Biomedical subjects

Sergio Carmona

Publications and source records attributed to Sergio Carmona.

11 recordsLinked to original sources

PubMed2007

Specific inhibition of HBV replication in vitro and in vivo with expressed long hairpin RNA.

Activating RNA interference to achieve specific gene silencing has shown promise for the development of RNA-based treatment of chronic hepatitis B virus (HBV) infection. To further this approach, we assessed the efficacy of expressed long hairpin RNAs (lhRNAs) that target the conserved HBx open reading frame of HBV. As substrates for Dicer, lhRNAs have the potential to generate multiple short interfering RNAs (siRNAs) to enable simultaneous targeting of different sites. Two U6 Pol III vectors were constructed that encode anti-HBV lhRNAs with a 62 base pair stem sequence containing multiple G:U pairings. Assessment in transfected cultured cells and also in vivo using the murine hydrodynamic injection model showed that one of the lhRNA vectors (lhRNA 1) diminished markers of virus replication by 70-90% without evidence of interferon response induction. Greatest silencing efficacy was observed for targets that are complementary to sequences located at the base of the hairpin stem and this correlated with a higher concentration of siRNAs derived from this region of the lhRNA. Although lhRNA 1 has the advantage of targeting a greater viral sequence, incomplete cellular processing may result in unequal silencing across the span of the viral target RNA.

Animals↗

PubMed2006

Silencing of HIV-1 subtype C primary isolates by expressed small hairpin RNAs targeted to gag.

Discovery of sequence-specific silencing by activating the RNA interference (RNAi) pathway has led to exciting new strategies for treating infection with human immunodeficiency virus type 1 (HIV-1). Of the HIV-1 subtypes, C is especially common in areas of the world that are worst affected. Although prone to mutation, genome plasticity of this subtype is limited in functionally important regions. We identified conserved sequences within the HIV-1 subtype C gag open reading frame and assessed whether they are suitable targets for inhibition of viral replication by RNA Pol III-driven small hairpin RNAs (shRNAs). Initially, the efficacy of each of a panel of 10 shRNAs against HIV-1 was determined using a reporter assay. shRNAs A and B, which targeted the 5 end of gag, were most effective and were used to assess inhibition of replication in cultured cells of two R5 isolates (Du151 and Du422) and one X4 virus (SW7). These shRNAs diminished intracellular HIV-1 gag RNA and HIV-1 protein concentrations as well as p24 secretion by up to 80% without inducing an interferon response. However, shRNA-mediated knockdown efficacy against each of these viral isolates varied slightly. These data show successful activation of RNAi to inhibit the replication of biologically distinct HIV-1 subtype C isolates. The effector shRNAs described here are potential candidates for gene therapy applications against the most common global subtype of HIV-1.

Cell Line↗

PubMed2005

Effective inhibition of HBV replication in vivo by anti-HBx short hairpin RNAs.

Exploiting the RNA interference pathway has shown promise for developing novel and effective treatment of hepatitis B virus (HBV) infection. To advance this approach, we analyzed the antiviral efficacy of a panel of 10 Pol III U6 promoter-encoded short hairpin RNAs (shRNAs) that target conserved sequences of the oncogenic HBx open reading frame. To facilitate intracellular processing, the shRNAs included mismatches in the 25-bp stem region and a terminal loop of miRNA-23. Two shRNAs (shRNA 5 and shRNA 6) showed knockdown of HBV markers by 80-100% in transfected hepatocytes and also in a murine hydrodynamic injection model of HBV replication. Intracellular processing of hairpin RNA with the intended strand bias correlated with antiviral efficacy. Moreover, markers of HBV replication were inhibited without inducing genes associated with the nonspecific interferon response. To assess the antiviral efficacy of the shRNAs in a context that is similar to natural HBV infection, shRNA-encoding cassettes were tested against the virus in a HBV transgenic murine model. When delivered using recombinant adenovirus vectors, U6 shRNA 5 and U6 shRNA 6 mediated significant HBV knockdown. Collectively, these observations indicate that U6 shRNA 5 and U6 shRNA 6 are promising candidates for therapy of chronic HBV infection.

Adenoviridae↗

PubMed2005

[A proposal of new indices for hospital management].

