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Idiopathic intracranial hypertension (IIH) is a condition of increased intracranial pressure of unknown aetiology. Principal symptoms are headache, visual disturbances, and obesity, together with elevated intracranial pressure. Unspecified MRI, despite normal ventricle size, suggests alterations in the water flux cellular mediated by the brain water channel aquaporin-4 (AQP4). The association among IIH, cerebral spinal fluid malfunction, reabsorption, and functional or regulatory modifications of AQP4 is a hypothesis not confirmed.

Introduction: Spontaneous cerebrospinal fluid (CSF) fistula, of unknown origin, is a rare condition whose aetiology is increasingly related to idiopathic intracranial hypertension (IIH). This study tries to raise awareness that they should not be considered as two different processes, but that fistulas can be a form of debut, requiring a study and subsequent treatment. Repair techniques are described, as well as the study of HII., Results: We treated 8 patients, 5 women and three men, aged between 46 and 72 years, with a diagnosis of spontaneous CSF fistula, four nasal and four otics who underwent surgical treatment. After repair, a diagnostic study was performed for IIH by MRI and Angio-MRI, presenting in all cases a transverse venous sinus stenosis. The intracranial pressure values obtained by lumbar puncture showed values of 20mm Hg or higher. All patients were diagnosed with HII. The one-year follow-up did not reveal any recurrence of the fistulas, maintaining a control of the HII., Conclusion: Despite their low frequency of both cranial CSF fistula and IIH, an association of both conditions should be considered by continuing the study and surveillance of these patients after fistula closure., (Copyright © 2023 Sociedad Española de Neurocirugía. Published by Elsevier España, S.L.U. All rights reserved.)

The critical enzyme dihydrofolate reductase-thymidylate synthase in Leishmania major ( Lm DHFR-TS) serves a dual-purpose role and is essential for DNA synthesis, a cornerstone of the parasite's reproductive processes. Consequently, the development of inhibitors against Lm DHFR-TS is crucial for the creation of novel anti- Leishmania chemotherapies. In this study, we employed an in-house database containing 314 secondary metabolites derived from cinnamic acid that occurred in the Asteraceae family. We conducted a combined ligand/structure-based virtual screening to identify potential inhibitors against Lm DHFR-TS. Through consensus analysis of both approaches, we identified three compounds, i.e., lithospermic acid ( 237 ), diarctigenin ( 306 ), and isolappaol A ( 308 ), that exhibited a high probability of being inhibitors according to both approaches and were consequently classified as promising hits. Subsequently, we expanded the binding mode examination of these compounds within the active site of the test enzyme through molecular dynamics simulations, revealing a high degree of structural stability and minimal fluctuations in its tertiary structure. The in silico predictions were then validated through in vitro assays to examine the inhibitory capacity of the top-ranked naturally occurring compounds against Lm DHFR-TS recombinant protein. The test compounds effectively inhibited the enzyme with IC 50 values ranging from 6.1 to 10.1 μM. In contrast, other common cinnamic acid derivatives (i.e., flavonoid glycosides) from the Asteraceae family, such as hesperidin, isovitexin 4'- O -glucoside, and rutin, exhibited low activity against this target. The selective index (SI) for all tested compounds was determined using Hs DHFR with moderate inhibitory effect. Among these hits, lignans 306 and 308 demonstrated the highest selectivity, displaying superior SI values compared to methotrexate, the reference inhibitor of DHFR-TS. Therefore, continued research into the anti-leishmanial potential of these C6C3-hybrid butyrolactone lignans may offer a brighter outlook for combating this neglected tropical disease.

Vaccination against polio generates herd immunity (both with the attenuated (OPV) and inactivated (IPV) vaccines) and this will allow the eradication of the disease. The OPV vaccine produces 2-4 polio cases per cohort of one million children and therefore IPV is used in countries that can afford its cost (about 15 times more expensive than OPV). In 1988 the World Health Assembly established the polio eradication goal as "interruption of wild poliovirus transmission". If the elimination of wild poliovirus were achieved, the use of OPV will produce annually between 250 and 500 cases of polio in the world. From 1999, it was clear that eradication would require ending of immunization with OPV. On the 25th of January, 2013 it is approved the plan for the eradication and containment of all polioviruses, wild or not, so that no child suffers paralytic poliomyelitis. The most important landmarks include the lack of wild polio cases after 2014, the introduction of at least one dose of IPV in all immunization programs and to cease the type 2 OPV vaccination by the end of 2016 and to stop the use of the oral bivalent vaccine in 2019. To achieve all this, a complex scientific work and economic solidarity will be required.

