Endovascular stenting using a sagittal sinus approach for sigmoid sinus wall dehiscence related to intractable pulsatile tinnitus: a case series.

BACKGROUND: Sigmoid sinus wall dehiscence can lead to pulsatile tinnitus with a significant decrease in quality of life, occasionally leading to psychiatric disorders. Several surgical and endovascular procedures have been described for resolving dehiscence. Within endovascular procedures, the sagittal sinus approach could be a technical alternative for tracking and accurate stent positioning within the sigmoid sinus when the jugular bulb anatomy is unfavorable. CASE PRESENTATION: A retrospective case series of three patients with pulsatile tinnitus due to sigmoid sinus wall dehiscence without intracranial hypertension was reviewed from January 2018 to January 2022. From the participants enrolled, the median age was 50.3 years (range 43-63), with 67% self-identifying as female and 33% as male. They self-identified as Hispanic. Sigmoid sinus dehiscence was diagnosed using angiotomography, and contralateral transverse sinus stenosis was observed in all patients. Patients underwent surgery via a navigated endovascular sagittal sinus approach for sigmoid sinus stenting. No neurological complications were associated with the procedure. Pulsatile tinnitus improved after the procedure in all patients. CONCLUSIONS: Superior sagittal sinus resection for sigmoid sinus wall stenting is a safe and effective technique. Pulsatile tinnitus due to sigmoid sinus wall dehiscence could be treated using the endovascular resurfacing stenting technique. However, further research is needed to evaluate the potential benefit of contralateral stenting for removing sinus dehiscence when venous stenosis is detected. However, resurfacing sigmoid sinus wall dehiscence results in symptomatic improvement.

Melphalan and Exportin 1 Inhibitors Exert Synergistic Antitumor Effects in Preclinical Models of Human Multiple Myeloma.

High-dose chemotherapy with melphalan followed by autologous transplantation is a first-line treatment for multiple myeloma. Here, we present preclinical evidence that this treatment may be significantly improved by the addition of exportin 1 inhibitors (XPO1i). The XPO1i selinexor, eltanexor, and KOS-2464 sensitized human multiple myeloma cells to melphalan. Human 8226 and U266 multiple myeloma cell lines and melphalan-resistant cell lines (8226-LR5 and U266-LR6) were highly sensitized to melphalan by XPO1i. Multiple myeloma cells from newly diagnosed and relapsed/refractory multiple myeloma patients were also sensitized by XPO1i to melphalan. In NOD/SCIDγ mice challenged with either parental 8226 or U266 multiple myeloma and melphalan-resistant multiple myeloma tumors, XPO1i/melphalan combination treatments demonstrated stronger synergistic antitumor effects than single-agent melphalan with minimal toxicity. Synergistic cell death resulted from increased XPO1i/melphalan-induced DNA damage in a dose-dependent manner and decreased DNA repair. In addition, repair of melphalan-induced DNA damage was inhibited by selinexor, which decreased melphalan-induced monoubiquitination of FANCD2 in multiple myeloma cells. Knockdown of FANCD2 was found to replicate the effect of selinexor when used with melphalan, increasing DNA damage (γH2AX) by inhibiting DNA repair. Thus, combination therapies that include selinexor or eltanexor with melphalan may have the potential to improve treatment outcomes of multiple myeloma in melphalan-resistant and newly diagnosed patients. The combination of selinexor and melphalan is currently being investigated in the context of high-dose chemotherapy and autologous transplant (NCT02780609). SIGNIFICANCE: Inhibition of exportin 1 with selinexor synergistically sensitizes human multiple myeloma to melphalan by inhibiting Fanconi anemia pathway-mediated DNA repair.

Proteolytic Processing of Neurexins by Presenilins Sustains Synaptic Vesicle Release.

