Tocilizumab in COVID-19 interstitial pneumonia.

BACKGROUND: Published reports on tocilizumab in COVID-19 pneumonitis show conflicting results due to weak designs or heterogeneity in critical methodological issues. METHODS: This open-label trial, structured according to Simon's optimal design, aims to identify factors predicting which patients could benefit from anti-IL6 strategies and to enhance the design of unequivocal and reliable future randomized trials. A total of 46 patients with COVID-19 pneumonia needing of oxygen therapy to maintain SO2 > 93% and with recent worsening of lung function received a single infusion of tocilizumab. Clinical and biological markers were measured to test their predictive values. Primary end point was early and sustained clinical response. RESULTS: Twenty-one patients fulfilled pre-defined response criteria. Lower levels of IL-6 at 24 h after tocilizumab infusion (P = 0.049) and higher baseline values of PaO2/FiO2 (P = 0.008) predicted a favourable response. CONCLUSIONS: Objective clinical response rate overcame the pre-defined threshold of 30%. Efficacy of tocilizumab to improve respiratory function in patients selected according to our inclusion criteria warrants investigations in randomized trials.

Prediction of heterosis in rice based on divergence of morphological and molecular markers.

Identifying the best performing hybrid without a field test was essential to save resources and time. In this study, the genetic divergence was estimated using morphological and expressed sequence tag (EST)-derived simple sequence repeats (SSR) markers. Cluster analysis showed that APMS6A and RPHR 1005 belong to groups I and II, respectively, and the hybrid combination recorded the highest mean grain yield of 32.25 g among generated 40 F1s with standard heterosis of 8.4% over hybrid check, KRH2. The coefficient of marker polymorphism (CMP) value was calculated based on EST-SSRmarkers; it ranged from 0.40 to 0.80, and a higher CMP value of 0.80 was obtained for the parental combination APMS6A × RPHR1005. We predicted heterosis for 40 F1s based on correlation between CMP and standard heterosis in different traits with standard varietal and hybrid checks indicating positive correlation and significant value for grain yield per plant (r = 0.58**),productivity per day (r = 0.54**), productive tillers (r = 0.34*) and panicle weight (r = 0.42**). This study revealed that the relationship of molecular marker heterozygosity, along with the combining ability, high mean value of different traits,grouping of parental lines based on morphological and molecular characterization is helpful to identify heterotic patterns in rice.

Simplified hybrid algorithms for pressure wire interrogation exploiting advantages of a baseline and contrast Pd/Pa ratio indexes to predict stenosis significance: Insight from the SPARE multicenter prospective study.

BACKGROUND: Simplification of functional stenosis assessment with pressure guidewires may facilitate adoption of physiology-guided revascularization. An important step in this regard is the avoidance of hyperemic agents, required for fractional flow reserve (FFR) calculation. We evaluate the merits of a hybrid algorithms that combines the translesional pressure ratio (Pd/Pa) obtained at rest, after contrast medium injection (cFFR) and after adenosine administration (FFR). METHODS AND RESULTS: Eighty-six patients with 108 de novo intermediate coronary stenoses were included in this prospective, multicenter study. Using prespecified cut-off values that correctly identified stenosis with a 95% of agreement (<0.89 and >0.96 for Pd/Pa; <0.84 and > 0.87 for cFFR) we tested the efficiency of three different multi-step strategies combining the three indices to classify stenosis severity, using FFR-only measurement as reference. All three different hybrid algorithms (Pd/Pa-FFR; cFFR-FFR; Pd/Pa-cFFR-FFR) have more than 95% of agreement with FFR. Yet, the novel Pd/Pa-cFFR-FFR hybrid strategy demonstrated the best performance, avoiding the need of adenosine and medium contrast in 90% and 48% of cases, respectively. CONCLUSIONS: A hybrid Pd/Pa-cFFR-FFR decision-making algorithm could be an alternative and valuable strategy to increase the adoption of a physiology-guided PCI using conventional pressure guidewires and consoles.

