The C. elegans deglutamylase CCPP-6 does not operate redundantly with CCPP-1 in gross cilia integrity.

Tubulin glutamylation is a reversible modification of the microtubules that regulates cilia stability and function. The addition of glutamates to the microtubule is catalyzed by members of the TTLL family of enzymes, while the removal is carried out by a family of cytosolic carboxypeptidase (CCP) enzymes. C. elegans has two deglutamylating enzymes, CCPP-1 and CCPP-6 . CCPP-1 is required for ciliary stability and function in the worm, however CCPP-6 is dispensable for cilia integrity. To investigate redundancy between the two deglutamylating enzymes we made a ccpp-1 ( ok1821 ); ccpp-6 ( ok382 ) double mutant. The double mutant shows normal viability, and the dye-filling phenotypes are not worse than the ccpp-1 single mutant, suggesting that CCPP-1 and CCPP-6 do not function redundantly in C. elegans cilia .

Endophytes and Plant Extracts as Potential Antimicrobial Agents against Candidatus Liberibacter Asiaticus, Causal Agent of Huanglongbing.

Huanglongbing (HLB), also known as citrus greening, is an insidious disease in citrus and has become a threat to the sustainability of the citrus industry worldwide. In the U.S., Candidatus Liberibacter asiaticus (CLas) is the pathogen that is associated with HLB, an unculturable, phloem-limited bacteria, vectored by the Asian Citrus Psyllid (ACP, Diaphorina citri). There is no known cure nor treatment to effectively control HLB, and current control methods are primarily based on the use of insecticides and antibiotics, where effectiveness is limited and may have negative impacts on beneficial and non-target organisms. Thus, there is an urgent need for the development of effective and sustainable treatment options to reduce or eliminate CLas from infected trees. In the present study, we screened citrus-derived endophytes, their cell-free culture supernatants (CFCS), and crude plant extracts for antimicrobial activity against two culturable surrogates of CLas, Sinorhizobium meliloti and Liberibacter crescens. Candidates considered high-potential antimicrobial agents were assessed directly against CLas in vitro, using a propidium monoazide-based assay. As compared to the negative controls, statistically significant reductions of viable CLas cells were observed for each of the five bacterial CFCS. Subsequent 16S rRNA gene sequencing revealed that each of the five bacterial isolates were most closely related to Bacillus amyloliquefaciens, a species dominating the market of biological control products. As such, the aboveground endosphere of asymptomatic survivor citrus trees, grown in an organic orchard, were found to host bacterial endophytes capable of effectively disrupting CLas cell membranes. These results concur with the theory that native members of the citrus microbiome play a role in the development of HLB. Here, we identify five strains of Bacillus amyloliquefaciens demonstrating notable potential to be used as sources of novel antimicrobials for the sustainable management of HLB.

A ccpp-6 deletion mutation does not impair gross cilia integrity in C. elegans.

Tubulin glutamylation is a reversible modification that regulates microtubule function in cilia. The removal of glutamylation from microtubules is carried out by a family of cytosolic carboxypeptidase (CCP) enzymes. C. elegans has two deglutamylating enzymes, CCPP-1 and CCPP-6, homologs of mammalian CCP1 and CCP5 respectively. CCPP-1 is required for ciliary stability and function. To determine whether CCPP-6 is similarly required for cilia integrity in C. elegans we analyzed the ccpp-6(ok382) deletion mutant. We find that both dye-filling and male mating are normal, suggesting that CCPP-6 is not required for ciliary integrity in C. elegans.

MRI predicts intracranial hemorrhage in patients who receive long-term oral anticoagulation.

