Who is the biological patient? A new gradational and dynamic model for one health medicine.

One Health medicine aims to improve health by focusing on the relations between the health of humans, animals, and the environment. However, One Health does not provide a clear idea of these relations, which are still represented as conceptually separated and not as one health, as the name implies. Inspired by holobiont research, I suggest a new model and conceptual framework for One Health that expands the notion of the biological patient by providing a gradational and dynamic understanding of environments, patients, and their relations. This new model conceptualizes humans and non-humans, individual organisms, and collectives, as belonging to one system that allows for more or less inclusive understandings of patients. As such, it resolves the conceptual tensions of different One Health approaches and supports the implementation of One Health as an interdisciplinary research field.

On recovery: re-directing the concept by differentiation of its meanings.

Recovery is a commonly used concept in both professional and everyday contexts. Yet despite its extensive use, it has not drawn much philosophical attention. In this paper, I question the common understanding of recovery, show how the concept is inadequate, and introduce new and much needed terminology. I argue that recovery glosses over important distinctions and even misrepresents the process of moving away from malady as "going back" to a former state of health. It does not invite important nuances needed to distinguish between biomedical, phenomenological, and social perspectives. In addition, I claim that there are many conditions where we are making use of the concept of recovery, although the person recovered from the condition in question, has not regained the same degree of soundness. I show how the concept of recovery leads to conceptual discrepancies that can result in worsening patients' conditions. To gain a fuller understanding, I propose to rethink the direction of the process in question. I define the process of moving away from malady as a move forward towards a new state of soundness. I also suggest three terms, corresponding to different perspectives, to describe this movement forward: 'curing' (biomedical perspective), 'healing' (first-person perspective), and 'habilitating' (social perspective). This new terminology provides a more nuanced understanding of the states of both malady and soundness and an attentiveness as to how they differ and relate.

Mitochondrial matrix-localized p53 participates in degradation of mitochondrial RNAs.

Mitochondrial RNA degradation plays an important role in maintenance of the mitochondria genetic integrity. Mitochondrial localization of p53 was observed in non-stressed and stressed cells. p53, as an RNA-binding protein, exerts 3'→5' exoribonuclease activity. The data suggest that in non-stressed cells, mitochondrial matrix-localized p53, with exoribonuclease activity, may play a housekeeping positive role. p53, through restriction the formation of new RNA/DNA hybrid and processing R-loop, might serve as mitochondrial R-loop suppressor. Conversely, stress-induced matrix-p53 decreases the amount of mitochondrial single-stranded RNA transcripts (including polyA- and non-polyA RNAs), thereby leading to the decline in the amount of mitochondria-encoded oxidative phosphorylation components.

p53 regulates its own expression by an intrinsic exoribonuclease activity through AU-rich elements.

The onco-suppressor p53 protein plays also an important role in the control of various aspects of health and disease. p53 levels are low in normal cells and elevated under stress conditions. While low levels of p53 promote tumor formation, overactive p53 leads to premature aging and cell death. RNA degradation is a critical level of regulation contributing to the control of gene expression. p53, as an RNA-binding protein, exerts 3' → 5' exoribonuclease activity, mediating degradation of adenylate/uridylate-rich elements (ARE)-containing ssRNAs. The 3'-UTR of p53-mRNA, which is a target of p53 itself, harbors cis-acting AREs. Our results suggest that p53 controls its own expression through murine double-minute 2 (mdm2)-independent "RNA decay" function in cytoplasm. We demonstrate that p53 expresses an exoribonuclease activity through the binding to ARE sequences of p53-mRNA via translation-independent and translation-dependent polysome-associated pathways. Antagonistic interplay was detected between p53 levels and execution of its exoribonuclease function mirrored in low p53 levels in normal cells, due to the efficient exoribonuclease activity, and in the accumulation of p53 in cells exposed to p53-activating drugs in accordance with the reduced exoribonuclease activity. Apparently, p53, via control of its own mRNA stability and/or translation in cytoplasm, might act as a negative regulator of p53-mRNA levels. The observed connection between exoribonuclease activity and p53 abundance highlights the importance of this function affecting p53 expression, imperative for multiple functions, with implications for the steady-state levels of protein and for the p53 stress response. The modulation in expression of exoribonuclease activity would be translated into the alterations in p53 level. KEY MESSAGES: p53 controls its own expression through mdm2-independent "RNA decay" function in cytoplasm. p53 expresses an exoribonuclease activity through the binding to ARE sequences of p53-mRNA. Antagonistic interplay exists between stress-induced p53 and execution of its exoribonuclease function.

Comparison of Snellen and Early Treatment Diabetic Retinopathy Study charts using a computer simulation.

