Short Cyclic Regimen With Parathyroid Hormone (PTH) Results in Prolonged Anabolic Effect Relative to Continuous Treatment Followed by Discontinuation in Ovariectomized Rats.

Despite the potent effect of intermittent parathyroid hormone (PTH) treatment on promoting new bone formation, bone mineral density (BMD) rapidly decreases upon discontinuation of PTH administration. To uncover the mechanisms behind this adverse phenomenon, we investigated the immediate responses in bone microstructure and bone cell activities to PTH treatment withdrawal and the associated long-term consequences. Unexpectedly, intact female and estrogen-deficient female rats had distinct responses to the discontinuation of PTH treatment. Significant tibial bone loss and bone microarchitecture deterioration occurred in estrogen-deficient rats, with the treatment benefits of PTH completely lost 9 weeks after discontinuation. In contrast, no adverse effect was observed in intact rats, with sustained treatment benefit 9 weeks after discontinuation. Intriguingly, there is an extended anabolic period during the first week of treatment withdrawal in estrogen-deficient rats, during which no significant change occurred in the number of osteoclasts, whereas the number of osteoblasts remained elevated compared with vehicle-treated rats. However, increases in number of osteoclasts and decreases in number of osteoblasts occurred 2 weeks after discontinuation of PTH treatment, leading to significant reduction in bone mass and bone microarchitecture. To leverage the extended anabolic period upon early withdrawal from PTH, a cyclic administration regimen with repeated cycles of on and off PTH treatment was explored. We demonstrated that the cyclic treatment regimen efficiently alleviated the PTH withdrawal-induced bone loss, improved bone mass, bone microarchitecture, and whole-bone mechanical properties, and extended the treatment duration. © 2021 American Society for Bone and Mineral Research (ASBMR).

Basophil-lineage commitment in acute promyelocytic leukemia predicts for severe bleeding after starting therapy.

Severe hemorrhagic events occur in a significant fraction of acute promyelocytic leukemia patients, either at presentation and/or early after starting therapy, leading to treatment failure and early deaths. However, identification of independent predictors for high-risk of severe bleeding at diagnosis, remains a challenge. Here, we investigated the immunophenotype of bone marrow leukemic cells from 109 newly diagnosed acute promyelocytic leukemia patients, particularly focusing on the identification of basophil-related features, and their potential association with severe bleeding episodes and patient overall survival.From all phenotypes investigated on leukemic cells, expression of the CD203c and/or CD22 basophil-associated markers showed the strongest association with the occurrence and severity of bleeding (p ≤ 0.007); moreover, aberrant expression of CD7, coexpression of CD34+/CD7+ and lack of CD71 was also more frequently found among patients with (mild and severe) bleeding at baseline and/or after starting treatment (p ≤ 0.009). Multivariate analysis showed that CD203c expression (hazard ratio: 26.4; p = 0.003) and older age (hazard ratio: 5.4; p = 0.03) were the best independent predictors for cumulative incidence of severe bleeding after starting therapy. In addition, CD203c expression on leukemic cells (hazard ratio: 4.4; p = 0.01), low fibrinogen levels (hazard ratio: 8.8; p = 0.001), older age (hazard ratio: 9.0; p = 0.002), and high leukocyte count (hazard ratio: 5.6; p = 0.02) were the most informative independent predictors for overall survival.In summary, our results show that the presence of basophil-associated phenotypic characteristics on leukemic cells from acute promyelocytic leukemia patients at diagnosis is a powerful independent predictor for severe bleeding and overall survival, which might contribute in the future to (early) risk-adapted therapy decisions.

Agarose-Based Hydrogels as Suitable Bioprinting Materials for Tissue Engineering.