OBJECTIVE: We tested the hypothesis that the risk of intracranial hemorrhage (ICH) in patients with cardioembolic ischemic stroke who are treated with oral anticoagulants (OAs) can be predicted by evaluating surrogate markers of hemorrhagic-prone cerebral angiopathies using a baseline MRI. METHODS: Patients were participants in a multicenter and prospective observational study. They were older than 64 years, had a recent cardioembolic ischemic stroke, and were new users of OAs. They underwent a baseline MRI analysis to evaluate microbleeds, white matter hyperintensities, and cortical superficial siderosis. We collected demographic variables, clinical characteristics, risk scores, and therapeutic data. The primary endpoint was ICH that occurred during follow-up. We performed bivariate and multivariate Cox regression analyses. RESULTS: We recruited 937 patients (aged 77.6 ± 6.5 years; 47.9% were men). Microbleeds were detected in 207 patients (22.5%), moderate/severe white matter hyperintensities in 419 (45.1%), and superficial siderosis in 28 patients (3%). After a mean follow-up of 23.1 ± 6.8 months, 18 patients (1.9%) experienced an ICH. In multivariable analysis, microbleeds (hazard ratio 2.7, 95% confidence interval [CI] 1.1-7, p = 0.034) and moderate/severe white matter hyperintensities (hazard ratio 5.7, 95% CI 1.6-20, p = 0.006) were associated with ICH (C index 0.76, 95% CI 0.66-0.85). Rate of ICH was highest in patients with both microbleed and moderate/severe WMH (3.76 per 100 patient-years, 95% CI 1.62-7.4). CONCLUSION: Patients taking OAs who have advanced cerebral small vessel disease, evidenced by microbleeds and moderate to severe white matter hyperintensities, had an increased risk of ICH. Our results should help to determine the risk of prescribing OA for a patient with cardioembolic stroke. CLINICALTRIALSGOV IDENTIFIER: NCT02238470.

Sudden hemichorea and frontal lobe syndrome: a rare presentation of unbalanced polycythaemia vera.

Polycythaemia vera (PV) is an haematological neoplasm that frequently presents neurological symptoms. However, chorea is a rare complication of this disease, occurring in less than 5% of the patients. Cognitive impairment related to PV unbalanced is also a rare complication, and it can improve with proper treatment. We present a 96-year-old-man with acute-onset hemichorea and frontal lobe syndrome with no vascular pathology in the basal ganglia or frontal region. A clear relationship was observed between the onset of involuntary movements and the cognitive impairment and worsening of haematological parameters in the patient. After causal and symptomatic treatment, the patient's clinical status improved. In the elderly, PV must be considered as a cause of acute chorea and sudden cognitive impairment, as early diagnosis leads to effective treatment and prevention of complications.

Statins do not increase Markers of Cerebral Angiopathies in patients with Cardioembolic Stroke.

We investigated whether pre-treatment with statins is associated with surrogate markers of amyloid and hypertensive angiopathies in patients who need to start long-term oral anticoagulation therapy. A prospective multicenter study of patients naive for oral anticoagulants, who had an acute cardioembolic stroke. MRI was performed at admission to evaluate microbleeds, leukoaraiosis and superficial siderosis. We collected data on the specific statin compound, the dose and the statin intensity. We performed bivariate analyses and a logistic regression to investigate variables associated with microbleeds. We studied 470 patients (age 77.5 ± 6.4 years, 43.7% were men), and 193 (41.1%) of them received prior treatment with a statin. Microbleeds were detected in 140 (29.8%), leukoaraiosis in 388 (82.5%) and superficial siderosis in 20 (4.3%) patients. The presence of microbleeds, leukoaraiosis or superficial siderosis was not related to pre-treatment with statins. Microbleeds were more frequent in patients with prior intracerebral hemorrhage (OR 9.7, 95% CI 1.06-90.9) and in those pre-treated antiplatelets (OR 1.66, 95% CI 1.09-2.53). Prior treatment with statins was not associated with markers of bleeding-prone cerebral angiopathies in patients with cardioembolic stroke. Therefore, previous statin treatment should not influence the decision to initiate or withhold oral anticoagulation if these neuroimaging markers are detected.

High prevalence of co-infection between human papillomavirus (HPV) 51 and 52 in Mexican population.

BACKGROUND: Human papillomavirus (HPV) is associated with the genesis of cervical carcinoma. The co-infection among HPV genotypes is frequent, but the clinical significance is controversial; in Mexico, the prevalence and pattern of co-infection differ depending on the geographic area of study. We analyzed the mono- and co-infection prevalence of multiple HPV genotypes, as well as preferential interactions among them in a Mexico City sample population. METHODS: This study was designed as a retrospective cohort study. Cervical cytology samples from 1163 women and 166 urethral scraping samples of men were analyzed between 2010 and 2012. The detection of HPV infection was performed using the hybrid capture and the genotyping was by PCR (HPV 6, 11, 16, 18, 30, 31, 33, 35, 45, 51, and 52). RESULTS: 36% of women were HPV-positive and the most prevalent genotypes were HPV 51, 52, 16, and 33 (42, 38, 37, and 34%, respectively). The prevalence of co-infection was higher (75.37%) than mono-infection in women HPV positives. All genotypes were co-infected with HPV 16, but the co-infection with 51-52 genotypes was the most frequent combination in all cases. CONCLUSION: The co-infection was very common; each HPV genotype showed different preferences for co-infection with other genotypes, HPV 51-52 co-infection was the most frequent. The HPV 16, 33, 51 and 52 were the most prevalent and are a public health concern to the Mexican population.

