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Aims: To evaluate the impact of elexacaftor/tezacaftor/ivacaftor (ETI) therapy on Cystic Fibrosis Related Diabetes (CFRD) glycemic control and insulin treatment in patients with CFRD during clinical practice., Methods: We carried out a retrospective observational study of 23 adult patients with CFRD who started treatment with ETI. They had, at least, one F508del mutation. Data were collected before ETI initiation and 3, 6, and 12 months after., Results: Glycemic control measured by HbA1c significantly improved by 0.3 % (0.1-0.5) after 3 months of ETI therapy (p = 0.004) and kept this improvement during follow-up (p < 0.001). The proportion of patients needing multiple daily injections of insulin was reduced by 16 % (p = 0.023). Total daily insulin dose dropped by 0.12 (0.05-0.18) UI/kg/day (p < 0.001). Data derived from Flash Continuous Glucose Monitoring (CGM) for patients treated with insulin stayed unchanged after insulin reduction, except for a significant 8 % (0.3-15.6) increase in the Time In Tight Range (TITR) between 70 and 140 mg/dL (p = 0.043)., Conclusion: ETI therapy impacted CFRD in clinical practice reducing insulin needs and improving glycemic control measured by HbA1c and CGM. The improvements can be observed from the first 3 months of treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective: To assess the efficacy of calcium dobesilate on the quality-of-life (QoL) of patients with chronic venous disease (CVD)., Design: Randomised, parallel, double blind, placebo-controlled clinical trial., Methods: Patients were recruited from vascular surgery clinics and randomised to 500mg capsules of calcium dobesilate twice a day for 3 months or placebo. The primary outcome measure was 'QoL after 3 months' treatment measured by the specific Chronic Insufficiency Venous International Questionnaire (CIVIQ). Secondary outcomes were QoL at 12 months and assessment of the CVD signs and symptoms. The principal analysis was undertaken on the intention-to-treat (ITT) data., Results: Five hundred and nine patients were recruited (246 to calcium dobesilate and 263 to placebo). The analysis of the 'QoL after 3 months' showed no significant differences between groups (p=0.07). For secondary outcomes, oedema and symptoms of CVD, there were no significant differences between groups. In a multi-factorial analysis, the 'QoL at 12 months' was better in the calcium dobesilate group than in placebo group (p=0.02)., Conclusions: Treatment with calcium dobesilate was not found to be superior to placebo on the QoL of CVD patients. The sustained effect of calcium dobesilate observed after treatment should be confirmed in future studies.

Background: Chronic venous insufficiency (CVI) is a common condition caused by inadequate blood flow through the veins, usually in the lower limbs. It can result in considerable discomfort with symptoms such as pain, itchiness and tiredness in the legs. Sufferers may also experience swelling and ulcers. Phlebotonics are a class of drugs that are often used to treat CVI., Objectives: To assess the efficacy of oral or topical phlebotonics., Search Strategy: We searched the Cochrane Peripheral Vascular Diseases Group trials register (April 2005), the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 2, 2005), MEDLINE (January 1966 to April 2005), EMBASE (January 1980 to April 2005) and reference lists of articles. We also contacted pharmaceutical companies., Selection Criteria: Randomised, double blind, placebo-controlled trials (RCTs) assessing the efficacy of rutosides, hidrosmine, diosmine, calcium dobesilate, chromocarbe, centella asiatica, disodium flavodate, french maritime pine bark extract, grape seed extract and aminaftone in CVI patients at any stage of the disease., Data Collection and Analysis: Two reviewers independently extracted data and assessed trial quality. The effects of treatment were estimated by relative risk (RR) or by standardised mean differences (SMD) by applying a random effects statistical model. Sensitivity analyses were also performed., Main Results: Fifty-nine RCTs of oral phlebotonics were included, but only 44 trials involving 4413 participants contained quantifiable data for the efficacy analysis: 23 of rutosides, ten of hidrosmine and diosmine, six of calcium dobesilate, two of centella asiatica, one of french maritime pine bark extract, one of aminaftone and one of grape seed extract. No studies evaluating topical phlebotonics, chromocarbe, naftazone or disodium flavodate fulfilled the inclusion criteria. Outcomes included oedema, venous ulcers, trophic disorders, subjective symptoms (pain, cramps, restless legs, itching, heaviness, swelling and paraesthesias), global assessment measures and side effects. The results of many variables were heterogeneous. Phlebotonics showed some global benefit (i.e. oedema reduction) (relative risk 0.72, 95% confidence interval 0.65 to 0.81). The benefit for the remaining CVI signs and symptoms must be evaluated by phlebotonic group. There were no quantifiable data on quality of life., Authors' Conclusions: There is not enough evidence to globally support the efficacy of phlebotonics for chronic venous insufficiency. There is a suggestion of some efficacy of phlebotonics on oedema but this is of uncertain clinical relevance. Due to the limitations of current evidence, there is a need for further randomised, controlled clinical trials with greater attention paid to methodological quality.

