Inhibition of rat liver fibrogenesis through noradrenergic antagonism

The effect of adrenergic innervation and/or circulating catecholamines on the function of liver fibrogenic cells is poorly understood. Our aim was to investigate the effects of noradrenergic antagonism on carbon tetrachloride (CCl4)-induced liver fibrosis in rats. Two weeks of CCl4 induced an approximately 5-fold increase in the area of fibrosis as compared with controls. The addition of 6-hydroxydopamine (OHDA), a toxin that destroys noradrenergic fibers, decreased fibrosis by 60%. After 6 weeks of CCl4, the area of fibrosis increased about 30-fold in CCl4-treated animals and was decreased by 36% with OHDA. At 2 weeks, OHDA abrogated the CCl4-induced increase in mRNA level of tissue inhibitor of matrix metalloproteinases-1 (TIMP-1), an inhibitor of extracellular matrix degradation, and it greatly reduced it at 6 weeks. Finally, when rats treated with CCl4 for 2 weeks also received prazosin, an antagonist of alpha1-adrenergic receptors, fibrosis was decreased by 83%. In conclusion, destruction of noradrenergic fibers or antagonism of noradrenergic signaling through alpha1 receptors inhibited the development of liver fibrosis. Because adrenoreceptor antagonists have a very sound safety profile, they appear as attractive drugs to reduce liver fibrogenesis.     

Phlegmonous gastritis associated with HIV-1 seroconversion

Summary A 40-year-old man presented with peritonitis. Diagnosis of phlegmonous gastritis was made by laparotomy. Conservative treatment combined with antibiotics was successful. Multiple endoscopies with biopsies illustrate the natural history of this disease. The patient developed HIV-1 seroconversion during hospital stay. Prompt diagnosis and treatment may improve the prognosis of this often lethal disease.     

Bcl-2 protein expression is the strongest independent prognostic factor of survival in primary cutaneous large B-cell lymphomas

Bcl-2 protein expression has been associated with poor prognosis in patients with noncutaneous diffuse large B-cell lymphomas. In primary cutaneous large B-cell lymphomas, the location on the leg, the round-cell morphology defined as the predominance of centroblasts and immunoblasts over large centrocytes, and multiple skin lesions were identified as adverse prognostic factors. The prognostic value of bcl-2 protein expression has not been studied in large series of patients. We evaluated 80 primary cutaneous large B-cell lymphomas collected by the French Study Group on Cutaneous Lymphomas. The prognostic value of age, sex, number of lesions, cutaneous extent, location, serum lactate dehydrogenase (LDH) level, B symptoms, morphology, and bcl-2 protein expression was studied. The overall 5-year specific survival rate was 65%. In univariate analysis, advanced age, multiple skin lesions (n = 48), location on the leg (n = 25), round-cell morphology (n = 32), and bcl-2 expression (n = 39) were significantly related to death from lymphoma. In multivariate analysis, bcl-2 expression (P =.0003), multiple skin lesions (P =.004), and age remained independent prognostic factors. The 5-year specific survival rates in bcl-2-positive and bcl-2-negative patients were 41% and 89%, respectively (P <.0001). A new prognostic classification of primary cutaneous B-cell lymphoma should be based primarily on bcl-2 protein expression rather than the location of skin lesions.     

Neuromodulatory pathways in learning and memory: Lessons from invertebrates

In an ever‐changing environment, animals have to continuously adapt their behaviour. The ability to learn from experience is crucial for animals to increase their chances of survival. It is therefore not surprising that learning and memory evolved early in evolution and are mediated by conserved molecular mechanisms. A broad range of neuromodulators, in particular monoamines and neuropeptides, have been found to influence learning and memory, although our knowledge on their modulatory functions in learning circuits remains fragmentary. Many neuromodulatory systems are evolutionarily ancient and well‐conserved between vertebrates and invertebrates. Here, we highlight general principles and mechanistic insights concerning the actions of monoamines and neuropeptides in learning circuits that have emerged from invertebrate studies. Diverse neuromodulators have been shown to influence learning and memory in invertebrates, which can have divergent or convergent actions at different spatiotemporal scales. In addition, neuromodulators can regulate learning dependent on internal and external states, such as food and social context. The strong conservation of neuromodulatory systems, the extensive toolkit and the compact learning circuits in invertebrate models make these powerful systems to further deepen our understanding of neuromodulatory pathways involved in learning and memory.     

Metabolic Syndrome in Offspring of Parents with Metabolic Syndrome: A Meta-Analysis

BackgroundThe metabolic syndrome (MetS) represents a clustering of risk factors for cardiovascular diseases that includes abdominal obesity, hypertension, dyslipidemia, and insulin resistance.ObjectivesThe objective of this study was to reassess the parent-offspring association of MetS since the available findings are still controversial.MethodsThe Cochrane Library, PubMed, Embase, and Web of Science databases were searched to identify relevant articles. All studies comparing MetS status between the offspring of parents with MetS and offspring of parents without MetS were included in the analysis.ResultsA total of 9 studies met the inclusion criteria and they were analyzed. Offspring of at least 1 parent with MetS had a higher risk of MetS (OR 3.88, 95% CI 2.58–5.83, p < 0.001). Sons and daughters of fathers with MetS both had a higher risk of MetS (OR 2.31, 95% CI 1.70–3.12, p < 0.001, and OR 1.73, 95% CI 1.37–2.18, p < 0.001, respectively). Sons and daughters of mothers with MetS both had a higher risk of MetS (OR 1.95, 95% CI 1.37–2.76, p = 0.0002, and OR 1.91, 95% CI 1.54–2.35, p < 0.001, respectively).ConclusionThis meta-analysis showed that there is a higher risk of MetS in the offspring of parents with MetS. However, there was no differential association of MetS according to gender and/or age of the offspring.     

