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.     

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.     

Adverse drug reactions in internal medicine units and associated risk factors

Objectives  

This study was designed to assess the prevalence of adverse drug reactions (ADRs) in the internal medicine wards of two teaching Hospitals, identify the most common ADRs, the principal medications involved, and determine the risk factors implicated in the occurrence of such ADRs.     

Media Review

E_mergency M_edicine P_rocedures.: By Eric F. Reichman and Robert R. Simon. New York, NY     

Molecular characterization of a coxsackievirus A24 variant that caused an outbreak of acute haemorrhagic conjunctivitis in Spain, 2004

BACKGROUND: Coxsackievirus A24 variant is one of the major etiological agents involved in acute haemorrhagic conjunctivitis. STUDY DESIGN: An outbreak of acute hemorrhagic conjunctivitis occurred in the Southeast of Spain between September and November 2004. Cellular and molecular methods were used to identify and characterize the viral agent associated with the epidemic. RESULTS: Enterovirus was detected in the conjunctival swabs of 35 patients. None of the viruses isolated could be typed by conventional neutralization assays; however, amplification and sequencing of the 3'-end VP1 region of 19 of the samples identified coxsackievirus A24 variant as the serotype causing the outbreak. Phylogenetic analysis of the 5'-half VP1 region of the genome revealed that Spanish sequences, like other strains isolated during outbreaks of hemorrhagic conjunctivitis in American and African countries in 2003 and 2004, were closely related to the isolates detected in Korea (2002), thus proving their worldwide spread. CONCLUSIONS: This is the first report of an epidemic of acute hemorrhagic conjunctivitis due to a coxsackievirus A24 variant in Spain. Molecular typing in combination with phylogenetic analysis is useful to study the enterovirus epidemiology associated with epidemics.     

Anticocaine catalytic antibodies

Cocaine mediates its reinforcing and toxic actions through a "loss of function" effect at multiple receptors. The difficulties inherent in blocking a pleiotropic blocker pose a great obstacle for the classical receptor-antagonist approach and have contributed to the failure (to date) to devise specific treatments for cocaine overdose and addiction. As an alternative, we have embarked on an investigation of catalytic antibodies, a programmable class of artificial enzyme, as "peripheral blockers" -- agents designed to bind and degrade cocaine in the circulation before it partitions into the central nervous system to exert reinforcing or toxic effects. We synthesized transition-state analogs of cocaine's hydrolysis at its benzoyl ester, immunized mice, prepared hybridomas and developed the first anticocaine catalytic antibodies with the capacity to degrade cocaine to nonreinforcing, nontoxic products. We subsequently identified several families of anticocaine catalytic antibodies and found that the most potent antibody possessed sufficient activity to block cocaine-induced reinforcement, organ dysfunction and sudden death in rodent models of addiction, toxicity and overdose, respectively. With the potential to promote cessation of use, prolong abstinence and provide a treatment for acute overdose, the artificial enzyme approach comprehensively responds to the problem of cocaine.     

Diisocyanate asthma and gene-environment interactions with IL4RA, CD-14, and IL-13 genes.

BACKGROUND: Diisocyanate asthma (DA) affects 2% to 10% of exposed workers, yet the pathogenetic mechanisms underlying this disorder remain ill defined. OBJECTIVE: To determine if specific single nucleotide polymorphisms (SNPs) of interleukin 4 receptor alpha (IL4RA), IL-13, and CD14 promoter genes are associated with DA. METHODS: Sixty-two workers with DA confirmed by specific inhalation challenge (SIC) and 75 diisocyanate-exposed, SIC-negative workers were analyzed for SNPs associated with IL4RA, IL-13, and CD14 promoter genes. RESULTS: No associations were found with individual SNPs and DA. When stratified according to specific diisocyanate exposure, a significant association was found between IL4RA (I50V) II and DA among individuals exposed to hexamethylene diisocyanate (HDI) (odds ratio [OR], 3.29; 95% confidence interval [CI], 1.33-8.14; P = .01) only. Similarly, the IL4RA (I50V) II and IL-13 (R110Q) RR combination was significantly associated with DA in HDI-exposed workers (OR, 4.13; 95% CI, 1.35-12.68; P = .01), as was the IL4RA (I50V) II and CD14 (C159T) CT genotype combination (OR, 5.2; 95% CI, 1.82-14.88; P = .002) and the triple genotype combination IL4RA (I50V) II, IL-13 (R110Q) RR, and CD14 (C159T) CT (OR, 6.4; 95% CI, 1.57-26.12; P = .01). CONCLUSIONS: Gene-environmental interactions may contribute to the pathogenesis of DA, and gene-gene interactions may modulate this relationship.     

Prevalences, genotypes, and risk factors for HIV transmission in South America

HIV cross-sectional studies were conducted among high-risk populations in 9 countries of South America. Enzyme-linked immunosorbent assay screening and Western blot confirmatory testing were performed, and env heteroduplex mobility assay genotyping and DNA sequencing were performed on a subset of HIV-positive subjects. HIV prevalences were highest among men who have sex with men (MSM; 2.0%-27.8%) and were found to be associated with multiple partners, noninjection drug use (non-IDU), and sexually transmitted infections (STIs). By comparison, much lower prevalences were noted among female commercial sex workers (FCSWs; 0%-6.3%) and were associated mainly with a prior IDU and STI history. Env subtype B predominated among MSM throughout the region (more than 90% of strains), whereas env subtype F predominated among FCSWs in Argentina and male commercial sex workers in Uruguay (more than 50% of strains). A renewed effort in controlling STIs, especially among MSM groups, could significantly lessen the impact of the HIV epidemic in South America.     

Encuesta nacional sobre valoración de la actividad de los médicos internos residentes en los servicios de urgencias españoles

Introduction

The care activity of internal resident doctors is common to practically all medical and surgical training programs; however, there are no national data available regarding the situation of this activity from the perspective of the resident. The present study has sought to collect the opinion of the resident internal physicians on the health care performance and the teaching character that links them to their corresponding emergency departments, in the following areas: overall training value, appreciation of the workload, characteristics of the morning rotation, supervision or tutoring, etc.