BACKGROUND: Diagnosis related groups (DRGs) are the most reliable patient classification system in hospital management. When this information is unavailable, other reliable classification system must be used. AIM: To obtain useful indices for hospital management, based on descriptive multivariate techniques. MATERIAL AND METHODS: Data on admissions to a University Hospital during 2003 were analyzed. Number of discharges, lethality rate, re-admission rate, number of outpatient consultations, length of hospital stay and surgical complexity index were analyzed, using information obtained by the Operations Management Department. The Principal Components Analysis (PCA) technique was applied and the R correlation matrix was used. RESULTS: A total of 24,345 discharges were analyzed. The first two principal components were selected, accounting cumulatively for 76% of data variability (47% for the first and 29% for the second). CONCLUSIONS: The first component may be assimilated to a new index representing the difficulty of the attended cases, which we have termed Case Complexity. The second principal component would explain the number of attended persons, which we have termed Case Load. These two indices allow us to classify hospital services.

Chile↗

PubMed2005

Exploiting the RNA interference pathway to counter hepatitis B virus replication.

Chronic infection with hepatitis B virus (HBV) is endemic to sub-Saharan Africa and parts of Asia where persistence of the virus is commonly associated with complicating cirrhosis and hepatocellular carcinoma (HCC). Licensed therapies for HBV are partially effective in selected patients and development of novel treatments remains an important global medical objective. HBV has an unusually compact genome that restricts the ability of the virus to evade potentially therapeutic nucleic acid hybridization. Thus, exploiting the RNA interference (RNAi) pathway, which enables sequence-specific target RNA degradation using small interfering RNA (siRNA), is well suited to developing novel treatment for HBV infection. Several studies, both in vitro and in vivo, have demonstrated that HBV replication can be inhibited in transfected cells by synthetic siRNA duplexes and also Pol III-derived short hairpin RNA (shRNA) sequences. The effectiveness of anti-HBV sequences varies considerably, and is likely to result from differences in activation of the RNAi pathway by individual siRNA species. Exclusion of potentially toxic off-target effects and also development of efficient methods of hepatotropic nucleic acid delivery are important prerequisites before RNAi can be used successfully for anti-HBV treatment.

Gene Expression Regulation, Viral↗

PubMed2005

The specificity and sensitivity of uninhibited COR in labyrinthine-defective patients.

The Cervico-ocular reflex (COR), which depends on proprioceptive afferents from neck muscles to the vestibular nucleus, makes little contribution to the stabilization of gaze in humans. If labyrinthine function is lost because of disease, however, the COR may increase in gain and assume greater importance in generating compensatory eye rotations during natural head movements. We tested the COR, i.e., eye movement responses to rotation of the trunk about the earth fixed head (swinging test with fixed head STFH). If the vestibular function is intact, normally there should be no nystagmus. A total of 88 labyrinthine defective patients and 78 controls were studied. Of the 166 subjects evaluated, 88 presented some kind of alteration (either central or peripheral) and had STFH results showing "no inhibition" in 85 patients. Therefore, the STFH's sensibility is 96.6%. The remaining 3.4% were false negatives (i.e., pathology that could not be detected by the test). Of the 166 subjects evaluated, 78 had normal results and normal STFH. Therefore, STFH's specificity was 100%. We conclude that the study of the COR through STFH is a simple, useful, and clinically reliable test which should improve our knowledge of the interesting relationship between VOR and COR.

Eye Movements↗

PubMed2005

Recurrent vertigo in extrinsic compression of the brain stem.

We present four patients who suffered from recurrent vertigo crises, which in most cases lasted hours or even days. In all of them the coincident finding was the presence of vascular compression of the brainstem (mainly vertebral dolichoectasia). Given the fact that the vertigo was always episodic and in that in the two cases where a treatment with carbamazepine could be used the result was the total suppression of the crises, we propose an ictal mechanism for them. Our findings differ from previous descriptions because: 1) the crises last longer, hours or even days, and 2) the involvement of the brainstem structures was extrinsic.

Adult↗

PubMed2005

Use of topiramate (topamax) in a subgroup of migraine-vertigo patients with auditory symptoms.

Five-three percent of the patients who suffer from migraine present severe incapacity and need rest in bed. If we add to this the incapacity produced by vertigo, then the quality of life of these patients is seriously affected. Migraine/Vertigo (MV) should be another criterion in the selection of preventive treatment even when other criteria are not fulfilled. Auditory symptoms may accompany MV. We treated 10 patients with Topiramate in an open trial, twice a day, with an average dose of 100 mg/day. The treatment period for these patients ranges between 6 and 16 months, with a mean of 9. As of today, all patients present no crisis. Regarding auditory symptoms, all the patients referred that they were stabilized. The effect began quickly, from the first month in most patients as it has been reported in other studies.

Adult↗

PubMed2004

[Indices of public health services and resource allocation from the Health Ministry of Chile].