Proteolytic processing of synaptic adhesion components can accommodate the function of synapses to activity-dependent changes. The adhesion system formed by neurexins (Nrxns) and neuroligins (Nlgns) bidirectionally orchestrate the function of presynaptic and postsynaptic terminals. Previous studies have shown that presenilins (PS), components of the gamma-secretase complex frequently mutated in familial Alzheimer's disease, clear from glutamatergic terminals the accumulation of Nrxn C-terminal fragments (Nrxn-CTF) generated by ectodomain shedding. Here, we characterized the synaptic consequences of the proteolytic processing of Nrxns in cultured hippocampal neurons from mice and rats of both sexes. We show that activation of presynaptic Nrxns with postsynaptic Nlgn1 or inhibition of ectodomain shedding in axonal Nrxn1-ß increases presynaptic release at individual terminals, likely reflecting an increase in the number of functional release sites. Importantly, inactivation of PS inhibits presynaptic release downstream of Nrxn activation, leaving synaptic vesicle recruitment unaltered. Glutamate-receptor signaling initiates the activity-dependent generation of Nrxn-CTF, which accumulate at presynaptic terminals lacking PS function. The sole expression of Nrxn-CTF decreases presynaptic release and calcium flux, recapitulating the deficits due to loss of PS function. Our data indicate that inhibition of Nrxn processing by PS is deleterious to glutamatergic function.SIGNIFICANCE STATEMENT To gain insight into the role of presenilins (PS) in excitatory synaptic function, we address the relevance of the proteolytic processing of presynaptic neurexins (Nrxns) in glutamatergic differentiation. Using synaptic fluorescence probes in cultured hippocampal neurons, we report that trans-synaptic activation of Nrxns produces a robust increase in presynaptic calcium levels and neurotransmitter release at individual glutamatergic terminals by a mechanism that depends on normal PS activity. Abnormal accumulation of Nrxn C-terminal fragments resulting from impaired PS activity inhibits presynaptic calcium signal and neurotransmitter release, assigning synaptic defects to Nrxns as a specific PS substrate. These data may provide links into how loss of PS activity inhibits glutamatergic synaptic function in Alzheimer's disease patients.

An Intelligent Parking Management System for Urban Areas.

In this article we describe a low-cost, minimally-intrusive system for the efficient management of parking spaces on both public roads and controlled zones. This system is based on wireless networks of photoelectric sensors that are deployed on the access roads into and out of these areas. The sensors detect the passage of vehicles on these roads and communicate this information to a data centre, thus making it possible to know the number of vehicles in the controlled zone and the occupancy levels in real-time. This information may be communicated to drivers to facilitate their search for a parking space and to authorities so that they may take steps to control traffic when congestion is detected.

Circulating Tumor Cells Identify Early Recurrence in Patients with Non-Small Cell Lung Cancer Undergoing Radical Resection.

BACKGROUND: Surgery is the treatment of choice for patients with non-small cell lung cancer (NSCLC) stages I-IIIA. However, more than 20% of these patients develop recurrence and die due to their disease. The release of tumor cells into peripheral blood (CTCs) is one of the main causes of recurrence of cancer. The objectives of this study are to identify the prognostic value of the presence and characterization of CTCs in peripheral blood in patients undergoing radical resection for NSCLC. PATIENTS AND METHODS: 56 patients who underwent radical surgery for previously untreated NSCLC were enrolled in this prospective study. Peripheral blood samples for CTC analysis were obtained before and one month after surgery. In addition CTCs were phenotypically characterized by epidermal growth factor receptor (EGFR) expression. RESULTS: 51.8% of the patients evaluated were positive with the presence of CTCs at baseline. A decrease in the detection rate of CTCs was observed in these patients one month after surgery (32.1%) (p = 0.035). The mean number of CTCs was 3.16 per 10 ml (range 0-84) preoperatively and 0.66 (range 0-3) in postoperative determination. EGFR expression was found in 89.7% of the patients at baseline and in 38.9% patients one month after surgery. The presence of CTCs after surgery was significantly associated with early recurrence (p = 0.018) and a shorter disease free survival (DFS) (p = .008). In multivariate analysis CTC presence after surgery (HR = 5.750, 95% CI: 1.50-21.946, p = 0.010) and N status (HR = 0.296, 95% CI: 0.091-0.961, p = 0.043) were independent prognostic factors for DFS. CONCLUSION: CTCs can be detected and characterized in patients undergoing radical resection for non-small cell lung cancer. Their presence might be used to identify patients with increased risk of early recurrence.

Phylogeography of the reef fish Cephalopholis argus (Epinephelidae) indicates Pleistocene isolation across the Indo-Pacific Barrier with contemporary overlap in The Coral Triangle.

BACKGROUND: The Coral Triangle (CT), bounded by the Philippines, the Malay Peninsula, and New Guinea, is the epicenter of marine biodiversity. Hypotheses that explain the source of this rich biodiversity include 1) the center of origin, 2) the center of accumulation, and 3) the region of overlap. Here we contribute to the debate with a phylogeographic survey of a widely distributed reef fish, the Peacock Grouper (Cephalopholis argus; Epinephelidae) at 21 locations (N = 550) using DNA sequence data from mtDNA cytochrome b and two nuclear introns (gonadotropin-releasing hormone and S7 ribosomal protein). RESULTS: Population structure was significant (ΦST = 0.297, P < 0.001; FST = 0.078, P < 0.001; FST = 0.099, P < 0.001 for the three loci, respectively) among five regions: French Polynesia, the central-west Pacific (Line Islands to northeastern Australia), Indo-Pacific boundary (Bali and Rowley Shoals), eastern Indian Ocean (Cocos/Keeling and Christmas Island), and western Indian Ocean (Diego Garcia, Oman, and Seychelles). A strong signal of isolation by distance was detected in both mtDNA (r = 0.749, P = 0.001) and the combined nuclear loci (r = 0.715, P < 0.001). We detected evidence of population expansion with migration toward the CT. Two clusters of haplotypes were detected in the mtDNA data (d = 0.008), corresponding to the Pacific and Indian Oceans, with a low level of introgression observed outside a mixing zone at the Pacific-Indian boundary. CONCLUSIONS: We conclude that the Indo-Pacific Barrier, operating during low sea level associated with glaciation, defines the primary phylogeographic pattern in this species. These data support a scenario of isolation on the scale of 105 year glacial cycles, followed by population expansion toward the CT, and overlap of divergent lineages at the Pacific-Indian boundary. This pattern of isolation, divergence, and subsequent overlap likely contributes to species richness at the adjacent CT and is consistent with the region of overlap hypothesis.

