiological stimulator of adrenocorticotrophin release ([Ca²⁺]i values; 145±78 nM at 100 nM TRH versus 300±140 at 10 nM arginine vasopressin, n = 15; P<0.05). Moreover, the effect of arginine vasopressin on [Ca²⁺]i was detectable at concentrations as low as 0.1 nM while TRH was effective at concentrations higher than 1 nM. By contrast, gonadotrophin-releasing hormone was ineffective in increasing [Ca²]i in all the adrenocorticotrophin-secreting adenomas studied. Collectively, these data indicate that sensitivity to TRH is present in almost all the growth hormone- and adrenocorticotrophin-secreting adenomas independently of the responsiveness of the individual patients to the peptide.     

Caries experience and fluorosis prevalence in Chilean children from different socio-economic status

Abstract Caries experience and enamel fluorosis prevalence in 8-year-old children belonging to different socio-economic classes were determined in two Chilean twin cities that are served by optimally fluoridated community water from the same waterworks facility. Low socio-economic status (LSES) children had a higher mean dm ft and DMFT indices (P<0.001) than high socioeconomic status (HSES) children. Prevalence of enamel fluorosis in the permanent teeth of LSES children was 0.79, significantly higher (X²= 9.0; P<0.003) than the value 0.59 found in HSES children. The proportion of Dean's scores 2. 3, 4 and 5 in first molars, mandibular and maxillary incisors in LSES children was higher than in HSES children (P<0.001). Differences in prevalence and seventy of enamel fluorosis between both groups are tentatively attributed lo a different pattern of tap water and tea consumption at pre-school ages. Suggestions are advanced to minimize the undesirable prevalence and severity of enamel fluorosis.     

采用直接血管成形术治疗的急性心肌梗死患者中入院心电图存在左束支、右束支与无束支传导阻滞的预后比较：来自多项急性心肌梗死直接血管成形术试验

急性心肌梗死患者出现束支传导阻滞（BBB）被认为与预后差有关。这种观点在血管成形术时代是否正确尚不清楚。本研究旨在评估采用直接血管成形术治疗的急性心肌梗死伴BBB患者的预后。评估了急性心肌梗死直接血管成形术试验中3053例接受急诊导管术的患者。将入院心电图存在左束支传导阻滞的患者（LBBB，n=48，1．6％）与右束支传导阻滞患者（RBBB，n=95，3．1％）或无BBB患者（n=2910，95．3％）进行比较。具有BBB的患者年龄较大，更多见糖尿病、外周血管疾病和曾行冠状动脉搭桥术，射血分数较低，多支血管病变多见。     

Melatonin reduces nitric oxide synthase activity in rat hypothalamus

Abstract: In this report, rat hypothalamic nitric oxide synthase (NOS) activity is shown to be partially inhibited by physiological concentrations of the pineal hormone melatonin. In vitro studies demonstrate that 1 nM melatonin, which approximates the physiological concentration of the hormone at night, significantly inhibited NOS activity. In vivo studies show that administering melatonin or collecting the hypothalamus from animals at night, when endogenous melatonin levels are elevated, results in a significant decrease of NOS activity. Results also show that calmodulin may be involved in this process since its presence in the incubation medium prevents the inhibitory effect of melatonin on NOS activity.     

HPV types in women with normal cervical cytology.

PCR-based hybridization methods have been used to show that some women with normal cytology are carriers of HPV DNA of the types strongly related to cervical cancer. How these women should be managed remains unclear. This chapter selectively reviews reports which have estimated type-specific HPV prevalence in relation to the presence or absence of morphological signs of HPV infection. Overall, these reports indicate that among women who were identified as carriers of HPV DNA (by PCR-based methods) and who also had a normal cytological smear, the HPV type detected in the majority of instances was a high-risk viral type for cervical cancer (HPV types 16/18 = 44.7%; HPV types 31/33/35 = 8.1%; other and unknown types = 37.9%). This suggests that screening programmes which include PCR-based HPV detection could reduce the false negative rates currently reported by screening programmes based on cytology alone.