Bronchial benign tumors comprise fewer than 4% of pulmonary neoplasms. Endobronchial lipoma is an extremely rare benign neoplasm accounting for only 0.1% to 0.5% of all lung tumors. Clinical symptoms of lipoma depend on the location of the tumor, the severity of bronchial obstruction, and the functional and anatomical effects on the parenchyma distal to the obstruction. Computed axial tomography usually reveals the adipose composition of the lipomatous tumor. We report the case of an 83-year-old man diagnosed with community-acquired pneumonia that led to complications: pleural empyema caused by Haemophilus influenzae infection and atelectasis of the right middle and lower lobes secondary to a lipomatous endobronchial obstruction. Removal of the bronchial lipoma was performed by laser resection.

The presence of cholinesterases (ChE) is reported in T. pseudospiralis excretion-secretion products (ESP) by spectrophotometric method, using acetylthiocholine (ATCI) and butyrilthiocholine (BTCI) as substrates. By inhibition assays, we found that T. pseudospiralis release both acetyl- and butiryl-cholinesterases (AchE and BchE, respectively). The sedimentation coefficientes of these enzymes were determined by sucrose density gradient. We studied the in vivo ChE secretion by immunoblot assays using AchE from Electrophorus (electric eel) and sera from normal or infected mice with T. pseudospiralis or T. spiralis. The presence of anti-AchE antibodies was only demonstrated in the sera from T. pseudospiralis infected mice. Moreover the in vivo secretion was corroborated by the high difference determinate between the ChE activity of the immuno complexes from T. pseudospiralis infected sera and the immunocomplexes from T. spiralis infected sera as well as normal sera. Finally, we analyzed the effect of the organophosphate Neguvón (metrifonate) on the ChE activity from the T. pseudospiralis ESP. The drug inhibits in part this activity. Moreover Neguvón (metrifonate) showed a high activity against the T. pseudospiralis viability.

The regulation of blood pressure during pregnancy involves several biological pathways. Candidate genes implicated in hypertensive diseases during pregnancy include those of the renin-angiotensin system and nitric oxide synthase (NOS). We evaluated blood pressure and metabolic characteristics during pregnancy in mutant mice. These included mice with a null mutation in the endothelial NOS (eNOS) gene (Nos3(-/-)), four copies of the angiotensinogen gene (Agt(2/2)), and mutations in both genes [four copies of Agt and heterozygous deficient for eNOS (Agt(2/2)Nos3(+/-)), four copies of Agt and homozygous deficient for eNOS (Agt(2/2)Nos3(-/-))]. Blood pressure measurements of nulliparous females from mutant strains were compared with two common laboratory strains C57Bl6/J and SV129 throughout their first pregnancy. Serum and urine analysis for the evaluation of renal and liver physiology were measured in the prepregnant state and during the third trimester of pregnancy. Throughout pregnancy blood pressures in all mutant strains were higher compared with controls. Agt(2/2)Nos3(-/-) showed the highest blood pressures and C57Bl6/J the lowest. Control mice, but not mutant mice, showed a second trimester decline in blood pressure. No immediate differences were noted regarding behavioral characteristics, renal or liver function parameters. Mice deficient for eNOS, mice with overexpression of Agt, and mice with mutations in both genes demonstrated higher blood pressure throughout pregnancy. There was no evidence of renal dysfunction, liver dysfunction, or hemolysis among any of the strains studied. We conclude that Nos3 and Agt are important genes in the regulation of blood pressure during pregnancy.