BACKGROUND: Chile has a National Health Services System, formed by 29 Health Services. An efficient resource distribution among this services is crucial for an efficient health care delivery. AIM: To obtain indices from the Chilean Public Health Services, that could improve allocation of resources. MATERIAL AND METHODS: Information from the Chilean Public Health Services, corresponding to activities during 2001 budgetary period, was collected. This is the latest complete and official information for the totality of Health Services in the country. Seventeen variables generated or monitored by the Instituto Nacional de Estadísticas (INE), the Ministerio de Salud (MINSAL), the Ministerio de Hacienda, the Ministerio de Planificación y Cooperación (MIDEPLAN) and the Fondo Nacional de Salud (FONASA) were studied. The Main Components Analysis (ACP) was used, obtained from the R correlation matrix. RESULTS: The first two main components were selected, with an accumulated percentage of explained variability of 63.05%. The first component is related to the population assigned to each Health Service. This corresponds to the number of people needed to treat in the hospitals of these Services and their answer to this demand, justified by the expenses in which each Health Service incurs. There is an inverse relation of the first component with health indicators, measured by burden of disease and death. The second main component would represent the social and economic characteristics of the population, poor and very poor populations and public health insurance beneficiaries, to take care of in each Health Service. CONCLUSIONS: Health indicators in each Health Service are not considered a priority for resource distribution among Health Services in the country. The transference is done considering the indices contained in the two main components defined.

Chile↗

PubMed2003

Inflammatory aneurysm in the infrarenal portion of thoracoabdominal aneurysms: an uncommon variant.

INTRODUCTION: We present an unusual variant of type IV thoracoabdominal aneurysm with inflammatory changes in part of the aortic wall. MATERIAL AND METHODS: Between January 1990 and December 2000, 5 male patients (mean age, 68 years) with inflammatory aneurysms of 29 with type IV thoracoabdominal aneurysms (17.2%) underwent surgery. All five had arterial hypertension. The diagnosis of inflammatory aneurysm was made on the basis of clinical suspicion supported by characteristic features on CT scans. Endoaneurysmorraphy was performed in all cases; a tube graft was inserted in three cases, and bifurcation was performed in 2. The macroscopic appearance of periaortic fibrosis was detected at the infrarrenal portion of the aneurysm in the 5 patients, but no retroperitoneal fibrosis was found at the level of the distal thoracic aorta in any case. RESULTS: There was no operative mortality. Paraparesis was not detected in any patient. One patient had acute kidney failure, and another required an extended stay in the intensive care unit because of respiratory insufficiency. Pathologic examination confirmed the diagnosis of inflammatory aneurysm in all 5 patients, with characteristic adventitial thickening caused by lymphoplasmacytic infiltrate and fibrosis around the ganglionic and nerve structures. CONCLUSIONS: Type IV thoracoabdominal aneurysm with inflammatory changes can be treated at surgery with a retroperitoneal approach. Usually the fibrotic response is confined to the infrarenal portion of the aneurysm.

Aged↗

PubMed2003

[Study of polymorphism of Fc gamma IIa receptors in Chilean patients with systemic lupus erythematosus].

BACKGROUND: Polymorphisms of Fc receptors for IgG (Fc gamma R) have been proposed as a genetic factor that influences susceptibility for systemic lupus erythematosus (SLE). Human Fc gamma RIIa has 2 codominantly expressed alleles, H131 and R131, which differ at amino acid position 131 in the second extracellular domain (histidine or arginine respectively) and differ substantially in their ability to bind human IgG2. The H131 allele binds IgG2 efficiently, whereas R131 binds it poorly. Because IgG2 is a poor activator of the classical complement pathway, the H131 is essential for the disposal of IgG2 immune complexes. AIM: To determine the distribution of Fc gamma RIIA genes in a cohort of Chilean SLE patients, with or without a history of lupus nephritis. PATIENTS AND METHODS: We studied 52 Chilean SLE patients fulfilling the 1982 American College of Rheumatology (ACR) criteria, 20 of whom had a history of nephritis, and 44 ethnically matched disease-free controls. Fc gamma RIIa allotypes were genotyped by PCR. RESULTS: No significant association was observed between the low affinity Fc gamma RII receptor (FcgRIIa-R131) and the presence of SLE or lupus nephritis. However, genotype frequencies in SLE patients but not in controls, departed from the proportions predicted by the Hardy-Weinberg equilibrium, suggesting this locus might be related to the disease. CONCLUSIONS: Our results suggest that in Chilean patients with SLE, as well as in many other populations, the R131 allotype is not a major factor predisposing to the development of SLE or lupus nephritis.

Alleles↗