[Case fatality of COVID-19 in patients with neurodegenerative dementia]. / Análisis de letalidad por COVID-19 en pacientes con demencia neurodegenerativa.

Introduction: The elderly population is the group most threatened by COVID-19, with the highest mortality rates. This study aims to analyse the case fatality of COVID-19 in a cohort of patients with degenerative dementia. Methods: We conducted a descriptive case-control study of a sample of patients diagnosed with primary neurodegenerative dementia. Results: Twenty-four of the 88 patients with COVID-19 included in the study died: 10/23 (43.4%) patients diagnosed with dementia and 14/65 (21.5%) controls; this difference was statistically significant. Discussion: Our results suggest that case fatality of COVID-19 is significantly higher among patients with primary degenerative dementia than in other patients with similar mean ages and comorbidities.

Barcelona consensus on supermicrosurgery.

The popularity of supermicrosurgery has increased dramatically over the past few years, but the lack of agreement regarding the name of the technique and its applications has caused misunderstandings among microsurgeons when trying to communicate and compare surgical procedures. We report the consensus reached on the name used to refer to supermicrosurgery techniques following the First European Conference on Supramicrosurgery held in Barcelona (Spain) on March 4-5, 2010. Present applications, advantages, and disadvantages of supermicrosurgery are discussed. It was agreed that supermicrosurgery was the most accurate name to reflect the essence of this extremely delicate technique. According to Koshima, supermicrosurgery is a technique of microneurovascular anastomosis for vessels of 0.3 to 0.8 mm and single nerve fascicles. The range of applications for this technique has increased rapidly and now includes lymphedema treatment, nerve reconstruction, replantation and reconstruction of amputated fingertips, microsurgical flap salvage, and new possibilities for free tissue transfer. Supermicrosurgery is a remarkably useful reconstructive tool that involves a great deal of skill and has a steep learning curve for the microsurgeon to master. Although it is currently performed by only a minority of microsurgeons, we consider it will be incorporated into conventional microsurgery in the near future.

miRNA-7 and miRNA-324-5p regulate alpha9-Integrin expression and exert anti-oncogenic effects in rhabdomyosarcoma.

The prognosis of patients with metastatic rhabdomyosarcoma (RMS), the most common type of soft tissue sarcoma in children, is poor and no strategies have been identified to improve their dismal prognosis. Alpha-9 integrin (ITGA9) plays a particularly crucial role in cancer progression and invasiveness. Despite the consensus on the remarkable pro-oncogenic potential of this protein, the miRNA-mediated regulation of ITGA9 has barely been studied to date. In the present study, miR-7 and miR-324-5p were selected as the best candidates after a screening to find ITGA9 regulators, and their effects on cell proliferation and invasion in RMS are described and characterized for the first time. Interestingly, the overexpression of both miRNA produced a clear impairment of cell proliferation, while miR-7 also induced a remarkable drop in cell invasion. Furthermore, the stable overexpression of both miRNA was found to reduce tumor growth in orthotopic RMS models and miR-7 was able to impair metastatic lung colonization. Consequently, we conclude that miR-7 and miR-324-5p show anti-oncogenic and anti-metastatic potential, thereby opening up the possibility of being used as novel therapeutic tools to avoid RMS progression.

Case fatality of COVID-19 in patients with neurodegenerative dementia. / Análisis de letalidad por COVID-19 en pacientes con demencia neurodegenerativa.

INTRODUCTION: The elderly population is the group most threatened by COVID-19, with the highest mortality rates. This study aims to analyse the case fatality of COVID-19 in a cohort of patients with degenerative dementia. METHODS: We conducted a descriptive case-control study of a sample of patients diagnosed with primary neurodegenerative dementia. RESULTS: Twenty-four of the 88 patients with COVID-19 included in the study died: 10/23 (43.4%) patients diagnosed with dementia and 14/65 (21.5%) controls; this difference was statistically significant. DISCUSSION: Our results suggest that case fatality of COVID-19 is significantly higher among patients with primary degenerative dementia than in other patients with similar mean ages and comorbidities.

Pre-clinical and clinical evaluation of nuclear tracers for the molecular imaging of vulnerable atherosclerosis: an overview.