The endoplasmic reticulum (ER) has been posited as a potential anticancer target. The synthetic antitumor alkyl-lysophospholipid analogue edelfosine accumulates in the ER of solid tumor cells. This ER accumulation of the drug leads to the inhibition of phosphatidylcholine and protein synthesis, G(2)-M arrest, depletion of ER-stored Ca(2+), Bax up-regulation and activation, transcriptional factor growth arrest and DNA damage-inducible gene 153 up-regulation, caspase-4 and caspase-8 activation, and eventually to apoptosis. Edelfosine prompted ER stress apoptotic signaling, but not the survival unfolded protein response. Edelfosine also induced persistent c-Jun NH(2)-terminal kinase (JNK) activation. Gene transfer-mediated overexpression of apoptosis signal-regulating kinase 1, which plays a crucial role in ER stress, enhanced edelfosine-induced JNK activation and apoptosis. Inhibition of JNK, caspase-4, or caspase-8 activation diminished edelfosine-induced apoptosis. Edelfosine treatment led to the generation of the p20 caspase-8 cleavage fragment of BAP31, directing proapoptotic signals between the ER and the mitochondria. bax(-/-)bak(-/-) double-knockout cells fail to undergo edelfosine-induced ER-stored Ca(2+) release and apoptosis. Wild-type and bax(-/-)bak(-/-) cells showed similar patterns of phosphatidylcholine and protein synthesis inhibition, despite their differences in drug sensitivity. Thus, edelfosine-induced apoptosis is dependent on Bax/Bak-mediated ER-stored Ca(2+) release, but phosphatidylcholine and protein synthesis inhibition is not critical. Transfection-enforced expression of Bcl-X(L), which localizes specifically in mitochondria, prevented apoptosis without inhibiting ER-stored Ca(2+) release. These data reveal that edelfosine induces an ER stress response in solid tumor cells, providing novel insights into the edelfosine-mediated antitumor activity. Our data also indicate that mitochondria are indispensable for this edelfosine-induced cell death initiated by ER stress.

Polymyxin B (PXB) and the cecropin A-melittin hybrid CA(1-8)M(1-18) (KWKLFKKIGIGAVLKVLTTGLPALIS-NH2) were compared for antibiotic activity on reference and multiresistant Acinetobacter baumannii strains. Significant differences for both peptides were observed on their inner membrane interaction and inhibition by environmental factors, supporting the use of CA(1-8)M(1-18) as a potential alternative to PXB against ACINETOBACTER:

The in vitro antibiotic activity of CA(1-8)M(1-18), a synthetic cecropin A-melittin hybrid peptide, was determined by broth microdilution on 20 clinical Acinetobacter baumannii isolates with different resistance profiles. The MIC(50), MIC(90) and ranges were 4 mg/l, 4 mg/l and 2-8 mg/l, respectively, and were independent of resistance pattern. Different assay parameters such as microplate plastic (polystyrene or polypropylene), addition of supplements (5-10% fetal calf serum or 5% horse blood), inoculum size (10(5), 10(6), 10(7) and 10(8) CFU/ml) or incubation period (24 or 48 h) were studied. MIC was independent of the first two parameters, although the MIC values increased both with inoculum size or incubation period. Killing curves were obtained both for a standard strain and a multiresistant isolate over a 45.7-2.8 mg/l (16-1 mM) peptide range, using an initial inoculum of 10(5)-10(6) CFU/ml and 10(9)-10(10) CFU/ml. A concentration of 45.7 mg/l was required for complete killing. Accordingly, CA(1-8)M(1-18) showed good in vitro activity against the A. baumannii strains tested irrespective of the resistance to classical antibiotics, and could be a future candidate for multiresistant A. baumannii infections, although further cytotoxicity and pharmacological studies will be needed.

