Mechanisms of hyperpolarization in regenerated mature motor axons in cat

We found persistent abnormalities in the recovery of membrane excitability in long-term regenerated motor nerve fibres in the cat as indicated in the companion paper. These abnormalities could partly be explained by membrane hyperpolarization. To further investigate this possibility, we compared the changes in excitability in control nerves and long-term regenerated cat nerves (3–5 years after tibial nerve crush) during manoeuvres known to alter axonal membrane Na⁺–K⁺ pump function: polarization, cooling to 20°C, reperfusion after 10 min ischaemia, and up to 60 s of repetitive stimulation at 200 Hz. The abnormalities in excitability of regenerated nerves were reduced by depolarization and cooling and increased by hyperpolarization and during postischaemia. Moreover, the time course of recovery of excitability from repetitive stimulation and ischaemia was prolonged in regenerated nerves. Our data are consistent with an increased demand for electrogenic Na⁺–K⁺ pumping in regenerated nerves leading to membrane hyperpolarization. Such persistent hyperpolarization may influence the ability of the axon to compensate for changes in membrane potential following normal repetitive activity.     

Exact one-sided confidence limits for the difference between two correlated proportions

We construct exact and optimal one-sided upper and lower confidence bounds for the difference between two probabilities based on matched binary pairs using well-established optimality theory of Buehler. Starting with five different approximate lower and upper limits, we adjust them to have coverage probability exactly equal to the desired nominal level and then compare the resulting exact limits by their mean size. Exact limits based on the signed root likelihood ratio statistic are preferred and recommended for practical use.     

Tamoxifen stimulates calcitonin-producing thyroid C-cells and prevents trabecular bone loss in a rat model of androgen deficiency

Thyroid C-cells produce calcitonin (CT), a hypocalcemic hormone, that acts as an inhibitor of bone resorption. In this study, we investigated the effects of tamoxifen (TAM) as a selective estrogen receptor modulator on thyroid C-cells, trabecular bone and biochemical markers of bone metabolism in an animal model of androgen deficiency, represented by middle-aged orchidectomized (Orx) rats. Fifteen-month-old male Wistar rats were divided into: Orx and sham-operated (SO) groups. Rats from one Orx group were injected subcutaneously with TAM citrate (Orx + TAM; 0.3 mg kg⁻¹ b.w.), while the rats from SO and a second Orx group received vehicle alone, once a day for 3 weeks. The peroxidase–antiperoxidase method was applied for localization of CT in C-cells. Thyroid C-cells were morphometrically and ultrastructurally analyzed. An ImageJ image-processing program was used to measure bone histomorphometric parameters. Blood serum samples were analyzed for CT, osteocalcin (OC), calcium (Ca²⁺) and phosphorus (P). Urinary Ca²⁺ concentrations were measured. TAM treatment significantly increased thyroid C-cell volume (V_c) and serum CT when compared with vehicle-treated Orx rats. Analysis of trabecular microarchitecture of the tibia showed that administration of TAM significantly increased cancellous bone area, trabecular thickness and trabecular number, whereas trabecular separation was significantly decreased compared with vehicle-treated Orx rats. Serum OC and urinary Ca²⁺ concentrations were significantly lower in comparison with the control Orx group. These results indicate that in our rat model of androgen deficiency, TAM stimulated calcitonin-producing thyroid C-cells and increased trabecular bone mass.     

F12‐46C/T polymorphism as modifier of the clinical phenotype of hereditary angioedema

The factors influencing the heterogeneous clinical manifestation of hereditary angioedema due to C1‐INH deficiency (C1‐INH‐HAE) represent one of the oldest unsolved problems of the disease. Considering that factor XII (FXII) levels may affect bradykinin production, we investigated the contribution of the functional promoter polymorphism F12‐46C/T in disease phenotype. We studied 258 C1‐INH‐HAE patients from 113 European families, and we explored possible associations of F12‐46C/T with clinical features and the SERPING1 mutational status. Given that our cohort consisted of related subjects, we implemented generalized estimating equations (GEEs), an extension of the generalized linear model accounting for the within‐subject correlation. F12‐46C/T carriers exhibited a significantly delayed disease onset (P < 0.001) and did not need long‐term treatment (P = 0.02). In a GEE linear regression model, the presence of F12‐46C/T was significantly associated with a 7‐year delay in disease onset (P < 0.0001) regardless of SERPING1 mutational status. It is concluded that F12‐46C/T carriage acts as an independent modifier of C1‐INH‐HAE severity.     

Cognitive evolutionary therapy for depression: a case study

We present an evolutionary‐driven cognitive–behavioral intervention for a moderately depressed patient. Standard cognitive and behavioral therapy techniques focused on the patient's perfectionistic and self‐downing beliefs, while novel, evolutionary‐informed techniques were used to guide behavioral activation and conceptualize secondary emotional problems related to anger. The treatment reduced depressive symptomatology and increased evolutionary fitness.     

Among a panel of polymorphisms in genes related to oxidative stress,CAT-262 C>T,GPX1 Pro198Leu and GSTP1 Ile105Val influence the risk of developing BCR-ABL negative myeloproliferative neoplasms

Objectives: To analyze the relationship between six polymorphisms in genes related to oxidative stress, namely CAT-262 C>T, MnSOD Ala16Val, GPX1 Pro198Leu, GSTM1 and GSTT1 null genotypes, and GSTP1 Ile105Val, and the occurrence of BCR-ABL negative myeloproliferative neoplasms (polycythemia vera, essential thrombocythemia, and primary myelofibrosis).

Methods: We genotyped for these polymorphisms 328 patients with a known mutation status for JAK2 V617F, MPL and CALR, and 363 controls, using molecular genetics assays.

Results: The CAT-262 C>T and GPX1 Pro198Leu polymorphisms were seen significantly less frequently, while the GSTP1 IleVal105 polymorphism was seen significantly more frequently in patients with BCR-ABL negative myeloproliferative neoplasms, regardless of the molecular sub-type (e.g. JAK2 V617F or CALR mutated).

Discussion and conclusion: Our study provides evidence that variation in genes related to oxidative stress might modulate the risk of developing BCR-ABL negative myeloproliferative neoplasms.     

Non-Aqueous Electrodeposition and Characterization of AlCrCuFeNi High Entropy Alloy Thin Films

Materials used in the marine industry are exposed to extreme conditions, so it is necessary to meet remarkable characteristics, such as mechanical resistance, low density, and good corrosion resistance. The challenging environment requires continuous performance improvements, so this work is focused on developing new materials with superior properties, using the electrochemical deposition technique, which are convenient for marine engineering. High-entropy alloys have been attracting tremendous interest in many applications, due to their simple crystal structures and advantageous physical-chemical properties, such as high strength, anti-corrosion, erosion, and electro-magnetic capabilities. To identify the most appropriate compositions, MatCalc software was used to predict the structure and characteristics of the required materials, and thermodynamic and kinetic criteria calculations were performed. The modelling processes generated a series of optimal compositions in the AlCrCuFeNi alloy system, that are suitable to be used in anticorrosive and tribological applications. The composition and morphology of the obtained high entropy alloy thin films revealed a uniform structure, with a small grain profile. The corrosion resistance was investigated in artificial seawater to observe the behavior of the newly developed materials in demanding conditions, and the results showed improved results compared to the copper foil substrate.