Mechanisms of Intestinal Barrier Dysfunction in Sepsis.

Intestinal barrier dysfunction is thought to contribute to the development of multiple organ dysfunction syndrome in sepsis. Although there are similarities in clinical course following sepsis, there are significant differences in the host response depending on the initiating organism and time course of the disease, and pathways of gut injury vary widely in different preclinical models of sepsis. The purpose of this study was to determine whether the timecourse and mechanisms of intestinal barrier dysfunction are similar in disparate mouse models of sepsis with similar mortalities. FVB/N mice were randomized to receive cecal ligation and puncture (CLP) or sham laparotomy, and permeability was measured to fluoresceinisothiocyanate conjugated-dextran (FD-4) six to 48 h later. Intestinal permeability was elevated following CLP at all timepoints measured, peaking at 6 to 12 h. Tight junction proteins claudin 1, 2, 3, 4, 5, 7, 8, 13, and 15, Junctional Adhesion Molecule-A (JAM-A), occludin, and ZO-1 were than assayed by Western blot, real-time polymerase chain reaction, and immunohistochemistry 12 h after CLP to determine potential mechanisms underlying increases in intestinal permeability. Claudin 2 and JAM-A were increased by sepsis, whereas claudin-5 and occludin were decreased by sepsis. All other tight junction proteins were unchanged. A further timecourse experiment demonstrated that alterations in claudin-2 and occludin were detectable as early as 1 h after the onset of sepsis. Similar experiments were then performed in a different group of mice subjected to Pseudomonas aeruginosa pneumonia. Mice with pneumonia had an increase in intestinal permeability similar in timecourse and magnitude to that seen in CLP. Similar changes in tight junction proteins were seen in both models of sepsis although mice subjected to pneumonia also had a marked decrease in ZO-1 not seen in CLP. These results indicate that two disparate, clinically relevant models of sepsis induce a significant increase in intestinal permeability mediated through a common pathway involving alterations in claudin 2, claudin 5, JAM-A, and occludin although model-specific differences in ZO-1 were also identified.

Intestine-specific deletion of microsomal triglyceride transfer protein increases mortality in aged mice.

BACKGROUND: Mice with conditional, intestine-specific deletion of microsomal triglyceride transfer protein (Mttp-IKO) exhibit a complete block in chylomicron assembly together with lipid malabsorption. Young (8-10 week) Mttp-IKO mice have improved survival when subjected to a murine model of Pseudomonas aeruginosa-induced sepsis. However, 80% of deaths in sepsis occur in patients over age 65. The purpose of this study was to determine whether age impacts outcome in Mttp-IKO mice subjected to sepsis. METHODS: Aged (20-24 months) Mttp-IKO mice and WT mice underwent intratracheal injection with P. aeruginosa. Mice were either sacrificed 24 hours post-operatively for mechanistic studies or followed seven days for survival. RESULTS: In contrast to young septic Mttp-IKO mice, aged septic Mttp-IKO mice had a significantly higher mortality than aged septic WT mice (80% vs. 39%, p = 0.005). Aged septic Mttp-IKO mice exhibited increased gut epithelial apoptosis, increased jejunal Bax/Bcl-2 and Bax/Bcl-XL ratios yet simultaneously demonstrated increased crypt proliferation and villus length. Aged septic Mttp-IKO mice also manifested increased pulmonary myeloperoxidase levels, suggesting increased neutrophil infiltration, as well as decreased systemic TNFα compared to aged septic WT mice. CONCLUSIONS: Blocking intestinal chylomicron secretion alters mortality following sepsis in an age-dependent manner. Increases in gut apoptosis and pulmonary neutrophil infiltration, and decreased systemic TNFα represent potential mechanisms for why intestine-specific Mttp deletion is beneficial in young septic mice but harmful in aged mice as each of these parameters are altered differently in young and aged septic WT and Mttp-IKO mice.

