Surgical Treatment of Spinal Meningiomas in the Elderly (≥75 Years): Which Factors Affect the Neurological Outcome? An International Multicentric Study of 72 Cases

(1) Background: With the increasing life expectancy in the Western world, an increasing number of old patients presents with spinal meningioma. Considering the benign nature of these tumors, the functional outcome remains of great importance, since more people reach old age in general conditions of well-being and satisfactory autonomy. (2) Methods: We conducted an international multicenter retrospective study to investigate demographic, clinical and radiological data in a population of elderly patients (≥75 years of age) undergoing surgery for SM from January 2000 to December 2020 in four European referral centers. The aim was to identify prognostic and predictive factors for a good postoperative functional outcome. (3) Results: 72 patients were included in the study. Complete tumor resection (Simpson I or II) was achieved in 67 (95.7%) cases. Intraoperative complications were reported in 7 (9.9%) patients while postoperative complications were found in 12 (16.7%). An excellent general postoperative status (McCormick I and II) was achieved in 65.3%. Overall, surgical resection had a good impact on patients’ functional outcome (86.1% either showing an improvement or maintaining a good preoperative status). Uni- and multivariate analyses found that both age and preoperative modified McCormick independently correlated with relative outcome (coeff = −0.058, p = 0.0251; coeff = 0.597, p < 0.0001) and with postoperative status (coeff = 0.058, p = 0.02507; coeff = 0.402, p = 0.00027), respectively. (4) Conclusions: Age and preoperative modified McCormick were found to be independent prognostic factors. Nevertheless, advanced age (≥75), per se, did not seem to contraindicate surgery, even in those with severe preoperative neurological deficits. The functional results sustain the need for surgical resection of SM in the elderly

Dual-regulated lentiviral vector for gene therapy of X-linked chronic granulomatosis

Regulated transgene expression may improve the safety and efficacy of hematopoietic stem cell (HSC) gene therapy. Clinical trials for X-linked chronic granulomatous disease (X-CGD) employing gammaretroviral vectors were limited by insertional oncogenesis or lack of persistent engraftment. Our novel strategy, based on regulated lentiviral vectors (LV), targets gp91(phox) expression to the differentiated myeloid compartment while sparing HSC, to reduce the risk of genotoxicity and potential perturbation of reactive oxygen species levels. Targeting was obtained by a myeloid-specific promoter (MSP) and posttranscriptional, microRNA-mediated regulation. We optimized both components in human bone marrow (BM) HSC and their differentiated progeny in vitro and in a xenotransplantation model, and generated therapeutic gp91(phox) expressing LVs for CGD gene therapy. All vectors restored gp91(phox) expression and function in human X-CGD myeloid cell lines, primary monocytes, and differentiated myeloid cells. While unregulated LVs ectopically expressed gp91(phox) in CD34(+) cells, transcriptionally and posttranscriptionally regulated LVs substantially reduced this off-target expression. X-CGD mice transplanted with transduced HSC restored gp91(phox) expression, and MSP-driven vectors maintained regulation during BM development. Combining transcriptional (SP146.gp91-driven) and posttranscriptional (miR-126-restricted) targeting, we achieved high levels of myeloid-specific transgene expression, entirely sparing the CD34(+) HSC compartment. This dual-targeted LV construct represents a promising candidate for further clinical development

Point-of-Care Ultrasound for Tuberculosis Management in Sub-Saharan Africa-A Balanced SWOT Analysis.

Point-of-care ultrasound (POCUS) is an increasingly accessible skill, allowing for the decentralization of its use to non-specialist healthcare workers to guide routine clinical decision making. The advent of ultrasound-on-a-chip has transformed the technology into a portable mobile health device. Due to its high sensitivity to detect small consolidations, pleural effusions and sub pleural nodules, POCUS has recently been proposed as a sputum-free likely triage tool for tuberculosis (TB). To make an objective assessment of the potential and limitations of POCUS in routine TB management, we present a Strengths, Weaknesses, Opportunities & Threats (SWOT) analysis based on a review of the relevant literature and focusing on Sub-Saharan Africa (SSA). We idenitified numerous strengths and opportunities of POCUS for TB management e.g.; accessible, affordable, easy to use & maintain, expedited diagnosis, extra-pulmonary TB detection, safer pleural/pericardial puncture, use in children/pregnant women/PLHIV, targeted screening of TB contacts, monitoring TB sequelae, and creating AI decision support. Weaknesses and external threats such as operator dependency, lack of visualization of central lung pathology, poor specificity, lack of impact assessments and data from Sub-Saharan Africa must be taken into consideration to ensure that the potential of the technology can be fully realized in research as in practice

Coxiella burnetii Phagocytosis Is Regulated by GTPases of the Rho Family and the RhoA Effectors mDia1 and ROCK

