Coexpression of Aspartic Proteinases and Human Leukocyte Antigen-DR in Human Transplanted Lung

Aspartic proteinases have recently been shown to be implicated in antigen processing. We explored the expression of two aspartic proteinases, cathepsins E and D, and of human leukocyte antigen-DR (HLA-DR) molecules in a consecutive series of 80 transbronchial biopsies from transplanted lungs. For controls, we studied five normal donor lungs (not suitable for transplantation on account of thoracic trauma) and macroscopically normal areas of three cancer-affected lungs. Two of the five unsuitable donor lungs showed minimal inflammatory changes. Macroscopically normal samples from the three cancerous lungs showed mild and focal inflammatory infiltrates. In histologically normal lungs, HLA-DR expression was limited to professional antigenpresenting cells. Macroscopically normal lung samples with minimal inflammatory changes from both donor and cancer lungs showed variable HLA-DR expression by alveolar and bronchial epithelial cells and by endothelial cells. All transplanted lung biopsies showed HLA-DR expression by epithelial (alveolar and bronchial) and endothelial cells, with a trend for increased positivity in acute rejection. Cathepsin E was restricted to Clara and to rare bronchus-associated lymphoid tissue-related epithelial cells in histologically normal lung samples, whereas minimal de novo cathepsin E expression by rare alveolar pneumocytes was noted in control lung samples exhibiting minimal inflammatory changes. In all transplanted lung biopsies, cathepsin E was diffusely expressed de novo by hyperplastic alveolar epithelial cells, regardless of the presence or degree of rejection. Cathepsin D was expressed only by alveolar macrophages and by ciliated bronchial cells of normal, minimally inflamed, and transplanted lungs. In transplanted lung, Clara cells and several hyperplastic alveolar pneumocytes coexpressed HLA-DR and cathepsin E, whereas all alveolar macrophages and a few ciliated cells coexpressed cathepsin D and HLA-DR The present investigation suggests that the de novo expression of cathepsin E and HLA-DR by hyperplastic alveolar pneumocytes of transplanted lung may be crucial for antigen processing and presentation to recipient competent T cells, and thus for the triggering of the immune-inflammatory cascade that leads to rejection.     

The ratio of older women to men: historical perspectives and cross-national comparisons

In nearly all populations throughout the world there are substantially more older women than men. Although there are many biological explanations for why women have greater longevity than men, the higher proportion of women in the older population appears to be a phenomenon of the twentieth century. Using contemporary data on population size and life expectancy in a large number of countries and historical life table data from a diverse subset of countries, cross-national contrasts and historical trends in the female to male ratio are explored. In the 1990's, only 4 countries had fewer women than men in the age group 75 years and older. The number of women per 100 men aged 75+ in the remainder of the world's countries ranged from 100 to 355. In general, countries with a lower overall life expectancy had a lower number of women per 100 men aged 75+, while countries with higher overall life expectancy had a higher female to male ratio in this age group. A hundred years ago there were nearly equal numbers of women and men aged 75+ in many countries. In all countries studied, the female to male ratio increased as the century progressed. Historical life table data were used to calculate the probability of surviving through 5 stages of life: ages 0 to 5, 5 to 15, 15 to 40, 40 to 65, and 65 to 85. Although the probability of survival through all age intervals increased dramatically during the century, the current disparity in the size of the older populations of men and women can be explained primarily by the divergence in male and female probabilities of survival for the two older age intervals as the century progressed. Thus, with higher life expectancy, whether it be comparing countries or over time within a country, the proportion of the older population that is female is greater. Changes in survival probability in middle and late life, rather than childhood and young adulthood, have been responsible for the increased number of women compared to men in the older population.     

Predictive Value of Admission N-Terminal Pro-B-Type Natriuretic Peptide and Renal Function in Older People Hospitalized for Dyspnoea