Inhibition of intestinal epithelial apoptosis improves survival in a murine model of radiation combined injury.

World conditions place large populations at risk from ionizing radiation (IR) from detonation of dirty bombs or nuclear devices. In a subgroup of patients, ionizing radiation exposure would be followed by a secondary infection. The effects of radiation combined injury are potentially more lethal than either insult in isolation. The purpose of this study was to determine mechanisms of mortality and possible therapeutic targets in radiation combined injury. Mice were exposed to IR with 2.5 Gray (Gy) followed four days later by intratracheal methicillin-resistant Staphylococcus aureus (MRSA). While either IR or MRSA alone yielded 100% survival, animals with radiation combined injury had 53% survival (p = 0.01). Compared to IR or MRSA alone, mice with radiation combined injury had increased gut apoptosis, local and systemic bacterial burden, decreased splenic CD4 T cells, CD8 T cells, B cells, NK cells, and dendritic cells, and increased BAL and systemic IL-6 and G-CSF. In contrast, radiation combined injury did not alter lymphocyte apoptosis, pulmonary injury, or intestinal proliferation compared to IR or MRSA alone. In light of the synergistic increase in gut apoptosis following radiation combined injury, transgenic mice that overexpress Bcl-2 in their intestine and wild type mice were subjected to IR followed by MRSA. Bcl-2 mice had decreased gut apoptosis and improved survival compared to WT mice (92% vs. 42%; p<0.01). These data demonstrate that radiation combined injury results in significantly higher mortality than could be predicted based upon either IR or MRSA infection alone, and that preventing gut apoptosis may be a potential therapeutic target.

Inhibition of IKKß in enterocytes exacerbates sepsis-induced intestinal injury and worsens mortality.

OBJECTIVES: Nuclear factor-κB is a critical regulator of cell-survival genes and the host inflammatory response. The purpose of this study was to investigate the role of enterocyte-specific NF-kB in sepsis through selective ablation of IkB kinase. DESIGN: Prospective, randomized controlled study. SETTING: Animal laboratories in university medical centers. SUBJECTS AND INTERVENTIONS: Mice lacking functional NF-kB in their intestinal epithelium (Vil-Cre/Ikkß) and wild-type mice were subjected to sham laparotomy or cecal ligation and puncture. Animals were killed at 24 hours or followed 7 days for survival. MEASUREMENTS AND MAIN RESULTS: Septic wild-type mice had decreased villus length compared with sham mice, whereas villus atrophy was further exacerbated in septic Vil-Cre/Ikkß mice. Sepsis induced an increase in intestinal epithelial apoptosis compared with sham mice, which was further exacerbated in Vil-Cre/Ikkß mice. Sepsis induced intestinal hyperpermeability in wild-type mice compared with sham mice, which was further exacerbated in septic Vil-Cre/Ikkß mice. This was associated with increased intestinal expression of claudin-2 in septic wild-type mice, which was further increased in septic Vil-Cre/Ikkß mice. Both, pro-inflammatory and anti-inflammatory cytokines were increased in serum following cecal ligation and puncture, and interleukin 10 and monocyte chemoattractant protein-1 levels were higher in septic Vil-Cre/Ikkß mice than in septic wild-type mice. All septic mice were bacteremic, but no differences in bacterial load were identified between wild-type and Vil-Cre/Ikkß mice. To determine the functional significance of these results, animals were followed for survival. Septic wild-type mice had lower mortality than septic Vil-Cre/Ikkß mice (47% vs 80%, p<0.05). Antitumor necrosis factor administration decreased intestinal apoptosis, permeability, and mortality in wild-type septic mice, and a similar improvement in intestinal integrity and survival were seen when antitumor necrosis factor was given to Vil-Cre/Ikkß mice. CONCLUSIONS: Enterocyte-specific NF-kB has a beneficial role in sepsis by partially preventing sepsis-induced increases in apoptosis and permeability, which are associated with worsening mortality.

Probiotic administration reduces mortality and improves intestinal epithelial homeostasis in experimental sepsis.