Insulin/glucose induces natriuretic peptide clearance receptor in human adipocytes: a metabolic link with the cardiac natriuretic pathway.

Cardiac natriuretic peptides (NP) are involved in cardiorenal regulation and in lipolysis. The NP activity is largely dependent on the ratio between the signaling receptor NPRA and the clearance receptor NPRC. Lipolysis increases when NPRC is reduced by starving or very-low-calorie diet. On the contrary, insulin is an antilipolytic hormone that increases sodium retention, suggesting a possible functional link with NP. We examined the insulin-mediated regulation of NP receptors in differentiated human adipocytes and tested the association of NP receptor expression in visceral adipose tissue (VAT) with metabolic profiles of patients undergoing renal surgery. Differentiated human adipocytes from VAT and Simpson-Golabi-Behmel Syndrome (SGBS) adipocyte cell line were treated with insulin in the presence of high-glucose or low-glucose media to study NP receptors and insulin/glucose-regulated pathways. Fasting blood samples and VAT samples were taken from patients on the day of renal surgery. We observed a potent insulin-mediated and glucose-dependent upregulation of NPRC, through the phosphatidylinositol 3-kinase pathway, associated with lower lipolysis in differentiated adipocytes. No effect was observed on NPRA. Low-glucose medium, used to simulate in vivo starving conditions, hampered the insulin effect on NPRC through modulation of insulin/glucose-regulated pathways, allowing atrial natriuretic peptide to induce lipolysis and thermogenic genes. An expression ratio in favor of NPRC in adipose tissue was associated with higher fasting insulinemia, HOMA-IR, and atherogenic lipid levels. Insulin/glucose-dependent NPRC induction in adipocytes might be a key factor linking hyperinsulinemia, metabolic syndrome, and higher blood pressure by reducing NP effects on adipocytes.

Adsorption of bentazone herbicide onto mesoporous silica: application to environmental water purification.

Within the last few years, the presence of bentazone herbicide has been observed in many water resources. For the first time, removal of bentazone using mesoporous silica was investigated revealing reversible adsorption. The adsorption isotherm was well described using the Freundlich model. The affinity towards bentazone is strongly affected by pH in the range of 2-7, decreasing with the increase of the pH, becoming negligible at the neutrality. Regeneration of the adsorbent was possible, and a recovery as high as 70 % was obtained using CH3OH-NaOH solution. Furthermore, appreciable recovery (47 %) was also obtained using water. Applications on the purification of lake water and wastewaters, both characterized by a significant organic carbon load, spiked with 2 mg L(-1) bentazone were tested, observing removal yields in the range of 61-73 %. Taking advantage of the fast adsorption kinetics observed, an in-flow purification treatment was set-up, with quantitative removal of bentazone from polluted water.

Perioperative fluid management in kidney transplantation: is volume overload still mandatory for graft function?

Kidney transplantation is now recognized as the treatment of choice for patients with chronic renal failure. Despite the extension of indications to patients suffering severe hypertension, ischemic heart disease, and chronic heart failure, the worldwide results are superb. However, perioperative cardiac complications occur in 6% to 10% of transplanted patients. Aggressive intraoperative volume expansion is still recommended to maximize graft functional recovery (up to 30 mL/kg/h, central venous pressure [CVP] > 15 mm Hg), but patients with preexistent cardiac disease or poor myocardial function are exposed to the risk of fluid overload, acute respiratory failure, and prolonged ventilation. Among the last 90 cases performed at our institution, good functional recovery of the graft was present in 94% of the patients within 2 weeks, despite a much more conservative intraoperative hydration policy (crystalloids 2400 +/- 1000 mL, 15 mL/kg/h, CVP 7-9 mm Hg). Graft failure which occurred in 5 patients was significantly correlated only with donor age, while perioperative cardiovascular complications had been present in 9 cases (10%) who were coronary artery disease patients (55%). Age above 50 years was the only significant risk factor. Supranormal volume loading is probably not always warranted in kidney transplantation.