Cardiovascular diseases (CVD) are the leading cause of mortality worldwide. Despite major advances in the treatment of CVD, a high proportion of CVD victims die suddenly while being apparently healthy, the great majority of these accidents being due to the rupture or erosion of a vulnerable coronary atherosclerotic plaque. A non-invasive imaging methodology allowing the early detection of vulnerable atherosclerotic plaques in selected individuals prior to the occurrence of any symptom would therefore be of great public health benefit. Nuclear imaging could allow the identification of vulnerable patients by non-invasive in vivo scintigraphic imaging following administration of a radiolabeled tracer. The purpose of this review is to provide an overview of radiotracers that have been recently evaluated for the detection of vulnerable plaques together with the biological rationale that initiated their development. Radiotracers targeted at the inflammatory process seem particularly relevant and promising. Recently, macrophage targeting allowed the experimental in vivo detection of atherosclerosis using either SPECT or PET. A few tracers have also been evaluated clinically. Targeting of apoptosis and macrophage metabolism both allowed the imaging of vulnerable plaques in carotid vessels of patients. However, nuclear imaging of vulnerable plaques at the level of coronary arteries remains challenging, mostly because of their small size and their vicinity with unbound circulating tracer. The experimental and pilot clinical studies reviewed in the present paper represent a fundamental step prior to the evaluation of the efficacy of any selected tracer for the early, non-invasive detection of vulnerable patients.

Relationship between GSTP1 Ile(105)Val polymorphism and docetaxel-induced peripheral neuropathy: clinical evidence of a role of oxidative stress in taxane toxicity.

BACKGROUND: Glutathione-S-transferases (GST) regulate the cellular response to oxidative stress. We previously highlighted the importance of oxidative stress in taxane toxicity and therefore investigated the relationship between the GST isoforms M1, T1 and P1 gene polymorphisms and docetaxel (Taxotere)-induced peripheral neuropathy (DIPN). PATIENTS AND METHODS: The GSTM1 (null), GSTT1 (null) and GSTP1 (Ile(105)Val and Ala(114)Val) polymorphisms were determined in a cohort of cancer patients treated with docetaxel and entered in a clinical trial database. The relationship between GST polymorphisms and grade > or = 2 DIPN as primary end point was studied. RESULTS: Fifty-eight patients (median age 61 years) received a total of 261 cycles of docetaxel given as single agent. Patients with GSTP1 (105)Ile/(105)Ile genotype had a higher risk of developing a grade > or = 2 DIPN than did those with other GSTP1 genotypes (8 of 27 versus 2 of 31, respectively, odds ratio 6.11; 95% confidence interval 1.17-31.94; P = 0.03). In multivariate analysis, grade > or = 2 DIPN was strongly correlated with GSTP1 (105)Ile/(105)Ile genotype (P = 0.01) and the number of cycles (P = 0.03). CONCLUSION: We found a significant correlation between GSTP1 (105)Ile/(105)Ile genotype and the development of grade > or = 2 DIPN. This finding strongly suggests a role of oxidative stress in the pathophysiology of DIPN.

Preoperative planning of lymphaticovenous anastomosis: The use of magnetic resonance lymphangiography as a complement to indocyanine green lymphography.

BACKGROUND: Lymphaticovenous anastomosis (LVA) is a surgical treatment for lymphedema that requires identification and mapping of functional lymphatic channels. This technique was performed blindly for years because of the lack of suitable methods of study. Progress in imaging techniques and the introduction of Indocyanine green lymphography (ICG-L) represented a significant advancement in lymphedema management. Magnetic resonance lymphangiography (MRL) has also helped improve knowledge about lymphedema anatomy and pathophysiology. We now present our protocol based on both ICG-L and MRL for optimal LVA preoperative planning. METHODS: A prospective study between April 2010 and June 2015 was conducted in 82 patients (77 females, mean age 45.5 years) with stage I (9.8%), II (73.2%), and III (17.0%) lymphedema. All patients underwent lymphedema surgical treatment with LVA. Surgery was planned based on preoperative information from ICG- L and MRL. RESULTS: We obtained a mean of 6.87 lymphatic locations per extremity from MRL and selected a mean of 4.04 for LVA. When MRL data coincided with ICG-L data, we found a functional lymphatic vessel in 96.9% of cases and performed LVA successfully in 91.4%. CONCLUSIONS: ICG-L and MRL are noninvasive techniques that provide images of the lymphatic system with sufficient temporal and spatial resolution to depict functional lymphatic vessels. Such knowledge is essential for preoperative planning of LVA microsurgery. We present our protocol for the approach of surgical treatment of lymphedema. This protocol represents a step forward in unifying patient selection criteria and achieving safe, effective, and rational surgery.