BACKGROUND: Recent clinical trials indicate that probiotic administration in critical illness has potential to reduce nosocomial infections and improve clinical outcome. However, the mechanism(s) of probiotic-mediated protection against infection and sepsis remain elusive. The authors evaluated the effects of Lactobacillus rhamnosus GG (LGG) and Bifidobacterium longum (BL) on mortality, bacterial translocation, intestinal epithelial homeostasis, and inflammatory response in experimental model of septic peritonitis. METHODS: Cecal ligation and puncture (n=14 per group) or sham laparotomy (n=8 per group) were performed on 3-week-old FVB/N weanling mice treated concomitantly with LGG, BL, or vehicle (orally gavaged). At 24 h, blood and colonic tissue were collected. In survival studies, mice were given probiotics every 24 h for 7 days (LGG, n=14; BL, n=10; or vehicle, n=13; shams, n=3 per group). RESULTS: Probiotics significantly improved mortality after sepsis (92 vs. 57% mortality for LGG and 92 vs. 50% mortality for BL; P=0.003). Bacteremia was markedly reduced in septic mice treated with either probiotic compared with vehicle treatment (4.39±0.56 vs. 1.07±1.54; P=0.0001 for LGG; vs. 2.70±1.89; P=0.016 for BL; data are expressed as mean±SD). Sepsis in untreated mice increased colonic apoptosis and reduced colonic proliferation. Probiotics significantly reduced markers of colonic apoptosis and returned colonic proliferation to sham levels. Probiotics led to significant reductions in systemic and colonic inflammatory cytokine expression versus septic animals. Our data suggest that involvement of the protein kinase B pathway (via AKT) and down-regulation of Toll-like receptor 2/Toll-like receptor 4 via MyD88 in the colon may play mechanistic roles in the observed probiotic benefits. CONCLUSIONS: Our data demonstrate that probiotic administration at initiation of sepsis can improve survival in pediatric experimental sepsis. The mechanism of this protection involves prevention of systemic bacteremia, perhaps via improved intestinal epithelial homeostasis, and attenuation of the local and systemic inflammatory responses.

Intestine-specific Mttp deletion decreases mortality and prevents sepsis-induced intestinal injury in a murine model of Pseudomonas aeruginosa pneumonia.

BACKGROUND: The small intestine plays a crucial role in the pathophysiology of sepsis and has been referred to as the "motor" of the systemic inflammatory response. One proposed mechanism is that toxic gut-derived lipid factors, transported in mesenteric lymph, induce systemic injury and distant organ failure. However, the pathways involved are yet to be defined and the role of intestinal chylomicron assembly and secretion in transporting these lipid factors is unknown. Here we studied the outcome of sepsis in mice with conditional, intestine-specific deletion of microsomal triglyceride transfer protein (Mttp-IKO), which exhibit a block in chylomicron assembly together with lipid malabsorption. METHODOLOGY/PRINCIPAL FINDINGS: Mttp-IKO mice and controls underwent intratracheal injection with either Pseudomonas aeruginosa or sterile saline. Mttp-IKO mice exhibited decreased seven-day mortality, with 0/20 (0%) dying compared to 5/17 (29%) control mice (p<0.05). This survival advantage in Mttp-IKO mice, however, was not associated with improvements in pulmonary bacterial clearance or neutrophil infiltration. Rather, Mttp-IKO mice exhibited protection against sepsis-associated decreases in villus length and intestinal proliferation and were also protected against increased intestinal apoptosis, both central features in control septic mice. Serum IL-6 levels, a major predictor of mortality in human and mouse models of sepsis, were elevated 8-fold in septic control mice but remained unaltered in septic Mttp-IKO mice. Serum high density lipoprotein (HDL) levels were reduced in septic control mice but were increased in septic Mttp-IKO mice. The decreased levels of HDL were associated with decreased hepatic expression of apolipoprotein A1 in septic control mice. CONCLUSIONS/SIGNIFICANCE: These studies suggest that strategies directed at blocking intestinal chylomicron secretion may attenuate the progression and improve the outcome of sepsis through effects mediated by metabolic and physiological adaptations in both intestinal and hepatic lipid flux.

The endogenous bacteria alter gut epithelial apoptosis and decrease mortality following Pseudomonas aeruginosa pneumonia.