Design, synthesis, DNA binding, and biological evaluation of water-soluble hybrid molecules containing two pyrazole analogues of the alkylating cyclopropylpyrroloindole (CPI) subunit of the antitumor agent CC-1065 and polypyrrole minor groove binders.

We have synthesized and evaluated a series of hybrids, denoted 22--27, for in vitro cytotoxic activity against a variety of cancer cell lines. These hybrids represent a molecular combination of polypyrrole minor groove binders structurally related to the natural antitumor agent distamycin A and two pyrazole analogues of the left-hand segment called cyclopropylpyrroloindole (CPI) of the potent antitumor antibiotic (+)-CC-1065. These novel water-soluble hybrids have been designed to enhance the minor groove binding ability of alkylating units 20 and 21, which should increase their clinical appeal by overcoming the administration problems of (+)-CC-1065 derivatives. The DNA alkylating and cytotoxic activities against several tumor cell lines are reported and discussed in terms of their structural differences in relation to both the number of N-methyl pyrrole rings and the type of the alkylating unit tethered to the oligopeptidic frame. It may be noted that, in general, and especially for 22--24, the cytotoxicity of the hybrids was much greater than that of the alkylating units alone. In only one case, compound 27, did the hybrid have cytotoxic activity comparable to that of the alkylating unit alone against FM3A/0 cells. The broadest spectrum of activity and greatest potency was shown by the hybrid 24, in which the alkylating unit 20 and the deformyl distamycin A are tethered by 1-methyl 2,5-dicarbonyl pyrazole, with IC(50) values for the different tumor cell lines ranging from 7 to 71 nM. For compounds 22--24, the increase of the length of the pseudopeptidic moiety from one to three N-methylpyrrole residues led to an increased cytotoxicity. Among the hybrids tested for their inhibitory effects on the proliferation of murine L1210 leukemia cell line, compound 24 proved to be the most active (IC(50) = 7.4 nM), and in the sequencing gel experiments, it showed the strongest and most highly sequence-specific DNA alkylation activity. For compounds 22-24, the sequence specificity of DNA alkylation appears to be affected by the modification of the number of pyrrole rings, and the correlation between cytotoxicity and alkylation pattern suggests that 24 exerts its cytotoxicity through DNA sequence-specific alkylation of the third adenine located in the sequence 5'-ACAAAAATCG-3'. The two other hybrids 22 and 23 were slightly less active for tumor cell proliferation, with IC(50) values of 58 and 19 nM, respectively. With only one exception, none of the compounds was endowed with antiviral activity at subtoxic concentrations. Compound 24 inhibited the effect of vaccinia virus at a concentration that was significantly lower than its minimum cytotoxic concentration for the E(6)SM host cells. These compounds gave distinct patterns of alkylation in AT-rich sequences, indicating that minor structural changes produced marked alterations in sequence selectivity.

[Severe and prolonged post-dural puncture headache: from pathological basis to therapeutic role and correct timing for epidural blood patch]. / Cefalea da deliquorazione grave e protratta: dal riconoscimento del substrato organico al ruolo terapeutico e alla corretta temporizzazione del blood patch peridurale.

Believed to be due to unbalance between cerebrospinal fluid (CSF) production rate and its loss through the spinal dural puncture hole, post-dural puncture headache (PDPH) is often considered as a physiological syndrome, usually reversible without pathological sequelae after dural hole's closure. The clinical case here presented (incapacitating headache associated with diagnostic dural puncture in a leukaemic young female patient who underwent bone marrow transplantation) shows potentially fatal pathological sequelae following prolonged headache (untreated, due to the severe postransplant immunodeficiency and coagulopathy). The observed RMI lesions suggest interesting conclusions about the clinical indications and correct timing of autologous epidural blood patch (EBP). We also suggest the ways to preventing rebound intracranial hypertension following autologous epidural blood patch in patients suffering from incapacitating and prolonged headache.