Non-flat audiograms in sensorineural hearing loss and speech perception

OBJECTIVE:

The audibility thresholds for the sound frequency of 137 upward- and downward-sloping audiograms showing sensorineural hearing loss were selected and analyzed in conjunction with speech recognition thresholds obtained from individuals seen at a public otolaryngology clinic to determine which frequencies in slope audiograms best represent speech recognition thresholds.

METHOD:

The linear regression model and mean square error were used to determine the associations between the threshold values.

RESULT:

The mean square error identified larger errors when using thresholds of 500, 1000, and 2000 Hz than when using audibility thresholds of 500, 1000, 2000, and 4000 Hz. The linear regression model showed a higher correlation (91%) between the audiogram thresholds for frequencies of 500, 1000, 2000, and 4000 Hz than for the frequencies of 500, 1000, and 2000 Hz (88%).

CONCLUSION:

Frequencies of 500, 1000, 2000, and 4000 Hz were the most significant in predicting the speech recognition threshold.     

In vitro activities of antifungal agents alone and in combination against fluconazole-susceptible and -resistant strains of Candida dubliniensis

In the present study we used two groups of Candida dubliniensis strains: one containing fluconazole-susceptible clinical isolates and another containing fluconazole-resistant laboratory derivative from the former to examine the changes on susceptibility accompanying the development of resistance to fluconazole. Our findings confirmed the ability of C. dubliniensis isolates to become resistant to fluconazole and indicated that this resistance was crossed with ketoconazole, itraconazole, ravuconazole and terbinafine. We also tested combinations of terbinafine, amphotericin B, itraconazole and voriconazole against both groups of isolates in a checkerboard assay. Surprisingly, most combinations evidenced indifferent interactions, and the best synergism appeared when terbinafine and itraconazole were combined against the fluconazole-resistant group.     

New therapy from old drugs: synergistic bactericidal activity of sulfadiazine with colistin against colistin-resistant bacteria,including plasmid-mediated colistin-resistant mcr-1 isolates

The recent emergence of colistin (COL) resistance, particularly mcr-1 plasmid-mediated COL resistance in Gram-negative bacteria, has led to renewed interest in antibiotic combinations to overcome clinical therapeutic impasses. The aim of this study was to evaluate the potential of the synergistic and bactericidal activity of COL in combination with sulphonamide compounds, including sulfadiazine (SDI), sulfamethoxazole (SMX) and trimethoprim/sulfamethoxazole (SXT), as well as trimethoprim (TMP) against clinical COL-resistant bacterial strains, including strains with the plasmid-encoded mcr-1 gene. A collection of 55 COL-resistant and -susceptible strains from different origins (Laos, Thailand and France) was used in this study. Several in vitro methods were used to determine the potential of the synergistic activity of these combinations, including Etest on agar pre-treated plates, the Etest cross method and the chequerboard assay. A time–kill assay was performed to evaluate the potential bactericidal activity of combinations in addition to synergistic activity. Significant synergistic activity was observed with all combinations tested. The combination of COL?+?SDI presented the highest synergistic effect against the various species of COL-resistant strains (92.7%). For the other combinations, a synergistic effect was also observed but with lower frequency for COL?+?SMX (33.3%), COL?+?TMP (47.3%) and COL?+?SXT (31.5%). Synergy was observed independently of the COL resistance mechanism. These in vitro results suggest that the combination of COL?+?SDI would appear to be justifiable in patients with multidrug-resistant bacterial infections that cannot be treated with COL monotherapy.     

A human postnatal lymphoid progenitor capable of circulating and seeding the thymus

Identification of a thymus-seeding progenitor originating from human bone marrow (BM) constitutes a key milestone in understanding the mechanisms of T cell development and provides new potential for correcting T cell deficiencies. We report the characterization of a novel lymphoid-restricted subset, which is part of the lineage-negative CD34⁺CD10⁺ progenitor population and which is distinct from B cell–committed precursors (in view of the absence of CD24 expression). We demonstrate that these Lin⁻CD34⁺CD10⁺CD24⁻ progenitors have a very low myeloid potential but can generate B, T, and natural killer lymphocytes and coexpress recombination activating gene 1, terminal deoxynucleotide transferase, PAX5, interleukin 7 receptor α, and CD3ε. These progenitors are present in the cord blood and in the BM but can also be found in the blood throughout life. Moreover, they belong to the most immature thymocyte population. Collectively, these findings unravel the existence of a postnatal lymphoid-polarized population that is capable of migrating from the BM to the thymus.