Suppression of multiple anti-apoptotic BCL2 family proteins recapitulates the effects of JAK2 inhibitors in JAK2V617F driven myeloproliferative neoplasms.

Several lines of research suggest that Bcl-xL-mediated anti-apoptotic effects may contribute to the pathogenesis of myeloproliferative neoplasms driven by JAK2V617F and serve as therapeutic target. Here, we used a knock-in JAK2V617F mouse model and confirmed that Bcl-xL was overexpressed in erythroid progenitors. The myeloproliferative neoplasm (MPN)-induced phenotype in the peripheral blood by conditional knock-in of JAK2V617F was abrogated by conditional knockout of Bcl2l1, which presented anemia and thrombocytopenia independently of JAK2 mutation status. Mx1-Cre Jak2V617W/VF /Bcl2l1f/f mice presented persistent splenomegaly as a result of extramedullary hematopoiesis and pro-apoptotic stimuli in terminally differentiated erythroid progenitors. The pan-BH3 mimetic inhibitor obatoclax showed superior cytotoxicity in JAK2V617F cell models, and reduced clonogenic capacity in ex vivo assay using Vav-Cre Jak2V617F bone marrow cells. Both ruxolitinib and obatoclax significantly reduced spleen weights in a murine Jak2V617F MPN model but did not show additive effect. The tumor burden reduction was observed with either ruxolitinib or obatoclax in terminal differentiation stage neoplastic cells but not in myeloid-erythroid precursors. Therefore, disrupting the BCL2 balance is not sufficient to treat MPN at the stem cell level, but it is certainly an additional option for controlling the critical myeloid expansion of the disease.

Fully Untethered Battery-free Biomonitoring Electronic Tattoo with Wireless Energy Harvesting.

Bioelectronics stickers that interface the human epidermis and collect electrophysiological data will constitute important tools in the future of healthcare. Rapid progress is enabled by novel fabrication methods for adhesive electronics patches that are soft, stretchable and conform to the human skin. Yet, the ultimate functionality of such systems still depends on rigid components such as silicon chips and the largest rigid component on these systems is usually the battery. In this work, we demonstrate a quickly deployable, untethered, battery-free, ultrathin (~5 µm) passive "electronic tattoo" that interfaces with the human skin for acquisition and transmission of physiological data. We show that the ultrathin film adapts well with the human skin, and allows an excellent signal to noise ratio, better than the gold-standard Ag/AgCl electrodes. To supply the required energy, we rely on a wireless power transfer (WPT) system, using a printed stretchable Ag-In-Ga coil, as well as printed biopotential acquisition electrodes. The tag is interfaced with data acquisition and communication electronics. This constitutes a "data-by-request" system. By approaching the scanning device to the applied tattoo, the patient's electrophysiological data is read and stored to the caregiver device. The WPT device can provide more than 300 mW of measured power if it is transferred over the skin or 100 mW if it is implanted under the skin. As a case study, we transferred this temporary tattoo to the human skin and interfaced it with an electrocardiogram (ECG) device, which could send the volunteer's heartbeat rate in real-time via Bluetooth.

Untethered Disposable Health Monitoring Electronic Patches with an Integrated Ag2O-Zn Battery, a AgInGa Current Collector, and Hydrogel Electrodes.

Stretchable electronics stickers that adhere to the human skin and collect biopotentials are becoming increasingly popular for biomonitoring applications. Such stickers include electrodes, stretchable interconnects, silicon chips for processing and communication, and batteries. Here, we demonstrate a material architecture and fabrication technique for a multilayer, stretchable, low-cost, rapidly deployable, and disposable sticker that integrates skin-interfacing hydrogel electrodes, stretchable interconnects, and a Ag2O-Zn (silver oxide-zinc) battery. In addition, the application of a printed biphasic current collector (AgInGa) for the Ag2O-Zn battery is reported for the first time. Surprisingly, and unlike previously reported batteries, the battery capacity increases after being subjected to strain cycles and reaches a record-breaking areal capacity of 6.88 mAh cm-2 post stretch. As a proof of concept, an application of heart rate monitoring is presented. The disposable patch is interfaced with a miniature battery-free electronics circuit for data acquisition, processing, and wireless transmission. A version of the patch partially covering the patient's chest can supply enough energy for continuous operation for ∼6 days.

Intestinal failure functional classification type associated with an extended length of stay at the intestinal failure unit, Central Hospital in Chihuahua, Mexico.