In the present study we report the presence of acetylcholinesterase activity and gamma-aminobutyric acid binding sites in crude extracts of Dicrocoelium dendriticum. This indirectly demonstrates the presence of acetylcholine and GABA. The presence of these neurotransmitters could indicate the existence of two systems implicated in the neurotransmission of the Digenea.

Cholinesterases were detected in protoscolices of Echinococcus granulosus spectrophotometrically and electrophoretically. To characterize these activities as acetylcholinesterases or pseudocholinesterases, BW284C51 and the organophosphate anthelmintic Neguvón were assayed as specific inhibitors of acetylcholinesterases, while Iso-OMPA was employed as specific inhibitor of pseudocholinesterases. We concluded that these cholinesterase (ChE) activities would be considered as possible targets in chemotherapy.

The purpose of this study was to evaluate the impact of angiotensinogen gene (Agt) deficiency on reproductive fitness in a rodent model. Mice with 0 (Agt(-/-)), 1 (Agt(-/+)), and 2 (Agt(+/+)) copies of Agt were bred according to the following schemes: 1) Agt(-/-) x Agt(-/-), 2) Agt(-/+) x Agt(-/+), 3) Agt(+/+) x Agt(+/+), and 4) Agt(+/+) female symbol x Agt(-/+) male symbol. There were 4 breeding pairs per scheme. Breedings were time mated. Mice and litters were weighed daily. Southern blotting was used for genotyping. We found that Agt(-/-) breeding pairs had fewer litters (2 [range 1-2] vs. 4 [range 3-5]; P = 0.01), fewer pups per litter (4 [range 1-7] vs. 6 [range 1-10]; P = 0.006), and longer interpregnancy intervals (43 days [range 31-44] vs. 35.5 days [range 22-58]; P = 0.04) compared to wild-type controls. The ratio of postcoital plugs to subsequent litters was 4.0 and 1.2 for Agt(-/-) and Agt(+/+) breedings, respectively (P = 0.03). Median maternal weights during all trimesters of pregnancy were significantly lower for Agt-deficient mice compared to wild-type controls. Among Agt(-/+) x Agt(-/+) breedings, the proportions of Agt(+/+) (n = 17), Agt(-/+) (n = 38), and Agt(-/-) (n = 4) offspring differed significantly from the expected 1:2:1 Mendelian inheritance pattern (P = 0.03). Neonatal survival among the offspring derived from the Agt(-/-) x Agt(-/-) breeding scheme was significantly reduced (P = 0. 001). We conclude that Agt deficiency is associated with an in utero lethal effect, decreased fertility, and impaired neonatal survival.

In the present report we study the proteolytic activity of the excretion-secretion and crude extracts of different stages of Trichinella spiralis (Owen, 1835) Railliet, 1895, (muscle-stage larvae, adult worms before and after mating, and newborn larvae) using natural substrates (structural and hematic mammalian proteins). The analysis of the results allow us to set up a certain stage-specificity, as well as an important relationship between the protease patterns throughout the parasite life cycle and how the parasite may overcome both mechanical and humoral barriers within the host. Muscle-stage larvae present a great activity against structural proteins (collagen), while newborn larvae and adult worms degrade principally hematic proteins (hemoglobin, fibrinogen and immunoglobulin G).

Objective: The walking test is a useful and objective method for evaluating the tolerance for exercise in patients with chronic bronchopulmonary diseases. Our objective was to check the reproducibility of this test and evaluate whether there are differences between tests of varying duration (2 and 6 minutes) in a group of patients with cystic fibrosis., Patients and Methods: We utilized the walking test on 29 patients who were in a stable phase and under care in the Cystic Fibrosis Unit of our hospital. Two tests were carried out, one of 2 minutes and the other of 6 minutes duration, both of which were repeated after a 15-minute interval., Results: The reproducibility of the walking test in this type of patient was very good and we found an excellent correlation between the two-minute test and the six-minute test. We did not observe a training effect when the test was repeated., Conclusions: The two minute walking test has a high reproducibility and we propose this test, because it is shorter and more comfortable for pediatric patients with cystic fibrosis, in order to evaluate the evolution, progressive deterioration of the of the patient and the response to different types of treatments.