Hydrogels are useful materials as scaffolds for tissue engineering applications. Using hydrogels with additive manufacturing techniques has typically required the addition of techniques such as cross-linking or printing in sacrificial materials that negatively impact tissue growth to remedy inconsistencies in print fidelity. Thus, there is a need for bioinks that can directly print cell-laden constructs. In this study, agarose-based hydrogels commonly used for cartilage tissue engineering were compared to Pluronic, a hydrogel with established printing capabilities. Moreover, new material mixtures were developed for bioprinting by combining alginate and agarose. We compared mechanical and rheological properties, including yield stress, storage modulus, and shear thinning, as well as construct shape fidelity to assess their potential as a bioink for cell-based tissue engineering. The rheological properties and printability of agarose-alginate gels were statistically similar to those of Pluronic for all tests (p > 0.05). Alginate-agarose composites prepared with 5% w/v (3:2 agarose to alginate ratio) demonstrated excellent cell viability over a 28-day culture period (>∼70% cell survival at day 28) as well matrix production over the same period. Therefore, agarose-alginate mixtures showed the greatest potential as an effective bioink for additive manufacturing of biological materials for cartilage tissue engineering.

Upper airway and systemic inflammation in obstructive sleep apnoea.

Obstructive sleep apnoea (OSA) is associated with pharyngeal inflammation, but the coexistence of systemic inflammation is controversial. This study investigated whether local and systemic inflammatory biomarkers are related in patients with OSA. An uncontrolled extension to the study assessed the response to effective treatment.We recruited 89 patients with OSA (apnoea/hypopnoea index (AHI) ≥5 events·h-1), 28 snorers and 26 healthy controls. Pharyngeal lavage (PHAL) and plasma samples were collected at baseline and after a 1-year follow-up. Inflammatory cells were evaluated by flow cytometry; interleukin (IL)-6, IL-8 and tumour necrosis factor-α were evaluated by immunoassay.In PHAL, CD4+ T-cells, IL-6 and IL-8 were higher in OSA patients than in snorers or healthy controls (p<0.05). The AHI correlated with CD4+, IL-6 and IL-8 in PHAL (all p-values <0.05). There were no differences in the inflammatory biomarkers in plasma between the study groups and no relationship between plasma and PHAL biomarkers. Biomarkers decreased significantly in PHAL but not in plasma after 1 year of therapy with continuous positive airway pressure or surgery.In patients with OSA, increased levels of inflammatory biomarkers were found in PHAL, which were reduced with effective treatment. No simultaneous increase in plasma inflammatory biomarkers was found.

A self-timed multipurpose delay sensor for Field Programmable Gate Arrays (FPGAs).

This paper presents a novel self-timed multi-purpose sensor especially conceived for Field Programmable Gate Arrays (FPGAs). The aim of the sensor is to measure performance variations during the life-cycle of the device, such as process variability, critical path timing and temperature variations. The proposed topology, through the use of both combinational and sequential FPGA elements, amplifies the time of a signal traversing a delay chain to produce a pulse whose width is the sensor's measurement. The sensor is fully self-timed, avoiding the need for clock distribution networks and eliminating the limitations imposed by the system clock. One single off- or on-chip time-to-digital converter is able to perform digitization of several sensors in a single operation. These features allow for a simplified approach for designers wanting to intertwine a multi-purpose sensor network with their application logic. Employed as a temperature sensor, it has been measured to have an error of  ±0.67 °C, over the range of 20-100 °C, employing 20 logic elements with a 2-point calibration.

Dosing and monitoring of enoxaparin therapy in children: experience in a tertiary care hospital.

Pediatric deep vein thrombosis (DVT) is an emerging problem in tertiary care hospitals, recent reviews shows a rate of 40.2/10,000 admissions. Experts affirm that enoxaparin has become in the drug of choice for DVT therapy. Despite this, there is a little information regarding the optimal dose schedule for enoxaparin therapy in children and the therapeutic guidelines for enoxaparin use in children are extrapolated from adult guidelines. Monitoring by antifactor Xa (anti-Xa) measurement and target concentrations between 0.5-1 U/ml at 4-6 h postdose are recommended. This study was designed to analyse our experience in paediatric-specific dosage requirements for enoxaparin therapy. A retrospective study was performed with patients less than 16 years old, who were treated with enoxaparin for DVT and monitored by anti-Xa concentration, between January 2005 and March 2012. Demographic and clinical characteristics and outcomes were obtained. Fourteen patients were analyzed: boy/girl ratio, 8/4; median age, 3.5 months. Cerebral venous sinus thrombosis was the most common indication for therapy. All patients presented thrombosis risks factors. Dose increases were necessary only in patients less than 6 years old. Target anti-Xa concentrations were achieved in 12 (85%) patients. Children younger than 1 year required a higher dose of enoxaparin/kg (1.5-2.7 mg/kg per 12 h). Complete resolutions of DVT were registered in all cases. The mean number of dose increases was three and a median of 11 days to achieve target anti-Xa concentration. This study indicates that an initial higher enoxaparin dose may be necessary in neonates and infants, but other factors must be considered to improve management.