Synthesis and biological effects of a new series of 2-amino-3-benzoylthiophenes as allosteric enhancers of A1-adenosine receptor.

New derivatives of PD 81,723, an allosteric enhancer of agonist binding to the A1-adenosine receptor, have been synthesized and evaluated in an intact cell assay. Compounds 3a, 3o and 3p appeared to be more potent than PD 81,723 and at a concentration of 0.1 microM caused significant reductions of cAMP content of CHO cells expressing the human A1-adenosine receptor. Compounds 4e and 4o appeared to be allosteric enhancers at a low concentration and antagonists at a higher concentration, whereas compounds 3c, 3g, 3s and 4l appeared to be weak antagonists that are also allosteric enhancers at the higher concentration of 10 microM.

Effects and mode of action of 1,4-naphthoquinones isolated from Calceolaria sessilis on tumoral cells and Trypanosoma parasites.

The naphthoquinones 2-hydroxy-3-(1,1-dimethylallyl)-1,4-naphthoquinone (CS-1), (-)-2,3,3-trimethyl-2-3-dihydronaphtho[2,3-b]furan-4,9-quinone (CS-3), and 2-acetoxy-3-(1,1-dimethylallyl)-1,4-naphthoquinone (CS-5) isolated from Calceolaria sessilis were tested against Trypanosoma cruzi epimastigotes, the TA3 tumor cell line and the methotrexate-resistant subline TA3-MTX-R. Naphthoquinone CS-3 was the most active; the 50% culture growth inhibition (I50) on T. cruzi (Tulahuén and LQ strain and DM28c clone) was at concentrations ranging from 2.1 to 5.2 mumolar. Also CS-3 inhibited TA3 and TA3-MTX-R culture growth with an I50 of 2.1 and 3.8 mumolar, respectively. Naphthoquinone CS-3 inhibited the respiration of the tumor cells by interfering with the electron transport at some point between NADH and ubiquinone. The respiration of T. cruzi was not inhibited by naphthoquinone CS-3. Naphthoquinone CS-3 produced a temporary increase of oxygen consumption in T. cruzi and tumor cells, suggesting the generation and participation of free radicals.

Inhibition of tumoral cell respiration and growth by nordihydroguaiaretic acid.

The effects of nordihydroguaiaretic acid (NDGA), best known as an inhibitor of lipoxygenase activities, on the culture growth, oxygen consumption, ATP level, viability, and redox state of some electron carriers of intact TA3 and 786A ascites tumor cells have been studied. NDGA inhibited the respiration rate of these two tumor cell lines by preventing electron flow through the respiratory chain. Consequently, ATP levels, cell viability and culture growth rates were decreased. NDGA did not noticeably inhibit electron flow through both cytochrome oxidase and ubiquinone-cytochrome b-c1 complex. Also, the presence of NDGA changed to redox state of NAD(P)+ to a more reduced level, and the redox states of ubiquinone, cytochrome b and cytochromes c + c1 changed to a more oxidized level. These observations suggest that the electron transport in the tumor mitochondria was inhibited by NDGA at the NADH-dehydrogenase-ubiquinone level (energy-conserving site 1). As a consequence, mitochondrial ATP synthesis would be interrupted. This event could be related to the cytotoxic effect of NDGA.

[The methodology and planning of an educational intervention in diabetic foot]. / Metodologia e programmazione di un intervento educativo sul piede diabetico.

Diabetic foot is considered one of the most threatening and disabling complications for a diabetic patient: lesions of the extremities can become so severe that the person may risk the amputation of the toe, foot or leg. Methodology of planning and implementation of an educational intervention for the prevention of the diabetic foot is presented in its various steps: from the identification of priorities and contents to the problems and difficulties encountered in the implementation of the program.