Emerging therapeutic options for breast cancer chemotherapy during pregnancy.

BACKGROUND: Breast cancer is the commonest solid tumor observed during pregnancy. Anthracycline-based chemotherapy is feasible during the 2nd and 3rd trimesters of pregnancy, but few data are available on recent and highly active drugs taxanes, vinorelbine and anti-HER-2 agents in this setting. PATIENTS AND METHODS: We carried out a comprehensive review of reports documenting the use of taxanes, vinorelbine, trastuzumab and lapatinib during pregnancy in the English literature, in order to evaluate their safety profile in pregnant patients. RESULTS: Twenty-four pregnancies are described, in which no grade 3-4 maternal toxicity nor malformation in the offspring was reported. Whereas only one report studied the pharmacokinetics of paclitaxel (Taxol) during pregnancy, several preclinical reports indicate that the placental P-glycoprotein could prevent the transplacental transfer of taxanes and vinorelbine. The use of trastuzumab was associated with the occurrence of anhydramnios in three of six cases. CONCLUSION: The administration of recent drugs taxanes and vinorelbine seems feasible during the 2nd and 3rd trimesters of pregnancy, with a favorable toxicity profile. In contrast, anti-HER-2 agents may obscure the normal development of the fetal kidney, and should be avoided during pregnancy.

Regulation of the proapoptotic BH3-only protein BIM by glucocorticoids, survival signals and proteasome in chronic lymphocytic leukemia cells.

Glucocorticoids induce apoptosis in chronic lymphocytic leukemia (CLL) cells through a caspase-dependent mechanism. However, their mechanism of action remains unknown. We have studied the regulation of the proapoptotic BH3-only Bcl-2 interacting mediator of cell death (BIM) in CLL cells. We demonstrate that glucocorticoids upregulate BIM at protein and mRNA levels. We have investigated the ability of different survival signals, such as 12-O-tetradecanoylphorbol 13-acetate (TPA), stromal cell-derived factor-1alpha (SDF-1alpha), interleukin 4 (IL-4) and B-cell receptor (BCR) activation, to influence the levels of BIM and its induction by glucocorticoids. TPA downregulates BIM(EL) by extracellular signal-regulated kinase (ERK)-mediated BIM phosphorylation and further proteasome-mediated degradation. However, SDF-1alpha and BCR activation induce transient BIM phosphorylation, without protein degradation. Proteasome inhibitors do not modify the levels of BIM with respect to untreated cells. However, they induce apoptosis and inhibit TPA-induced BIM(EL) degradation, leading to its accumulation. In conclusion, the results implicate BIM in glucocorticoid-induced apoptosis in CLL cells. BIM(EL) phosphorylation through the ERK pathway targets the protein for proteasomal degradation.

[Drug resistance in partial epilepsy: epidemiology, mechanisms, pharmacogenetics and therapeutical aspects]. / La pharmacorésistance des épilepsies partielles : épidémiologie, mécanismes, pharmacogénétique, perspectives thérapeutiques.

It has been established that 20-30% of epilepsies are not controlled by antiepileptic drugs. Drug resistance is associated with several major problems, including prognosis, cognitive function, behavior, mortality, cost and quality of life. Apart from classic risk factors for drug resistance, such as neurological, psychiatric, imaging, EEG abnormalities, a high frequency of seizures before medical therapy and complex febrile convulsions, the potential role of multidrug transporters as well as their genetic control and the altered sensitivity of neuronal drug receptors has gained growing attention. In the future, pharmaceutical engineering may bypass these factors. To a certain extent, drug resistance may develop progressively in a neurobiological process and the control of this process could limit its development.