Acinetobacter baumannii is a microorganism frequently implicated in colonization and infection in hospitalized patients. An increase of resistance has been observed in recent years making these infections difficult to treat. The in vitro activity of 24 antibiotics, 15 betalactam agents and nine nonbetalactams, was studied in 156 A. baumannii clinical isolates. The strains were collected from different clinical samples obtained from inpatients (92%) and 8% were from outpatients. Evolution of susceptibility from January 1995 to December 1997 was studied. MIC of the following antibiotics was determined by the agar dilution method: ampicillin, ticarcillin, piperacillin, ampicillin-sulbactam, amoxicillin- clavulanic acid, ticarcillin-clavulanic acid, piperacillin-tazobactam, cefotaxime, ceftazidime, cefepime, imipenem, meropenem, clavulanic acid, sulbactam, tazobactam, amikacin, gentamicin, tobramycin, ofloxacin, doxycycline, fosfomycin, rifampin, azithromycin and colistin. Low antimicrobial susceptibility was observed in most A. baumannii strains. Colistin, imipenem, meropenem and ampicillin-sulbactam showed the greatest susceptibility (100, 88.4, 88.4 and 84.6%, respectively). A. baumannii strains from inpatients showed a lower antimicrobial susceptibility than strains from outpatients, who showed a high percentage of susceptibility to most antibiotics. Rifampin and azithromycin showed certain in vitro activity against the most susceptible A. baumannii strains. A progressive decrease in susceptibility to most antibiotics was observed during the period studied. Carbapenem-resistant A. baumannii emerged in 1996 and increased in 1997.

Objectives: We have contributed to the Design Validation Protocol of the new Abbott AxSYM Testosterone assay with a study on reference values and methods comparison., Design and Methods: For reference values a population of 45 women and 30 men was tested. In methods comparison, 132 samples for the AxSYM vs. ACS-180, and 30 for the AxSYM vs. Elecsys were used. Pearson and intraclass concordance coefficients and Passing-Bablock test were performed for overall group, men and women., Results: Reference values were 0.9-3.1 (females) and 1.0-30.2 nmol/L (males). Globally, a good agreement between methods in both the AxSYM vs. ACS-180 (slope: 0.88, y-intercept: 0.67, r = 0.961) and the AxSYM vs. Elecsys (slope: 1.08, y-intercept: 0.31, r = 0.935) studies was found. Slightly worse results were observed for women., Conclusions: The reference range of testosterone by the AxSYM system matches with those published for other methods. An acceptable agreement between the AxSYM Testosterone assay and both a classical (ACS-180) and a more recent (Elecsys) methodology was observed.

Acinetobacter is a Gram-negative coccobacillus frequently associated with nosocomial infections, especially pneumonia in patients using mechanical ventilators in ICUs. Many of the clinical isolates of Acinetobacter baumannii are now resistant to most antibiotics, including the betalactams, making these infections difficult to treat. We compared the in vitro activity of betalactam agents (ampicillin, piperacillin and ticarcillin), betalactamase inhibitors (clavulanic acid, sulbactam and tazobactam) alone and in combination with betalactam agents (amoxicillin-clavulanic acid, ampicillin-sulbactam, piperacillin-tazobactam and ticarcillin-clavulanic) against 156 clinical isolates of A. baumannii using an agar dilution method. In general, we observed a low susceptibility to the betalactam agents tested (ampicillin: 1.9% susceptibility; piperacillin: 10.2%; ticarcillin: 19.8%). We did not observe a significant reduction of the MIC in the combination of betalactam agents and betalactamase inhibitors; only ampicillin/sulbactam showed a high antimicrobial activity (84.6% compared to 14.1%, 37.8% and 33.9% for amoxicillin-clavulanic acid, piperacillin-tazobactam and ticarcillin-clavulanic acid, respectively). Sulbactam was the only betalactamase inhibitor which showed good in vitro activity, with a low MIC(50) and MIC(90) (8 and 32 mg/l, respectively) similar to ampicillin/sulbactam (2 and 16 mg/l, respectively). Sulbactam could be a good therapeutic alternative for the treatment of multiresistant A. baumannii infections.

Our results suggest that parathion induces a stimulating effect on PAH uptake. The simultaneous presence of cadmium does not modify this effect. The simultaneous presence of cadmium and parathion produced an hepatotoxic effect in the rat.