Dual-promoter lentiviral vectors for constitutive and regulated gene expression in neurons.

Gene transfer methods for efficient co-expression of exogenous proteins in neurons are crucial tools towards the understanding of the molecular basis of the central nervous system. Lentiviruses are retroviral vectors that can transduce a wide variety of cells including differentiated neurons. In this work, we have generated lentiviral vectors containing dual promoters that allow efficient co-expression of exogenous proteins in neurons. We show that insertion of two copies of a human synapsin promoter/WPRE cassette in a single lentiviral vector directs robust co-expression of cDNAs in cultured neurons, while excluding expression in the surrounding glial cells. Furthermore, insertion of the tetracycline-inducible system (Tet-off) controlled by the synapsin promoter results in tightly regulated expression of EGFP when used as a transgene in cultured neurons. Transduction of primary neurons with this inducible system leads to a 100-fold increase in EGFP mRNA levels in the absence of doxycycline. In transduced cultures, EGFP transcription is inhibited within 24h upon addition of doxycycline. The viral systems we developed here provide neuron-specific and regulated expression mediated by single lentiviral vectors and will prove valuable tools for the study of neuronal function.

Alienated advocacy: perspectives of Latina mothers of young adults with developmental disabilities on service systems.

Although collaborative partnership between parents and professionals is a cornerstone of the special education and service systems, this relationship exists more as an ideal, especially when low-income, culturally diverse families are involved. Through three focus groups, we examined the beliefs of 16 low-income Latina mothers of young adults with developmental disabilities about their relationships with the educational and service delivery systems. Primary concerns identified were (a) poor communication, (b) low effort in providing services, (c) negative attitudes of professionals toward the client-children, (d) negative treatment of parents by professionals, and (e) the mother's role as central to the well-being of her child. Mothers tended to adopt a posture of alienated advocacy in relation to their child's educational and service needs.

Novel benzylidene-9(10H)-anthracenones as highly active antimicrotubule agents. Synthesis, antiproliferative activity, and inhibition of tubulin polymerization.

A novel series of 10-benzylidene-9(10H)-anthracenones and 10-(phenylmethyl)-9(10H)-anthracenones were synthesized and evaluated for antiproliferative activity in an assay based on K562 leukemia cells. The 3-hydroxy-4-methoxybenzylidene analogue 9h was found to be the most active compound (IC(50) K562: 20 nM). Structure-activity relationships are also considered. The highly active compound 9h and the 2,4-dimethoxy-3-hydroxybenzylidene analogue 9l were tested against five tumor cell lines using the XTT assay, including multidrug resistant phenotypes. Induction of cell death in a variety of tumor cell lines was determined in a monolayer assay using propidium iodide. Noteworthy, all compounds within the series induced elongations in K562 cells similar to vinblastine-treated cells. The effect of the lead compound 9h on K562 cell growth was associated with cell cycle arrest in G2/M. Concentrations for 50% KB/HeLa cells arrested in G2/M after treatment with 9h and 9l were determined and found to be in the range of 0.2 microM. Additionally, we monitored the dose dependent caspase-3-like protease activity in K562 cells and MCF-7/Casp-3 cells treated with 9h, indicating induction of apoptosis. Western blotting analysis demonstrated that 9h caused a shift in tubulin concentration from the polymerized state found in the cell pellet to the unpolymerized state found in the cell supernatant. Seven compounds strongly inhibited tubulin polymerization with activities higher or comparable to those of the reference compounds such as colchicine, podophyllotoxin, and nocodazole. In general, the antiproliferative activity correlated with inhibition of tubulin polymerization. The most active compounds strongly displaced [(3)H]colchicine from its binding site in the tubulin, yielding IC(50) values 3- to 4-fold lower than that of colchicine. The novel benzylidene-9(10H)-anthracenones described in the present study constitute an interesting group of highly active and easily accessible antimitotic agents that inhibit tubulin polymerization.