Functional antagonism between YY1 and the serum response factor.

The rapid, transient induction of the c-fos proto-oncogene by serum growth factors is mediated by the serum response element (SRE). The SRE shares homology with the muscle regulatory element (MRE) of the skeletal alpha-actin promoter. It is not known how these elements respond to proliferative and cell-type-specific signals, but the response appears to involve the binding of the serum response factor (SRF) and other proteins. Here, we report that YY1, a multifunctional transcription factor, binds to SRE and MRE sequences in vitro. The methylation interference footprint of YY1 overlaps with that of the SRF, and YY1 competes with the SRF for binding to these DNA elements. Overexpression of YY1 repressed serum-inducible and basal expression from the c-fos promoter and repressed basal expression from the skeletal alpha-actin promoter. YY1 also repressed expression from the individual SRE and MRE sequences upstream from a TATA element. Unlike that of YY1, SRF overexpression alone did not influence the transcriptional activity of the target sequence, but SRF overexpression could reverse YY1-mediated trans repression. These data suggest that YY1 and the SRF have antagonistic functions in vivo.

[Ibuprofen in childhood: evidence-based review of efficacy and safety]. / Quel niveau de preuve de l'efficacité et de la sécurité de l'ibuprofène dans ses indications pédiatriques?

Ibuprofen is the non-steroidal anti-inflammatory drug most prescribed for the treatment of fever and moderate pain in childhood. Its analgesic and antipyretic efficacy is now well documented: at equal doses ibuprofen appears slightly more effective than acetaminophen in the treatment of fever and is equivalent for analgesia. However, adverse effects should be taken into account in the choice between ibuprofen and acetaminophen. Lot of studies (case reports, cohort studies, case-control studies and one multicenter double-blind randomized control trial) have reported ibuprofen adverse effects at therapeutics doses. These data suggest there is an increased risk of invasive group A streptococcal infection after chickenpox and of acute renal failure in case of hypovolemia after a treatment by ibuprofen. Gastroduodenal and hemorrhagic adverse events could also happen, but the causality with ibuprofen is not demonstrated. Therefore, ibuprofen is not recommended for the treatment of fever or moderate pain during chickenpox or during a disease with a risk of dehydration, until other pharmacoepidemiology studies more accurately quantify the risk of adverse events of ibuprofen in children.

Pharmacokinetics and toxicity of docetaxel: role of CYP3A, MDR1, and GST polymorphisms.

OBJECTIVE: Patients initiating docetaxel chemotherapy were genotyped for CYP3A4, CYP3A5, MDR1, GSTM1, GSTT1, GSTM3, and GSTP1 to identify variability factors of docetaxel pharmacokinetics and toxicity. METHODS: Genotyping was performed by direct sequencing (CYP3A4), real-time polymerase chain reaction (CYP3A5), and polymerase chain reaction-restriction fragment length polymorphism (MDR1 and GST). The clearance and area under the curve of docetaxel were calculated by use of a Bayesian approach. Absolute neutrophil count was recorded twice weekly. RESULTS: With regard to the pharmacokinetic analysis, 58 patients were included. CYP3A4*1B carriers (*1A/*1B, n=4), who are also CYP3A5*1/*3 carriers, had a significantly higher clearance and lower dose-normalized area under the curve of docetaxel than those with the wild genotype (*1A/*1A, n=53): 55.2+/-13.5 L/h versus 37.3+/-11.7 L/h (P=.01) and 31.4+/-6.2 (microg . h/L)/(mg/m(2)) versus 52.7+/-18.2 (microg . h/L)/(mg/m(2)) (P=.005), respectively. No influence of MDR1 was evidenced. With regard to the pharmacodynamic analysis, febrile neutropenia occurred more frequently in GSTP1*A/*B carriers (31.6% versus 3.7% in *A/*A carriers and 0% in *A/*C, *B/*B, and *B/*C carriers) (P=.037). Grade 3 neutropenia occurred more frequently in 3435TT MDR1 genotype carriers: TT, 100%; CT, 77.3%; and CC, 54.5% (P=.046). No influence of GSTM1, GSTT1, or GSTM3 polymorphisms was evidenced on docetaxel toxicity. CONCLUSIONS: Patients carrying the CYP3A*1B allele may have enhanced docetaxel clearance and may be underexposed, whereas those carrying GSTP1*A/*B and 3435TT genotypes may have excessive hematologic toxicity. Further studies are warranted to determine the usefulness of genotyping before docetaxel treatment.