Avenzoar has been credited as the author of the first description of inflammation of the pericardium in medical historical literature. Our study shows that although Avenzoar authored a study of diseases of the pericardium with emphasis on pathologies, his epistemological framework was similar to that used by Galen and Avicenna, authors who constituted the source of knowledge for Islamic medicine. We show that the approach used by Avenzoar appears to derive from the absence of anatomical and physiological information, and from a detailed description of the indications and treatments, which distinguish his work from earlier writings.

In order to understand the neuronal mechanisms involved in acute and chronic pain, we studied the thalamic and cortical control action, which allows the suppression of the neuronal responses to noxious stimulation. As an experimental pain model we used carrageenin injected in the paw of male Wistar rats. The tonic facilitatory cortical control on centralis lateralis thalamic nuclei (CL) activity is described at different times after carrageenin-produced inflammation. Simultaneous extracellular unit recordings were carried out at CL and medial prefrontal cortex (PCx) cells in anesthetized male Wistar rats. The PCx control was tested by blocking in a transient and reversible manner, using the cortical spreading depression (CSD). Carrageenin injection (1%; 0.2 ml) into the plantar surface of the right hind paw, and the influence of Lidocaine (2%; 0.2 ml) applied in the inflamed paw, was tested on unit activity in PCx and CL cells. Thalamic cells recorded in acute and subacute stages (24-72 h after carrageenin administration) were activated by tactile, light pressure and joint movement stimulation yielded before the injection. After carrageenin, the thalamic cells displayed spontaneous high frequency burst discharges, also presenting a progressive and significant increase (p < 0.001, ANOVA test) of their spontaneous firing rate when compared with control cell activity. Lidocaine reduced the enhanced activity induced by carrageenin in thalamic neurones (p < 0.001, Student t test). In PCx neurones were also recorded in acute and subacute stages. Cortical cells from acute and subacute group were activated by nociceptive and non-nociceptive stimulation. In acute stage, cortical cells increased their firing rate after carrageenin and we could not observe modifications upon their firing rate due to Lidocaine. The CSD blocked all cortical activity in acute and subacute stages. During the CSDs, overall thalamic activity was suppressed in neurones from acute (91%) and subacute (87%) stages. The blockage was observed when the propagated wave produced by CSD arrived into the medial prefrontal cortex. The CSD also suppressed the PCx and the CL noxious responses evoked by pressure in the receptive field. This study shows the tonic facilitatory control of the PCx upon intralaminar thalamic noxious responses, during acute and subacute stages of carrageenin produced-inflammation. In the literature, it has been proposed that the CL thalamic nuclei and the prefrontal cortex are involved in processing the affective component of pain. It may be possible to suppress the thalamic activity during chronic pain, using the transient and reversible blockage of CSD, giving rise to a reduction in the affective reactions to pain. This could also be a therapeutic alternative in chronic pain treatment.

We present a 69 years old male patient diagnosed of rheumatoid arthritis (RA) with signs of pleuropulmonar disease. The diagnose of RA was done of 49 years and since then treated with non steroid antiinflammatory drugs and during the acute phases of RA with steroid drugs. The pleural effusions showed an exudate with pseudochilothorax criteria with acid pH acid low glucose concentrations. The cytological study of the effusion demonstrated the presence of characteristic mononuclear cells.

The Saccharomyces cerevisiae MRS6 gene belongs to the same gene family as that responsible for the mammalian Rab escort protein (REP) and the Rab GDP dissociation inhibitor protein (GDI). Both REP and GDI are regulators of the Ras-related small G-proteins Rab/YPT1 which are involved in intracellular vesicular trafficking in yeast and in mammals. Here we characterize an antiserum directed against Mrs6p and show that it specifically inhibits the geranylation of the YPT1 protein in an in vitro assay. These findings provide direct evidence for the role of Mrs6p as the REP component of the yeast Rab geranylgeranyl transferase enzyme.