Association between the proliferative rate of neoplastic B cells, their maturation stage, and underlying cytogenetic abnormalities in B-cell chronic lymphoproliferative disorders: analysis of a series of 432 patients.

Limited knowledge exists about the impact of specific genetic abnormalities on the proliferation of neoplastic B cells from chronic lymphoproliferative disorders (B-CLPDs). Here we analyze the impact of cytogenetic abnormalities on the proliferation of neoplastic B cells in 432 B-CLPD patients, grouped according to diagnosis and site of sampling, versus their normal counterparts. Overall, proliferation of neoplastic B cells highly varied among the different B-CLPD subtypes, the greatest numbers of proliferating cells being identified in diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma (BL). Compared with normal B cells, neoplastic B-CLPD cells showed significantly increased S + G(2)/M-phase values in mantle cell lymphoma (MCL), B-chronic lymphocytic leukemia (B-CLL), BL, and some DLBCL cases. Conversely, decreased proliferation was observed in follicular lymphoma, lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (LPL/WM), and some DLBCL patients; hairy cell leukemia, splenic marginal zone, and MALT-lymphoma patients showed S + G(2)/M phase values similar to normal mature B lymphocytes from LN. Interestingly, in B-CLL and MCL significantly higher percentages of S + G(2)/M cells were detected in BM versus PB and in LN versus BM and PB samples, respectively. In turn, presence of 14q32.3 gene rearrangements and DNA aneuploidy, was associated with a higher percentage of S + G(2)/M-phase cells among LPL/WM and B-CLL cases, respectively.

[Comparison between phlebotomy and erythrocytapheresis of iron overload in patients with HFE gene mutations]. / Comparación de la flebotomía con eritrocitaféresis en la sobrecarga de hierro en portadores de mutaciones del gen HFE.

BACKGROUND AND OBJECTIVE: Large-volume erythrocytapheresis (EA) is an useful and speedy method to treat iron overload (IO). We assesed the efficacy of EA in patients with HFE gene mutations and IO compared to the classical phlebotomies. PATIENTS AND METHOD: Data from 9 patients with IO treated with EA, using a discontinuous flow cell separator as a single needle procedure, for a period of 2 years, were compared to 9 matched patients who underwent conventional phlebotomies. RESULTS: The mean volume of red blood cells removed in each EA was 275 ml, with a median reduction of 23 g/l for haemoglobin and 55 microg/l for serum ferritin levels (vs. 17 microg/l between phlebotomies). The liver function test returned to normal values in 4 out of 5 patients undergoing EA, but none of the phlebotomies. The time required to achieve iron depletion was 3 times shorter in EA group. CONCLUSIONS: EA is an effective and safe procedure that achieves iron depletion more quickly than manual phlebotomies. Nevertheless, to determine its cost-effectiveness, economical, prospective, randomized studies are warranted.

Comparación de la flebotomía con eritrocitaféresis en la sobrecarga de hierro en portadores de mutaciones del gen HFE / Comparison between phlebotomy and erythrocytapheresis of iron overload in patients with HFE gene mutations

Fundamento y objetivo: Aunque la sangría terapéutica se considera el tratamiento de elección de la sobrecarga férrica (SF), la eritrocitaféresis (EA) se presenta como un método seguro y rápido para retirar el exceso de hierro, sin pérdida asociada de volumen, plasma ni plaquetas. En este estudio se compara la eficacia de la EA con la del método clásico. Pacientes y método: Se revisaron los datos de 9 pacientes con SF tratados con EA, mediante separador celular automático de flujo discontinuo por unipunción, en 24 meses, y se compararon con los de 9 pacientes apareados tratados con sangrías. Resultados: En cada EA se retiraron 275 ml de eritrocitos, con reducción de 23 g/l de la hemoglobina y de 55 µg/l de la ferritina, frente a los 17 µg/l de la sangría, lo que redujo a un tercio el tiempo requerido para la depleción férrica. Las pruebas hepáticas se normalizaron en el 80% de los pacientes con EA, y en ninguno de los tratados con sangría. Conclusiones: La EA es segura, efectiva y más rápida que las sangrías para eliminar la SF, aunque se necesitan estudios económicos aleatorizados para determinar si es además una alternativa coste-efectiva