Characterization of protein carboxyl-O-methyltransferase in the spontaneous in vivo murine C-1300 neuroblastoma.

Protein carboxy-O-methyltransferase (PCM) activity was determined in subcellular fractions prepared from C-1300 neuroblastoma tumors following transplantation and growth in male A/J mice. Fractions were obtained by differential centrifugation, and PCM activity was determined in all fractions in the presence (+gel) and absence (-gel) of an exogenous substrate, gelatin. Sixty % of the PCM activity in the absence of exogenous substrate (-gel) was contained in the crude 800 X g particulate fraction, whereas 80% of the PCM activity in the presence of gelatin (+gel) was present in the postmicrosomal (100,000 X g) supernatant. The latter fraction also contained the highest specific activity of PCM. A Km of 3.2 X 10(-6) M and a Vmax of 5.3 pmol per mg protein per min were obtained for PCM activity (+gel) in the high-speed supernatant. Cytoplasmic PCM was highly sensitive to competitive inhibition by S-adenosylhomocysteine and the S-adenosyl-homocysteine analogs sinefungin and A-9145C with Ki values of 0.64, 0.47, and 0.05 microM, respectively. These data demonstrate that PCM present in murine neuroblastoma has characteristics similar to those of PCM isolated from other adrenergic and neuronal tissues. S-Adenosyl-homocysteine analogs may be useful probes for studying the role of PCM as a modulator of cell function in neurogenic and neoplastic tissues.

Dynamic changes of depolarizing GABA in a computational model of epileptogenic brain: Insight for Dravet syndrome.

Abnormal reemergence of depolarizing GABAA current during postnatal brain maturation may play a major role in paediatric epilepsies, Dravet syndrome (DS) being among the most severe. To study the impact of depolarizing GABA onto distinct patterns of EEG activity, we extended a neural mass model as follows: one sub-population of pyramidal cells was added as well as two sub-populations of interacting interneurons, perisomatic-projecting interneurons (basket-like) with fast synaptic kinetics GABAA (fast, I1) and dendritic-projecting interneurons with slow synaptic kinetics GABAA (slow, I2). Basket-like cells were interconnected to reproduce mutual inhibition mechanisms (I1➔I1). The firing rate of interneurons was adapted to mimic the genetic alteration of voltage gated sodium channels found in DS patients, SCN1A(+/-). We implemented the "dynamic depolarizing GABAA" mediated post-synaptic potential in the model, as some studies reported that the chloride reversal potential can switch from negative to more positive value depending on interneuron activity. The "shunting inhibition" promoted by GABAA receptor activation was also implemented. We found that increasing the proportion of depolarizing GABAA mediated IPSP (I1➔I1 and I1➔P) only (i.e., other parameters left unchanged) was sufficient to sequentially switch the EEG activity from background to (1) interictal isolated polymorphic epileptic spikes, (2) fast onset activity, (3) seizure like activity and (4) seizure termination. The interictal and ictal EEG patterns observed in 4 DS patients were reproduced by the model via tuning the amount of depolarizing GABAA postsynaptic potential. Finally, we implemented the modes of action of benzodiazepines and stiripentol, two drugs recommended in DS. Both drugs blocked seizure-like activity, partially and dose-dependently when applied separately, completely and with a synergic effect when combined, as has been observed in DS patients. This computational modeling study constitutes an innovative approach to better define the role of depolarizing GABA in infantile onset epilepsy and opens the way for new therapeutic hypotheses, especially in Dravet syndrome.

Purification of 2,3-bisphosphoglycerate synthase-phosphatase from pig skeletal muscle.