The endogenous bacteria have been hypothesized to play a significant role in the pathophysiology of critical illness, although their role in sepsis is poorly understood. The purpose of this study was to determine how commensal bacteria alter the host response to sepsis. Conventional and germ-free (GF) C57Bl/6 mice were subjected to Pseudomonas aeruginosa pneumonia. All GF mice died within 2 days, whereas 44% of conventional mice survived for 7 days (P = 0.001). Diluting the dose of bacteria 10-fold in GF mice led to similar survival in GF and conventional mice. When animals with similar mortality were assayed for intestinal integrity, GF mice had lower levels of intestinal epithelial apoptosis but similar levels of proliferation and intestinal permeability. Germ-free mice had significantly lower levels of tumor necrosis factor and interleukin 1ß in bronchoalveolar lavage fluid compared with conventional mice without changes in systemic cytokine production. Under conventional conditions, sepsis unmasks lymphocyte control of intestinal epithelial apoptosis, because sepsis induces a greater increase in gut apoptosis in Rag-1 mice than in wild-type mice. However, in a separate set of experiments, gut apoptosis was similar between septic GF Rag-1 mice and septic GF wild-type mice. These data demonstrate that the endogenous bacteria play a protective role in mediating mortality from pneumonia-induced sepsis, potentially mediated through altered intestinal apoptosis and the local proinflammatory response. In addition, sepsis-induced lymphocyte-dependent increases in gut epithelial apoptosis appear to be mediated by the endogenous bacteria.

Neuromielitis recidivante sin neuritis óptica: a propósito de un caso / Recurring neuromyelitis without optic neuritis: a case report

Introducción. La neuromielitis óptica o enfermedad de Devic es una enfermedad inflamatoria y desmielinizante del sistema nervioso central que afecta selectivamente a los nervios ópticos y a la médula espinal, con alta frecuencia de recidivas. Los anticuerpos antiacuaporina 4 (AQP4) son un marcador altamente específico de esta entidad. Caso clínico. Mujer de 66 años de edad con una mielitis transversa longitudinalmente extensa dorsal con remisión completa tras tratamiento esteroideo y recidiva aguda posterior, con plejía de una extremidad. Entre los diagnósticos diferenciales se consideraron los de tumoración espinal y malformación arteriovenosa medular. La positividad de AQP4 fue el factor determinante en el diagnóstico final. Conclusión. La detección precoz de los anticuerpos anti-AQP4 junto con una inmunoterapia apropiada puede representar la clave de un mejor pronóstico. Es muy importante un diagnóstico precoz de cara a un inicio temprano del tratamiento y así evitar recurrencias y secuelas graves (AU)

Introduction. Neuromyelitis optica, or Devic’s disease, is an inflammatory, demyelinating disease of the central nervous system that selectively affects the optic nerves and the spinal cord, with a high rate of relapses. Anti-aquaporin-4 (AQP4) antibodies are a highly specific marker for this condition. Case report. A 66-year-old female with longitudinally extensive dorsal transverse myelitis with complete remission following steroidal treatment and later acute relapse, with palsy in one limb. The differential diagnoses considered included a spinal tumour and arteriovenous malformation of the spinal cord. Being positive for AQP4 was the decisive factor in the final diagnosis. Conclusions. Early detection of anti-AQP4 antibodies together with appropriate immunotherapy can be the key to a better prognosis. An early diagnosis is essential to be able to start treatment at an early stage and thus prevent relapses and severe sequelae (AU)

Quimioterapia neoadyuvante y tratamiento quirúrgico en pacientes con cáncer de mama localmente avanzado / Neoadjuvant chemotherapy and surgical treatment in patients locally advanced breast cancer