Background and objective: Large-volume erythrocytapheresis (EA) is an useful and speedy method to treat iron overload (IO). We assesed the efficacy of EA in patients with HFE gene mutations and IO compared to the classical phlebotomies. Patients and method: Data from 9 patients with IO treated with EA, using a discontinuous flow cell separator as a single needle procedure, for a period of 2 years, were compared to 9 matched patients who underwent conventional phlebotomies. Results: The mean volume of red blood cells removed in each EA was 275 ml, with a median reduction of 23 g/l for haemoglobin and 55 µg/l for serum ferritin levels (vs. 17 µg/l between phlebotomies). The liver function test returned to normal values in 4 out of 5 patients undergoing EA, but none of the phlebotomies. The time required to achieve iron depletion was 3 times shorter in EA group. Conclusions: EA is an effective and safe procedure that achieves iron depletion more quickly than manual phlebotomies. Nevertheless, to determine its cost-effectiveness, economical, prospective, randomized studies are warranted

[Polymorphisms in cystathionine beta-synthase and methylenetetrahydrofolate reductase genes as risk factors for cerebral vascular disease]. / Polimorfismos en los genes cistationina beta-sintasa y metilentetrahidrofolato reductasa como factores de riesgo de enfermedad vascular cerebral.

BACKGROUND AND OBJECTIVE: High plasma total homocysteine (tHcy), low dietary intake of folate and other B vitamins, and genetic polymorphisms related to the metabolism of homocysteine may interactively contribute to the risk of cerebral vascular disease (CVD). We explored interrelations between total homocysteine levels and mutations in genes for the two key enzymes in methionine-homocysteine metabolism. PATIENTS AND METHOD: We analyzed two polymorphisms, C677T in the MTHFR gene and 844ins68 in the CBS gene. We assessed their association with fasting homocysteine in 64 patients with CVD, and in 159 controls. RESULTS: No differences in CBS and MTHFR genotype frequencies between cases and controls were found (C677T p = 0.87 and 844ins68 p = 0.63), nor was a particular CBS and MTHFR genotype associated with an elevated risk of CVD. None of the genotypes defined by the CBS and MTHFR variants studied showed an association with elevated fasting homocysteine concentrations (C677T p = 0.07 and 844ins68 p = 0.47). CONCLUSIONS: We did not find any indication that genetic variation in the CBS and MTHFR genes are associated with homocysteine-related risk of CVD, hence needing further investigation. The contributions to total plasma homocysteine levels of the common mutations of genes coding for the enzymes controlling homocysteine metabolism are modest.

Polimorfismos en los genes cistationina â -sintasa y metilentetrahidrofolato reductasa como factores de riesgo de enfermedad vascular cerebral / Polymorphisms in cystathionine â -synthase and methylenetetrahydrofolate reductase genes as risk factors for cerebral vascular disease

FUNDAMENTO Y OBJETIVO: La interacción entre altas concentraciones de homocisteína plasmática, baja ingesta de folato y otras vitaminas B, y la presencia de polimorfismos en genes relacionados con el metabolismo de la homocisteína, puede aumentar el riesgo de padecer una enfermedad cerebrovascular (ECV). Se ha estudiado la interrelación entre la concentración de homocisteína y la presencia de mutaciones en dos genes relacionados con el metabolismo metionina homocisteína. PACIENTES Y MÉTODO: Se han analizado dos polimorfismos, C677T en el gen MTHFR y 844ins68 en el gen CBS, en 64 pacientes con ECV y 159 controles sanos, estableciendo su posible asociación con la homocisteína total. RESULTADOS: No se han encontrado diferencias en las frecuencias enotipificadas de los genes CBS y MTHFR entre casos y controles (C677T, p = 0,87, y 844ins68, p = 0,63). Ningún genotipo estuvo asociado con un mayor riesgo de ECV. Tampoco se pudo establecer su asociación con un aumento de la concentración de homocisteína total (C677T, p = 0,07, y 844ins68, p = 0,47). CONCLUSIONES: No se ha observado ningún indicio de asociación entre las variables genotipificadas en los genes CBS y MTHFR y la concentración de homocisteína que supongan un aumento del riesgo de ECV. La contribución de estas mutaciones al incremento de la concentración de homocisteína es modesto