The 19 S promoter of cauliflower mosaic virus was analyzed in host protoplasts. In spite of its weakness, it contains a fully functional core promoter. It can be strongly activated by 35 S enhancer elements, even when these elements are located downstream of it, comparable to the situation in the viral genome. The 19 S promoter also contains an element that can strongly enhance expression from a heterologous core promoter. A plasmid expressing the same CAT ORF from two overlapping transcription units, a dicistronic one under control of the 35 S promoter and a monocistronic one under control of the 19 S promoter, was constructed. While in the absence of the virus ORF VI product (pVI, "transactivator") only low levels of CAT activity deriving from the 19 S promoter were observed, in the presence of this protein high levels of CAT activity derived from the 35 S unit were observed in addition. This suggests autocatalytic activation of pVI expression during virus infection.

The effect of anther-derived substances on pollen function was studied using pollen produced by in vitro culture of immature pollen of tobacco (Nicotiana tabacum L.) and petunia (Petunia hybrida). Addition of conditioned medium consisting of diffusates from in situ matured pollen strongly increased pollen germination frequency and pollen tube growth, as well as seed set after in situ pollination. Thin-layer chromatography and depletion of phenolic substances by Dowex treatment indicated that flavonols are present in the diffusate and may be the active compounds. When added to the germination medium, flavonols (quercetin, kaempferol, myricetin) but not other flavonoids strongly promoted pollen germination frequency and pollen tube growth in vitro. The best results were obtained at very low concentrations of the flavonols (0.15-1.5 mum), indicating a signaling function. The same compounds were also effective when added during pollen development in vitro.

We have detected a plant beta-glucuronidase activity, present in several tissues and organs of plant species belonging to different families. The fluorimetric beta-glucuronidase assay was used to partially characterize this activity in post-ribosomal supernatants of tobacco leaves. The tobacco activity is very stable at low temperatures, but quickly inactivated above 45 degrees C. It is relatively resistant to proteases and insensitive to -SH group reagents and to ionic conditions. It does not require, nor is it inhibited by, divalent cations. Although these properties are shared by the Escherichia coli beta-glucuronidase, the two activities can be distinguished by: (i) their different sensitivity to the specific inhibitor saccharic acid-1,4-lactone; (ii) their different thermal stability (iii) their different pH optima (5.0 for the plant activity and close to neutral for the bacterial enzyme). Therefore, under appropriate experimental conditions, it should be possible to assay the E. coli beta-glucuronidase in transgenic plants without interference from the endogenous plant activity.

A simple method is described for the purification of murine monoclonal antibodies of the IgM class. Ascites fluid was subjected to ammonium sulfate precipitation. The precipitate was redissolved and dialyzed and subsequently subjected to gel filtration chromatography on Ultrogel AcA22 and finally ion exchange chromatography on DEAE-Sepharose. The purity of the antibody was assessed by reducing SDS gel electrophoresis, and estimated to be greater than 85% pure after gel filtration, and greater than 95% pure after the ion exchange chromatography. The immuno-activity of the antibody was assessed throughout the purification scheme by the ability of the antibody to bind to immunogen immobilized to nitrocellulose. Approximately 50% antibody activity was recovered from this purification scheme after gel filtration, but only 10% of the initial activity could be recovered after ion exchange chromatography. This result with ion exchange chromatography underscores the lability of IgM antibodies to immobilization. Therefore, if the recovery of immunoreactive IgM antibody is a goal, purification schemes of IgM antibodies should avoid ion exchange or affinity chromatography.

In in vitro cultures, isolated microspores and pollen grains can undergo two fundamentally different types of development. In conditions that simulate the tapetum they continue normal gametophytic development to produce functional pollen. Under stress conditions, they are induced to form haploid embryos and plants (sporophytes). In vitro matured pollen is a "minimal" pollen that lacks substances to enhance its reproductive success. In vitro pollen maturation is presented as an experimental system to study pollen development and its interaction with the tapetum. For young binucleate pollen grains, a starvation treatment is sufficient to induce sporophytic development, for microspores a heat shock treatment is required. During the stress treatments, transcription of specific mRNAs is activated. An important aspect of embryogenic induction of binucleate pollen is the derepression of the cell cycle in the G1-arrested vegetative cell.