Background. We investigated the relationship between NT-pro-BNP, glomerular filtration rate (GFR), and all-cause mortality rates in a cohort of older people discharged from an internal medicine unit after admission for dyspnoea. Patients and Methods. NT-pro-BNP was evaluated in serum samples of 134 patients aged 80 ± 6 years who presented to a single academic centre with worsening dyspnoea. History data and anthropometric, clinical, and biochemical parameters including GFR were collected at the time of admission. 119 out of 134 were discharged alive from hospital and were included in the follow-up of 779 ± 370 days. Results. 35 out of 119 subjects died after a follow-up of 266 ± 251 days. Cox proportional hazards model showed that GFR and Ln (NT-pro-BNP) were predictors for all-cause mortality with estimated hazard ratios of 0.969 (95% confidence interval: 0.950–0.988; P = 0.001) and 2.360 (95% confidence interval: 1.208–4.610; P = 0.012), respectively. Patients characterized by high NT-pro-BNP levels and GFR ≥ 60 mL/min/1.73 m² showed a dramatic reduction in survival duration compared with the groups with different combinations of the two variables (P = 0.008). Conclusions. In the elderly, NT-pro-BNP and GFR are predictors of all-cause mortality after admission because of dyspnoea. Since the fact that subjects with high NT-pro-BNP and GFR ≥ 60 mL/min/1.73 m² exhibited a reduced survival, high admission NT-pro-BNP suggests future negative outcome.     

Post Graphemic Impairments Of Writing: The Case Of Micrographia

Micrographia (MG), an acquired impairment of writing characterized by diminution of letter size, coupled with slowing and loss of accuracy, is most frequently observed in the course of degenerative disease of basal ganglia, such as Parkinson’s Disease. Only a few cases of MG without concomitant extrapyramidal signs have been described, mostly following vascular lesion of the left basal ganglia.

In this article we report an isolated pattern of MG following an extensive traumatic cerebral lesion centered in the left basal ganglia. The nature of this impairment is analyzed according to a cognitive model of writing and interpreted as a specific example of peripheral dysgraphia.     

The application of quality by design in the development of the liquid chromatography method to determine empagliflozin in the presence of its organic impurities

Analysis of impurities is an important step in the quality control of pharmaceutical ingredients and final products. From drug synthesis or excipients, even in small concentrations, impurities may affect efficacy and safety. The method was developed following Quality by Design (QbD) for the analysis of the antidiabetic empagliflozin. The concept of QbD is used as a tool for the development of methods and formulations. Through predefined objectives and risk analysis, robust methodologies and reduced solvent consumption are developed. A simple HPLC method was developed and validated for the quantitative determination of empagliflozin and its organic impurities from the synthesis process. The method was carried out in a Shim-pack phenyl column with a mobile phase consisting of an acetonitrile/water mixture (72 : 28), with isocratic elution and the detector wavelength was 230 nm. The validation process, in accordance with international guidelines, shows that the method was linear, precise and accurate for empagliflozin, impurity 1 and impurity 2. Limits of detection (0.01, 0.02 and 0.01 μg mL⁻¹) and quantification (0.10, 0.10 and 0.05 μg mL⁻¹) were determined for EMPA, IMP1 and IMP2, respectively. The HPLC method for impurity determination in empagliflozin was linear, precise, accurate and robust. It can be successfully applied in the quality control of empagliflozin and the synthesis of impurities, being adequate for routine analysis.

Analysis of impurities is an important step in the quality control of pharmaceutical ingredients and final products.     

Evaluating feeding as unconditioned stimulus for conditioning of an endocrine effect in Nile tilapia

This study tested the adequacy of feeding as an unconditioned stimulus (US) to condition an endocrine response (plasma cortisol increase) in the cichlid fish Nile tilapia (Oreochromis niloticus). In a first study, conditioning was confirmed in grouped fish in the only experiment using single-held Nile tilapia. In this test a conditioned stimulus (CS - aeration off) was associated with a stressor (air emersion for 2 min- US). We then assessed whether several events of paired CS-US resulted in a conditioned endocrine response (CR), in this case an increase in plasma cortisol after presentation of the CS only. Before testing feeding as US, the postprandial or social holding condition for feeding effects on cortisol levels was tested. Nile tilapia showed increased cortisol after feeding associated to social context (grouped fish), but not to food only (single-held fish). In a third study, feeding was tested as US in an experiment similar to the first study but an increase in feeding-induced cortisol could not be conditioned. The absence of CR suggests that the stressor affects acquisition of this response, which may be a consequence of stimulus intensity or biological relevance. This study expands the recently reported Pavlovian conditioning paradigm for endocrine response in fish.     

An indissoluble knot: An unexpected troubleshooting during Micra implantation

Micra is a transcatheter leadless pacing system delivered percutaneously through femoral vein access into the right ventricle. We are going to describe an initially standard procedure, with an unexpected troubleshooting at the end: the impossibility to release the device and retract the delivery due to a knot in the tether.