BACKGROUND AND OBJECTIVE: High plasma total homocysteine (tHcy), low dietary intake of folate and other B vitamins, and genetic polymorphisms related to the metabolism of homocysteine may interactively contribute to the risk of cerebral vascular disease (CVD). We explored interrelations between total homocysteine levels and mutations in genes for the two key enzymes in methionine-homocysteine metabolism. PATIENTS AND METHOD: We analyzed two polymorphisms, C677T in the MTHFR gene and 844ins68 in the CBS gene. We assessed their association with fasting homocysteine in 64 patients with CVD, and in 159 controls. RESULTS: No differences in CBS and MTHFR genotype frequencies between cases and controls were found (C677T p = 0.87 and 844ins68 p = 0.63), nor was a particular CBS and MTHFR genotype associated with an elevated risk of CVD. None of the genotypes defined by the CBS and MTHFR variants studied showed an association with elevated fasting homocysteine concentrations (C677T p = 0.07 and 844ins68 p = 0.47).CONCLUSIONS: We did not find any indication that genetic variation in the CBS and MTHFR genes are associated with homocysteine related risk of CVD, hence needing further investigation. The contributions to total plasma homocysteine levels of the common mutations of genes coding for the enzymes controlling homocysteine metabolism are modest

Scedosporium prolificans: infección diseminada en un paciente inmunodeprimido / Scedosporium prolificans: diseminated infection in immunocompromised patient

N disponible (AU)

Factores pronósticos moleculares en carcinoma dictal de mama / Molecular prognosttic factors in mammary ductal carcinoma

En el presente estudio se investigó en una serie de 65 pacientes con carcinoma ductal infiltrante de mama, la existencia de asociación de sobrexpresión de proteína c-erbB-2 y p53 mutada con factores pronósticos desfavorables aceptados en carcinoma mamario: receptores de estrogénos negativos, grado histológico alto, gran tamaño de tumor primario y presencia de matástasis en un número elevado de los ganglios linfáticos axilares. Se determinó y evaluó la expresión de la proteína de c-erbB-2 y de p53 en carcinomas ductales infiltrantes de mama de 65 pacientes mediante el método inmunohistoquímico de avidina-biotina (ABC) en el que se utilizaron anticuerpos monoclonales contra p185 de c-erbB-2 y contra proteína mutada de p53. Veinte de los tumores estudiados (30.7 por ciento) mostraron inumorreactividad significativa para c-erbB-2 y p53, definida por positividad de la membrana citoplásmica y del núcelo respectivamente. Se investigó la asociación de los resultados con el estado inmunohistoquimicó de los receptores hormonales de estrógenos, el grado morfológico tumoral y con otros parámetros clinicopatológicos como el tamaño del tumor y el estado de los ganglios linfáticos axilares. En conclusión, la expresión tumoral de la proteína de c-erbB-2 y de la proteína de p53 se vinculó con la ausencia de inmunorreactividad de receptores de estrógeno (p<0.01) y con número elevado de ganglios linfáticos axilares positivos (p<0.05). Los resultados sugieren que la expresión de la proteína c-erbB-2 de p53 en carcinoma ductal infiltrante de mama son indicadores pronósticos dependientes de los indicadores pronósticos tradicionales

Hemorragia gastrointestinal masiva asociada con tejido pancreático heterotópico del estómago / Massive gastrointestinal bleeding associated with gastric ectopic pancreatic tissue

El páncreas heterotópico es una anomalía no común del desarrollo, observada durante operaciones y autopsias, descrita habitualmente como un hallazgo incidental. Nosotros tratamos un caso de páncreas aberrante localizado en estómago, por ser la causa de hemorragia gastrointestinal masiva y choque hipovolémico. La endoscopía reveló un nódulo de seis centímetros de diámetro, con una úlcera en la mucosa de seis milímetros sin sangrado activo. La celiotomía demostró sangrado arterial en el páncreas ectópico ulcerado. El tratamiento fue la escisión del tumor. La evolución postoperatoria fue satisfactoria