Diagnóstico pré-natal por punçäo da vilosidade coriônica / Prenatal diagnosis by chorionic villus sampling

Resultado de 129 punçöes da vilosidade coriônica para diagnóstico pré-natal no primeiro trimestre de gestaçäo. Os métodos de rotina par preparaçäo direta, preparaçäo de 24 horas e cultura de longa duraçäo, bem como as indicaçöes säo descritos detalhadamente. Tendo em vista a precocidade desse exame e alto sucesso de técnica (97,4%), pode-se concluir pela sua aceitabilidade como método complementar de diagnóstico genético pré-natal

Changes in visual evoked potentials in children on chronic dialysis treatment.

Visual evoked potentials (VEP) were recorded in 20 children undergoing dialysis for chronic renal failure. VEP before treatment (72 h after last dialysis) were pathological in 17 patients (85%); responses obtained 3 h after treatment were abnormal in only 6 cases (30%). Furthermore, all patients improved after treatment, except two who were unchanged. However, VEP recorded immediately after dialysis were worse in 4 of 7 patients than before treatment, probably as an effect of the dysequilibrium syndrome; they improved spontaneously afterwards. The acute changes caused by dialysis seem to be more evident in children than in adults. No correlations have been found between blood chemistry indexes and VEP modifications. Finally, VEP have proved to be more sensitive than EEG in identifying a central nervous system (CNS) dysfunction in these uremic patients.

[Ipsilateral masking of auditory evoked potentials: a method of studying multiple sclerosis]. / Le masking ipsilatéral des potentiels évoqués auditifs: un moyen d'exploration de la sclérose en plaques.

20 normal subjects and 39 patients with multiple sclerosis were the control and the test groups. Auditory brainstem potentials to 60 dB nHL, 11/s clicks, were recorded under ipsilateral broad-band noise masking at S/N ratio of + 60 dB (unmasked condition), + 20 dB, + 10 dB and 0 dB. In the control group the ABP were absent only in 1 subject at S/N = 0 dB. In the group of 16/39 patients with definite multiple sclerosis, 11 had no ABP at S/N = 0 dB, 6 at S/N = + 10 dB and 5 at S/N = + 20 dB. The ABP waveform per se, in the same subjects, was abnormal in 7 and doubtful in 5. These results are discussed in terms of sensitivity, specificity and efficiency of the test to be applied. The best predictive value is achieved by combining a strict morphological criterion with the results of the ipsilateral masking. Moreover, the ipsilateral masking test positive findings are equally distributed in the group of patients with and without signs of neurological involvement of the brainstem.

Ultra-sonografia no prognostico da maturidade fetal pulmonar. / Ultrasonography in the prognosis of fetal pulmonary maturity

Previos estudos sugerem uma relacao entre grau placentario e maturidade fetal pulmonar, permitindo eliminar-se a amniocentese Para avaliar os potenciais de riscos e os beneficios, um estudo retrospectivo foi realizado, comparando-se os graus placentarios, segundo Grannum e cols, e as analises de teste de Clements e a contagem de celulas orangiofilas no liquido amniotico.Cerca de 196 pacientes foram estudadas no periodo de 7/1/82 a 7/7/82 com base nos parametros ultra-sonograficos de maturidade fetal. Nenhum dos recem-nascidos desenvolveu sindrome de angustia respiratoria.Nos concluimos com estes dados preliminares que a associacao DBP maior ou igual a 9,3 cm e placenta de grau III e tao sensivel quanto o teste de Clements e a contagem de celulas orangiofilas no prognostico da maturidade pulmonar fetal, em nossa populacao estudada

Encefalocentese tansabdominal sob monitorizacao ultra-sonografica.Relato de um caso. / Transabdominal encephalocentesis under ultrasonic monitoring. A case report

Os autores relatam um caso de encefalocentese transabdominal sob monitorizacao ultra-sonografica de um feto hidrocefalico, morto, na 40a. semana de gravidez, prevenindo-se as distocias graves decorrentes desta malformacao