Precondicionamiento isquémico inducido por el ejercicio en pacientes con enfermedad coronaria / Ischemic preconditioning induced by exercise in patients with coronary diseases

El precondicionamiento isquémico posee un efecto cardioprotector que depende de mecanismos metabólicos. Nos propusimos demostrar a través de la isquemia inducida por el ejercicio, la presencia del precondicionamiento isquémico clásico y la segunda ventana. Se incluyeron 14 pacientes, 9 masculinos y 5 femeninos, con una cardiopatía isquémica demostrada por coronariografia o estudio de perfusión miocárdica y prueba ergométrica positiva. A todos se les realizó 3 pruebas ergométricas consecutivas (Erg. I, Erg. II y Erg. III), con un intervalo entre Erg I y Erg II de 30 min y entre Erg II y Erg III de 24 h. Se encontraron diferencias significativas entre las medias de Erg. I y II (p ú,001) y entre Erg I y III ( p ú ,05) en las variables: duración de la isquemia (434 s ± 228, 300 s ± 177, 314 s ± 226); depresión del segmento ST (-2,9 mm ± 1,3, -2,1 mm ± 1,3, -2,2 mm ± 1,1); variación de la pendiente de la relación ST/FC (-507 mm/s ± 188, -360 mm/s ± 225, - 402 mm/s ± 180); y entre Erg. I y Erg. III (p ú,05) en la duración de angina (243 s ±66, 172 s ± 109, 122 s ± 90). Los doble productos en las variables medidas tuvieron incremento en Erg. II y III en relación con Erg. I, pero sin significación estadística p> , 05. Concluimos que la isquemia inducida por el ejercicio generó menor evidencia de isquemia a los 30 min. A las 24 h también se encontró una tendencia de reducción isquémica, aunque de menor intensidad. El precondicionamiento isquémico pudiera ser el mecanismo generador de ambas cardioprotecciones

Rehabilitación cardiaca en el anciano: revisión del tema / Cardiac rehabilitation in the elderly: topic review

Los programas de rehabilitación cardiaca integral han confirmado con el tiempo ser un tratamiento válido en la cardiopatía isquémica. En un comienzo estos programas excluían a los ancianos y a los pacientes considerados de alto riesgo, pero con el decursar del tiempo se han evidenciado útiles y provechosos resultados también en adultos de la tercera edad; por tal motivo, hemos decidido presentar un marco referencial que aborde todas las aristas de esta temática, permitiéndole al lector tener una clara percepción de los efectos y beneficios desarrollados por este grupo etáreo cuando se vincula a los citados programas, con el objetivo final de poder generalizar el concepto de la posible y necesaria incorporación del adulto mayor a esta modalidad terapéutica

Papel del especialista en ejercicio físico en el programa de rehabilitación cardíaca / Role played by the physical training specialist in the Program of Cardiac Rehabilitation

Se mencionan algunos de los efectos positivos del ejercicio físico en pacientes cardiópatas, como son el aumento de la capacidad funcional en mujeres y en pacientes clasificados de alto riesgo, la mejoría de la frecuencia cardíaca y la presión arterial, etc. El artículo tuvo como objetivo explicar el funcionamiento de la sección de entrenamiento físico dentro de los programas de rehabilitación cardíaca. Se explicó el funcionamiento de la sección de ejercicio físico del Centro de Rehabilitación del Instituto de Cardiología de La Habana, así como el papel preponderante del especialista en ejercicio físico dentro de la rehabilitación cardíaca. Como conclusión, se determinó que en los programas de rehabilitación cardíaca, siempre existiera el Especialista en ejercicio físico, con los conocimientos necesarios que garanticen la salud y la seguridad del paciente

Rehabilitacion del paciente con enfermedad coronaria: Estado actual y perspectivas para el siglo XXI / Rehabilitation of the patient presenting with coronary heart disease: State-of-the Art and perspectives for the XXI century

Se analizan algunas de las probables contribuciones de la rehabilitacion del paciente coronario para el futuro. La realizacion de procederes diagnosticos y terapeuticos mas tempranos y efectivos en pacientes con episodios coronarios agudos, ha propiciado que la rehabilitacion con ejercicios fisicos pueda iniciarse mas rapidamente y con mayor intensidad que antes. Esto ha producido cambios en los principios fundamentales del entrenamiento fisico en estos pacientes: en la intensidad, duracion y supervision de los ejercicios. La estratificacion del riesgo antes del alta hospitalaria ha permitido el diseno temprano de programas de rehabilitacion y la orientacion terapeutica precisa. Se insiste en que la edad avanzada y las cardiopatias severas ya no constituyen contraindicaciones estrictas para el entrenamiento fisico y son quizas los pacientes sintomaticos los mas beneficiados de la mejoria de la calidad de vida, que es un resultado relevante de la rehabilitacion de pacientes coronarios