BACKGROUND: Intestinal failure (IF) was first defined as "a reduction in the functioning gut mass below the minimal amount necessary for adequate digestion and absorption." In our environment, there are no statistical data for IF in adult patients' extended length of stay (LOS), nor the economic impact that it implies. OBJECTIVE: The objective of the study was to describe the association between the IF type and extended LOS. METHODS: Patients admitted to our IF Unit between March 2016 and March 2018 were enrolled. We conducted a 2-year retrospective cross-sectional study. RESULTS: From the total of 53 patients, 35% corresponded to type I IF, 58.5% to type II IF, and 7.5% to type III IF. The mean LOS, according to the type of functional IF was 51 days for type I, 77.48 days for type II, and 68.25 days for type III. The mean LOS for the three IF types was 67.79 days. CONCLUSION: Extended LOS occurs in an important proportion of patients with IF, resulting in increased morbidity and mortality, as well as in costs and associated side effects. Future research should focus on economic studies, to know the economic impact that this subject entails for our health systems.

ANTECEDENTES: En nuestro entorno no existen datos estadísticos sobre la falla intestinal en adultos, su estancia hospitalaria prolongada (EHP) ni el impacto económico que implica. OBJETIVO: Describir la asociación entre el tipo de falla intestinal y la estancia hospitalaria prolongada en pacientes de la unidad de falla intestinal del Hospital Central del Estado Chihuahua, México. MÉTODO: Se realizó un estudio transversal retrospectivo con un total de 53 participantes durante el periodo de marzo de 2016 a marzo de 2018. RESULTADOS: De los 53 pacientes, el 35% tuvieron falla intestinal tipo I, el 58.5% tipo II y el 7.5% tipo III. La media de estancia fue de 51 días para la falla intestinal tipo I, 77,48 días para la tipo II y 68,25 días para la tipo III. La media de estancia hospitalaria para los tres tipos de insuficiencia intestinal fue de 67,79 días. CONCLUSIONES: La estancia hospitalaria prolongada ocurre en una proporción importante de pacientes con falla intestinal, lo que resulta en un aumento de la morbilidad, la mortalidad y los costos. Investigaciones futuras deberían centrarse en la realización de estudios económicos para conocer el impacto que esta cuestión tiene para nuestros sistemas de salud.

Oscillatory squeeze film analysis of soft contact lenses.

The complex modulus of a soft contact lens affects the optical performance, fitting, on-eye movement, wettability, physiological impact and overall comfort of the lens. However, despite acknowledgement that the mechanical behaviour of contact lenses is time-dependent, the rheological characteristics of contact lenses remain under-defined. While existing studies have focussed on elasticity to describe lens behaviour, this paper proposes using oscillatory squeeze film analysis to evaluate the complex modulus. The effects of excitation amplitude, repeatability and surface wetness are examined for four commercially available lenses. Slip at the lens/platen interface is considered along with bias introduced by pre-compressing the lens between platens. Test results when compared to results reported from other test methods indicate that a high degree of slip occurs at the lens platen interface suggesting that deformation is primarily due to biaxial extension.

Enzymes involved in branched-chain amino acid metabolism in humans.

Branched-chain amino acids (leucine, isoleucine and valine) are structurally related to branched-chain fatty acids. Leucine is 2-amino-4-methyl-pentanoic acid, isoleucine is 2-amino-3-methyl-pentanoic acid, and valine is 2-amino-3-methyl-butanoic acid. Similar to fatty acid oxidation, leucine and isoleucine produce acetyl-coA. Additionally, leucine generates acetoacetate and isoleucine yields propionyl-coA. Valine oxidation produces propionyl-coA, which is converted into methylmalonyl-coA and succinyl-coA. Branched-chain aminotransferase catalyzes the first reaction in the catabolic pathway of branched-chain amino acids, a reversible transamination that converts branched-chain amino acids into branched-chain ketoacids. Simultaneously, glutamate is converted in 2-ketoglutarate. The branched-chain ketoacid dehydrogenase complex catalyzes the irreversible oxidative decarboxylation of branched-chain ketoacids to produce branched-chain acyl-coA intermediates, which then follow separate catabolic pathways. Human tissue distribution and function of most of the enzymes involved in branched-chain amino acid catabolism is unknown. Congenital deficiencies of the enzymes involved in branched-chain amino acid metabolism are generally rare disorders. Some of them are associated with reduced pyruvate dehydrogenase complex activity and respiratory chain dysfunction that may contribute to their clinical phenotype. The biochemical phenotype is characterized by accumulation of the substrate to the deficient enzyme and its carnitine and/or glycine derivatives. It was established at the beginning of the twentieth century that the plasma level of the branched-chain amino acids is increased in conditions associated with insulin resistance such as obesity and diabetes mellitus. However, the potential clinical relevance of this elevation is uncertain.