Two enzymes which possess 2,3-bisphosphoglycerate synthase, 2,3-bisphosphoglycerate phosphatase and phosphoglycerate mutase activities have been purified from pig skeletal muscle. One of the enzymes corresponds to type M phosphoglycerate mutase. The other enzyme shows properties similar to those of the 2,3-bisphosphoglycerate synthase-phosphatase present in mammalian erythrocytes. The erythrocyte and the muscle enzyme possess the same molecular (56 000) and subunit (27 000) weights. The synthase, phosphatase and mutase activity ratio is similar in both enzymes, and they are affected by the same inhibitor (glycerate 3-P) and activators (glycolate 2-P, pyrophosphate, sulfite and bisulfite).

Kinetic properties and essential amino acids of the 2,3-bisphosphoglycerate synthase-phosphatase from pig skeletal muscle.

Histidine, arginine and lysine residues are essential for the multifunctional 2,3-bisphosphoglycerate synthase-phosphatase purified from pig skeletal muscle. The synthase, phosphatase and phosphoglycerate mutase activities of the enzyme are concurrently lost upon treatment with diethylpyrocarbonate, phenylglyoxal and trinitrobenzenesulfonate. The phosphatase activity shows hyperbolic kinetics. In contrast, the synthase activity shows a nonhyperbolic pattern which fits to a second-degree polynomial. The Km values for glycerate 1,3-P2, glycerate 3-P and glycerate 2,3-P2 are similar to those of the enzyme from mammalian erythrocytes.

Effect of vanadate on the formation and stability of the phosphoenzyme forms of 2,3-bisphosphoglycerate-dependent phosphoglycerate mutase and of phosphoglucomutase.

2,3-Bisphosphoglycerate-dependent phosphoglycerate mutase (2,3-bisphospho-D-glycerate:2-phospho-D-glycerate phosphotransferase, EC 2.7.5.3) and phosphoglucomutase (alpha-D-glucose-1,6-bisphosphate:alpha -D-glucose-1-phosphate phosphotransferase, EC 2.7.5.1), which are markedly inhibited by vanadate, possess a ping-pong mechanism involving an intermediate phosphoenzyme. The formation and the stability of these phosphoenzymes have been examined spectrophotometrically in the absence of vanadate. Vanadate does not inhibit the phosphorylation of either mutase by its cofactor. The instability of the phosphoenzyme form of phosphoglycerate mutase increases in the presence of vanadate, but the stability of the phosphorylated phosphoglucomutase is not affected.

Lack of glucagon response to hypoglycemia in type I diabetics after long-term optimal therapy with a continuous subcutaneous insulin infusion pump.

Counterregulatory hormonal responses were studied in six patients after 4-18 mo treatment with a continuous subcutaneous insulin infusion pump. In response to insulin-induced hypoglycemia, significant increases in epinephrine, norepinephrine, cortisol, and growth hormone were measured in all subjects, while in five of the six patients glucagon levels did not increase at all. The persistence of these abnormal glucagon responses despite long-term optimal glucose control suggests that they are not due to hyperglycemia per se, but are due rather to a specific alpha cell abnormality. The high incidence of asymptomatic hypoglycemia in these patients emphasizes that caution is necessary to avoid serious hypoglycemia when striving for near-normal glucose control with insulin infusion pump therapy.

Prodigiosin induces apoptosis of B and T cells from B-cell chronic lymphocytic leukemia.

We have previously reported that prodigiosin (2-methyl-3-pentyl-6-methoxyprodigiosene) induces apoptosis in human hematopoietic cancer cell lines with no marked toxicity in nonmalignant cell lines. In this study, we demonstrate that prodigiosin induces apoptosis of B-cell chronic lymphocytic leukemia (B-CLL) cells (n=32 patients). The dose-response for the cytotoxic effect of prodigiosin was analyzed in cells from 12 patients showing an IC(50) of 116+/-25 nM. Prodigiosin induced apoptosis of B-CLL cells through caspase activation. We also analyzed the cytotoxic effect of prodigiosin in T cells from B-CLL samples and no differences were observed with respect to leukemia cells. This is the first report showing that prodigiosin induces apoptosis in human primary cancer cells.