The GTPases belonging to the Rho family control the actin cytoskeleton rearrangements needed for particle internalization during phagocytosis. ROCK and mDia1 are downstream effectors of RhoA, a GTPase involved in that process. Coxiella burnetii, the etiologic agent of Q fever, is internalized by the host´s cells in an actin-dependent manner. Nevertheless, the molecular mechanism involved in this process has been poorly characterized. This work analyzes the role of different GTPases of the Rho family and some downstream effectors in the internalization of C. burnetii by phagocytic and non-phagocytic cells. The internalization of C. burnetii into HeLa and RAW cells was significantly inhibited when the cells were treated with Clostridium difficile Toxin B which irreversibly inactivates members of the Rho family. In addition, the internalization was reduced in HeLa cells that overexpressed the dominant negative mutants of RhoA, Rac1 or Cdc42 or that were knocked down for the Rho GTPases. The pharmacological inhibition or the knocking down of ROCK diminished bacterium internalization. Moreover, C. burnetii was less efficiently internalized in HeLa cells overexpressing mDia1-N1, a dominant negative mutant of mDia1, while the overexpression of the constitutively active mutant mDia1-ΔN3 increased bacteria uptake. Interestingly, when HeLa and RAW cells were infected, RhoA, Rac1 and mDia1 were recruited to membrane cell fractions. Our results suggest that the GTPases of the Rho family play an important role in C. burnetii phagocytosis in both HeLa and RAW cells. Additionally, we present evidence that ROCK and mDia1, which are downstream effectors of RhoA, are involved in that processFil: Salinas Ojeda, Romina Paola. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Cienicas Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Ortiz Flores, Rodolfo Matias. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Cienicas Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Distel, Jesús Sebastián. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Cienicas Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Aguilera, Milton Osmar. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Cienicas Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Colombo, Maria Isabel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Cienicas Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Beron, Walter. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Cienicas Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; Argentin

Ligand-Receptor Interactions

The formation and dissociation of specific noncovalent interactions between a variety of macromolecules play a crucial role in the function of biological systems. During the last few years, three main lines of research led to a dramatic improvement of our understanding of these important phenomena. First, combination of genetic engineering and X ray cristallography made available a simultaneous knowledg of the precise structure and affinity of series or related ligand-receptor systems differing by a few well-defined atoms. Second, improvement of computer power and simulation techniques allowed extended exploration of the interaction of realistic macromolecules. Third, simultaneous development of a variety of techniques based on atomic force microscopy, hydrodynamic flow, biomembrane probes, optical tweezers, magnetic fields or flexible transducers yielded direct experimental information of the behavior of single ligand receptor bonds. At the same time, investigation of well defined cellular models raised the interest of biologists to the kinetic and mechanical properties of cell membrane receptors. The aim of this review is to give a description of these advances that benefitted from a largely multidisciplinar approach

Brown-Vialetto-Van Laere and Fazio Londe syndrome is associated with a riboflavin transporter defect mimicking mild MADD: a new inborn error of metabolism with potential treatment

We report on three patients (two siblings and one unrelated) presenting in infancy with progressive muscle weakness and paralysis of the diaphragm. Metabolic studies revealed a profile of plasma acylcarnitines and urine organic acids suggestive of a mild form of the multiple acyl-CoA dehydrogenation defect (MADD, ethylmalonic/adipic acid syndrome). Subsequently, a profound flavin deficiency in spite of a normal dietary riboflavin intake was established in the plasma of all three children, suggesting a riboflavin transporter defect. Genetic analysis of these patients demonstrated mutations in the C20orf54 gene which encodes the human homolog of a rat riboflavin transporter. This gene was recently implicated in the Brown-Vialetto-Van Laere syndrome, a rare neurological disorder which may either present in infancy with neurological deterioration with hypotonia, respiratory insufficiency and early death, or later in life with deafness and progressive ponto-bulbar palsy. Supplementation of riboflavin rapidly improved the clinical symptoms as well as the biochemical abnormalities in our patients, demonstrating that high dose riboflavin is a potential treatment for the Brown-Vialetto-Van Laere syndrome as well as for the Fazio Londe syndrome which is considered to be the same disease entity without the deafnes

Secukinumab shows high efficacy irrespective of HLA-Cw6 status in patients with moderate-to-severe plaque-type psoriasis: SUPREME study

Background: Understanding genetic variations is important in predicting treatment response and forms the basis for identifying new pharmacogenetic and pharmacogenomic targets for psoriasis treatment. There are limited data on the efficacy of secukinumab in relation to genetic markers. Objectives: To evaluate the efficacy and safety of secukinumab 300 mg in HLA-Cw6-positive (Cw6-POS) and HLA-Cw6-negative (Cw6-NEG) patients with moderate-to-severe chronic plaque-type psoriasis. Methods: SUPREME was a 24-week, phase IIIb study with an extension period up to 72 weeks. Primary end point was Psoriasis Area Severity Index (PASI) 90 response rate after 16 weeks. Results: In total, 434 patients were recruited: 185 (42\ub76%) were Cw6-POS and 246 (56\ub77%) were Cw6-NEG (three not assessed). Mean \ub1 SD age was 45\ub72 \ub1 13\ub72 years (Cw6-POS 42\ub77 \ub1 13\ub71; Cw6-NEG 47\ub72 \ub1 12\ub79). The baseline PASI score was comparable between the cohorts [Cw6-POS 20\ub77 \ub1 8\ub799; Cw6-NEG 21\ub75 \ub1 9\ub799 (P = 0\ub7777)]. At week 16, PASI 90 was achieved in 80\ub74% of Cw6-POS and 79\ub77% of Cw6-NEG patients (difference 0\ub776; 95% confidence interval 127\ub704 to 8\ub723). No differences in absolute PASI at week 16 (Cw6-POS 1\ub736 \ub1 3\ub758; Cw6-NEG 1\ub718 \ub1 2\ub729) were observed. The overall safety profile of secukinumab was consistent with that previously reported. No statistically significant difference was detected in the rate of treatment-emergent adverse events [Cw6-POS 42\ub77%; Cw6-NEG 49\ub76% (P = 0\ub7295)]. A high PASI 90 response was achieved with secukinumab with a fast reduction in absolute PASI. Conclusions: Determination of HLA-Cw6 status for secukinumab therapy is unnecessary, as it is highly effective regardless of HLA-Cw6 status