Rib plasmacytoma and IgA multiple myeloma with hyperviscosity syndrome.

Solitary bone plasmacytoma (SPB) can progress to generalized myeloma if not treated early. The elderly population is increasing and delays in diagnosis of plasma cell malignancies are frequent among them. Hyperglobulinemia of multiple myeloma (MM) plays a role in hyperviscosity syndrome (HVS). A 65-year-old woman with hypertension and diabetes mellitus was admitted due to loss of appetite, muscle weakness, breathlessness and discrete expectoration, without fever. Chest X-ray showed an abnormal shadow projection on the right lung field, while computed tomography (CT) revealed an osteolytic mass at the sixth rib. There were more than 50% of plasma cells in the bone marrow samples and high IgA levels according to serum electrophoresis. Rib plasmacytoma and overt IgA-producing myeloma with HVS were diagnosed, but treatment was unsuccessful. Case studies may enhance the awareness about this ominous condition, which may develop unnoticed, particularly in elderly patients with renal insufficiency, and can pose difficulties with diagnosis in primary care settings.

Câncer de mama disseminado com diagnóstico no puerpério: uso de bevacizumabe / Widespread breast cancer diagnosed in puerperium: use of bevacizumab

Relata-se o caso de uma mulher jovem assintomática com carcinoma de mama disseminado, que foi diagnosticado no puerpério. Foram detectadas metástases nos ossos, nos pulmões, no fígado e no sistema nervoso central. A paciente foi tratada com quimioterapia intravenosa (paclitaxel e bevacizumabe), além de radioterapia para a lesão no putâmen. Câncer de mama associado à gravidez constitui uma condição de mau prognóstico devido à demora no diagnóstico, e sua incidência tem aumentado nas últimas décadas. Embora considerada condição incomum e os relatosde caso sejam relativamente escassos, sua real frequência pode estar subestimada. A identificação dessa neoplasia durante a gravidez ou a lactação pode constituir um desafio devido à possibilidade de confundi-la com alterações fisiológicas das mamas. Recentes controvérsias sobre o uso de bevacizumabe no câncer de mama são comentadas

The case of an asymptomatic young woman with a widespread breast cancer, which was diagnosed in the puerperium is reported. Metastases were detected in the bones, lungs(?), liver and central nervous system. The patient was treated with intravenous chemotherapy (paclitaxel and bevacizumab), and radiotherapy for the lesion on putamen. Pregnancy-associated breast cancer constitutes a condition of poor prognosis due to diagnosis delay and its incidence has increased in the last decades. Although considered an uncommon condition, and case reports arerelatively scarce its real frequency may be underestimated. The identification of this neoplasm during pregnancy or lactation may be challenging, due to the possibility of misdiagnosis with physiologic changes of the breasts. Recent controversies about the utilization of bevacizumab in breast cancer are commented.

Late diagnosis of nodular melanoma of the foot in a 74-year-old Brazilian man / Diagnóstico tardío de melanoma nodular del pie en un varón con 74 años

The incidence and mortality of malignant melanoma is increasing. Its early diagnosis can contribute to a favorable prognosis. We report a 74-year-old black man with a dark brown mole in the right plantar area, that grew slowly in the last decade. A biopsy of the lesion revealed a nodular malignant melanoma. A wide excision of the tumor was performed 18 months ago, followed by chemotherapy for nine months. At admission, the patient was debilitated, and presented with numerous nodules in the lower limb and suprapubic area. Imaging studies disclosed chest and abdominal nodules. The patient died 13 days after admission.

Melanoma maligno constituye una importante preocupación debido al incremento de la incidencia y mortalidad. El diagnóstico precoz de esta malignidad puede contribuir para prognósticos favorables. Se describe el diagnóstico tardío de melanoma nodular del pie en un varón afro-brasileño con 74 años de edad. El propósito es aumentar el índice de sospecha acerca de esta infrecuente localización del tumor de la piel, y estimular a los médicos de cuidado primario para realizar examen minucioso del cuerpo entero, contribuyendo a la detección temprana de los cánceres de piel.

Late diagnosis of nodular melanoma of the foot in a 74-year-old Brazilian man.

The incidence and mortality of malignant melanoma is increasing. Its early diagnosis can contribute to a favorable prognosis. We report a 74-year-old black man with a dark brown mole in the right plantar area, that grew slowly in the last decade. A biopsy of the lesion revealed a nodular malignant melanoma. A wide excision of the tumor was performed 18 months ago, followed by chemotherapy for nine months. At admission, the patient was debilitated, and presented with numerous nodules in the lower limb and suprapubic area. Imaging studies disclosed chest and abdominal nodules. The patient died 13 days after admission.