Introducción: El cáncer de mama localmente avanzado es una forma evolucionada de enfermedad, con presentación variable. Aproximadamente, supone el 15% de las pacientes que tratamos con cáncer de mama. El manejo de estas pacientes es multidisciplinario. Objetivo: Exponer nuestra experiencia y el protocolo en el manejo del cáncer de mama localmente avanzado. Valoramos la tolerancia y la toxicidad del tratamiento neoadyuvante, así como también la respuesta clínica y patológica. Igualmente, se describen las complicaciones quirúrgicas y el resultado estético final. Pacientes y método: Realizamos un estudio retrospectivo en 20 mujeres con cáncer de mama localmente avanzado, tratadas en nuestra unidad durante un período de 2 años. Actualmente, seguimos un protocolo de quimioterapia neoadyuvante según el esquema TEC × 6 ( docetaxel + epirrubicina + ciclofosfamida) asociado a filgastrim, seguido de cirugía y radioterapia. Resultados: Los efectos secundarios más frecuentes fueron las náuseas (80%) y la astenia (50%). La respuesta patológica fue completa (tejido de mama y axila) en 6 pacientes (30%); parcial en 10 (50%), y presencia masiva de enfermedad (R0/R1) en 4 (20%). En todas las pacientes se realizó cirugía radical, con reconstrucción inmediata en 16 de ellas. Conclusión: El esquema TEC × 6 neoadyuvante presenta una alta tasa de eficacia y una tolerancia aceptable. Los resultados obtenidos con la técnica de mastectomía radical y reconstrucción inmediata fueron muy favorables(AU)

Locally advanced breast cancer is a progressive form of the disease with variable presentation. It affects around 15% of patients who suffer from breast cancer. The management of these patients is multidisciplinary. Objective: To describe our experience in using a management protocol for locally advanced breast cancer. The tolerance and toxicity of neoadjuvant therapy, and clinical and pathological response to it are assessed. Surgical complications and the final aesthetic results are also discussed. Patients and method: A retrospective study was conducted on 20 women with locally advanced breast cancer treated in our unit over a period of 2 years. A protocol is currently followed that includes neoadjuvant chemotherapy according to the scheme TEC × 6 (docetaxel + epirubicin + cyclophosphamide) combined with filgrastim followed by surgery and radiotherapy. Results: The most common side effects were nausea (80%) and asthenia (50%). The pathological response was complete (breast and axillary tissue) in 6 patients (30%), partial in 10 (50%), and massive presence of disease (R0/R1) in 4 (20%). All patients underwent radical surgery with 16 patients having immediate reconstruction. Conclusion: The neoadjuvant TEC × 6 scheme has a high rate of efficacy and an acceptable tolerance. The results obtained with radical mastectomy followed by immediate reconstruction were very favourable(AU)

Mechanisms of methicillin-resistant Staphylococcus aureus pneumonia-induced intestinal epithelial apoptosis.

Methicillin-resistant Staphylococcus aureus (MRSA) pneumonia-induced sepsis is a common cause of morbidity in the intensive care unit. Although pneumonia is initiated in the lungs, extrapulmonary manifestations occur commonly. In light of the key role the intestine plays in the pathophysiology of sepsis, we sought to determine whether MRSA pneumonia induces intestinal injury. FVB/N mice were subjected to MRSA or sham pneumonia and killed 24 h later. Septic animals had a marked increase in intestinal epithelial apoptosis by both hematoxylin-eosin and active caspase 3 staining. Methicillin-resistant S. aureus-induced intestinal apoptosis was associated with an increase in the expression of the proapoptotic proteins Bid and Bax and the antiapoptotic protein Bcl-xL in the mitochondrial pathway. In the receptor-mediated pathway, MRSA pneumonia induced an increase in Fas ligand but decreased protein levels of Fas, FADD, pFADD, TNF-R1, and TRADD. To assess the functional significance of these changes, MRSA pneumonia was induced in mice with genetic manipulations in proteins in either the mitochondrial or receptor-mediated pathways. Both Bid-/- mice and animals with intestine-specific overexpression of Bcl-2 had decreased intestinal apoptosis compared with wild-type animals. In contrast, Fas ligand-/- mice had no alterations in apoptosis. To determine if these findings were organism-specific, similar experiments were performed in mice subjected to Pseudomonas aeruginosa pneumonia. Pseudomonas aeruginosa induced gut apoptosis, but unlike MRSA, this was associated with increased Bcl-2 and TNF-R1 and decreased Fas. Methicillin-resistant S. aureus pneumonia thus induces organism-specific changes in intestinal apoptosis via changes in both the mitochondrial and receptor-mediated pathways, although the former may be more functionally significant.

[Transorbital echography for assessment of optical nerve atrophy in demyelinating diseases: a pilot study]. / Utilidad del dúplex orbitario para la valoración de atrofia del nervio óptico en enfermedades desmielinizantes: estudio piloto.

INTRODUCTION. Demielinating diseases are a group of heterogenic diseases in whom mieline is attacked. The optic nerve (ON) is one of the most commonly affected. SUBJECTS AND METHODS. An observational prospective case-control study with ON orbital echography was developed. The case group was formed by 31 demielinating diseases patients and the control group was formed by 24 healthy people. Mean age of cases: 48.3 ± 11.8 years old, controls 48.7 ± 9.9 years old. 46% of controls and 35% of cases were males. RESULTS. We found statistical significance differences between cases and controls regarding the diameter of right (controls 3.64 ± 0.58 mm vs patients 2.84 ± 0.56 mm; p < 0.001) and left ON (controls 3.95 ± 0.84 mm vs patients 2.74 ± 0.54 mm; p < 0.001). We found no differences between maximum systolic and median velocities regarding ophthalmic arteries in both groups, neither for previous acute optical neuritis history or visual evocated potentials. CONCLUSIONS. ON evaluation with transorbital echography is an easy, feasible, non invasive, useful and costless technique for the evaluation of the ON atrophy. As for visual evocated potentials are abnormal in a huge number of patients without previous optical neuritis evidence, the diameter of ON measured by transorbital Doppler could be a consistent paraclinic marker of these diseases.

Utilidad del dúplex orbitario para la valoración de atrofia del nervio óptico en enfermedades desmielinizantes: estudio piloto / Transorbital echography for assessment of optical nerve atrophy in demyelinating diseases: a pilot study

Introducción. Las enfermedades desmielinizantes son un grupo heterogéneo de procesos en los que se daña la mielina. Es bien conocida la predilección de estas patologías por el nervio óptico (NO).Sujetos y métodos. Estudio observacional prospectivo de casos y controles mediante ecografía del NO de pacientes diagnosticadosde enfermedad desmielinizante (n = 31) y de controles sanos (n = 24). La edad media de los casos es de 48,3 ±11,8 años, y de los controles, de 48,7 ± 9,9 años. El 46% de los controles y el 35% de los casos eran varones.Resultados. Se encontraron diferencias estadísticamente significativas entre casos y controles en cuanto al diámetro delNO tanto derecho (3,64 ± 0,58 mm en controles frente a 2,84 ± 0,56 mm en los pacientes; p < 0,001) como izquierdo (3,95 ± 0,84 mm en controles frente a 2,74 ± 0,54 mm en pacientes; p < 0,001). No se encontraron diferencias significativasen la velocidad pico sistólica de la arteria oftálmica entre ambos grupos, ni tampoco en el diámetro del NO de los casos con antecedentes de neuritis óptica y los que no presentaban dicho antecedente.Conclusiones. El dúplex del nervio óptico es una herramienta útil, accesible y no invasiva para la valoración de la existenciade atrofia óptica. De la misma forma que los potenciales evocados visuales están alterados en un número importante de pacientes sin antecedentes claros de haber sufrido neuritis óptica, el estudio del grosor del NO mediante Dopplertranscraneal también podría utilizarse como marcador paraclínico de enfermedad desmielinizante (AU)

Introduction. Demielinating diseases are a group of heterogenic diseases in whom mieline is attacked. The optic nerve(ON) is one of the most commonly affected.Subjects and methods. An observational prospective case-control study with ON orbital echography was developed. Thecase group was formed by 31 demielinating diseases patients and the control group was formed by 24 healthy people. Mean age of cases: 48.3 ± 11.8 years old, controls 48.7 ± 9.9 years old. 46% of controls and 35% of cases were males.Results. We found statistical significance differences between cases and controls regarding the diameter of right (controls3.64 ± 0.58 mm vs patients 2.84 ± 0.56 mm; p < 0.001) and left ON (controls 3.95 ± 0.84 mm vs patients 2.74 ± 0.54 mm; p < 0.001). We found no differences between maximum systolic and median velocities regarding ophthalmic arteries in both groups, neither for previous acute optical neuritis history or visual evocated potentials.Conclusions. ON evaluation with transorbital echography is an easy, feasible, non invasive, useful and costless technique for the evaluation of the ON atrophy. As for visual evocated potentials are abnormal in a huge number of patients withoutprevious optical neuritis evidence, the diameter of ON measured by transorbital Doppler could be a consistent paraclinic marker of these diseases (AU)