AIM: To compare accuracy, reproducibility and test duration for the Snellen and the Early Treatment Diabetic Retinopathy Study (ETDRS) charts, two main tools used to measure visual acuity (VA). METHODS: A computer simulation was programmed to run multiple virtual patients, each with a unique set of assigned parameters, including VA, false-positive and false-negative error values. For each virtual patient, assigned VA was randomly chosen along a continuous scale spanning the range between 1.0 to 0.0 logMAR units (equivalent to 20/200 to 20/20). Each of 30 000 virtual patients were run ten times on each of the two VA charts. RESULTS: Average test duration (expressed as the total number of characters presented during the test ±SD) was 12.6±11.1 and 31.2±14.7 characters, for the Snellen and ETDRS, respectively. Accuracy, defined as the absolute difference (± SD) between the assigned VA and the measured VA, expressed in logMAR units, was superior in the ETDRS charts: 0.12±0.14 and 0.08±0.08, for the Snellen and ETDRS charts, respectively. Reproducibility, expressed as test-retest variability, was superior in the ETDRS charts: 0.23±0.17 and 0.11±0.09 logMAR units, for the Snellen and ETDRS charts, respectively. CONCLUSION: A comparison of true (assigned) VA to measured VA, demonstrated, on average, better accuracy and reproducibility of the ETDRS chart, but at the penalty of significantly longer test duration. These differences were most pronounced in the low VA range. The reproducibility using a simulation approach is in line with reproducibility values found in several clinical studies.

The influence of varying the number of characters per row on the accuracy and reproducibility of the ETDRS visual acuity chart.

BACKGROUND: As part of an effort to improve upon the Snellen chart, we provide a standardized version of the ETDRS chart utilizing five characters in each row. The choice of five characters contradicts the recommended ten characters per row determined by the NAS-NRC, a committee established to provide guidelines for testing visual acuity. We set out to quantify the influence of varying the number of characters per line on the ETDRS chart with respect to the accuracy and reproducibility of visual acuity measurement. METHODS: Eleven different ETDRS charts were created, each with a different number of characters appearing in each row. A computer simulation was programmed to run 10,000 virtual patients, each with a unique visual acuity, false-positive and false-negative error value. RESULTS: Accuracy and reproducibility were found to roughly correlate with the number of characters present in each row, such that charts with 1, 3, 5, 7, 9, and 11 characters per row provided accuracy of 0.164, 0.094, 0.078, 0.073, 0.071, and 0.070 logMAR, respectively. A non-linear relationship was observed, with little improvement found beyond seven characters per row. In addition, charts with an even number of characters per row provided higher accuracy than their greater-number odd counterparts. In certain instances, accuracy and reproducibility were not well correlated. CONCLUSIONS: Increasing the number of characters per row in the ETDRS chart provides a trade-off between accuracy and test duration. An optimized chart layout would take these findings into account, allowing for the use of different chart layouts for clinical versus research settings.

Histologic RNFL Thickness in Glaucomatous Versus Normal Human Eyes.

PURPOSE: To compare the retinal nerve fiber layer (RNFL) thickness in histologic sections of glaucomatous eyes to nonglaucomatous eyes, to ascertain whether RNFL thinning can be confirmed histologically in human eyes. MATERIALS AND METHODS: Seven postmortem glaucomatous eyes were compared with 17 normal postmortem eyes. The eyes were sectioned using the "umbrella technique" and measurements were performed on 4 concentric peripapillary rings with diameters of 3.0, 3.5, 4.0, and 4.5 mm. An overall average thickness, as well as an average for each of the temporal, superior, nasal, and inferior quadrants was obtained. The RNFL thickness of both groups in each of the quadrants in each of the rings were compared. RESULTS: The overall average thickness (µm±SD) of the glaucomatous eyes for the 3.5-mm diameter rings was 36.5±10.6 compared with an average thickness of 60.3±19.5 in the nonglaucomatous eyes (P=0.006). The average sectorial thickness of the 3.5-mm diameter rings for the glaucomatous and normal eyes, respectively, was: temporal 30.9±10.6, 49.2±26.4 (P=0.080); superior 41.0±13.2, 75.3±26.5 (P=0.003); nasal 32.7±7.8, 48.1±15.0 (P=0.023); and inferior 41.6±14.4, 69.4±22.4 (P=0.012). The overall physiological "double hump" pattern was less preserved in the glaucomatous eyes. CONCLUSIONS: In this study a statistically significant loss of RNFL tissue was demonstrated when comparing glaucomatous to normal postmortem human eyes. These findings strengthen data obtained using imaging techniques that quantify RNFL thickness.

Metformin downregulates the insulin/IGF-I signaling pathway and inhibits different uterine serous carcinoma (USC) cells proliferation and migration in p53-dependent or -independent manners.

Accumulating epidemiological evidence shows that obesity is associated with an increased risk of several types of adult cancers, including endometrial cancer. Chronic hyperinsulinemia, a typical hallmark of diabetes, is one of the leading factors responsible for the obesity-cancer connection. Numerous cellular and circulating factors are involved in the biochemical chain of events leading from hyperinsulinemia and insulin resistance to increased cancer risk and, eventually, tumor development. Metformin is an oral anti-diabetic drug of the biguanide family used for treatment of type 2 diabetes. Recently, metformin was shown to exhibit anti-proliferative effects in ovarian and Type I endometrial cancer, although the mechanisms responsible for this non-classical metformin action remain unclear. The insulin-like growth factors (IGFs) play a prominent role in cancer biology and their mechanisms of action are tightly interconnected with the insulin signaling pathways. Given the cross-talk between the insulin and IGF signaling pathways, the aim of this study was to examine the hypothesis that the anti-proliferative actions of metformin in uterine serous carcinoma (USC) are potentially mediated via suppression of the IGF-I receptor (IGF-IR) pathway. Our results show that metformin interacts with the IGF pathway, and induces apoptosis and inhibition of proliferation and migration of USC cell lines with both wild type and mutant p53. Taken together, our results suggest that metformin therapy could be a novel and attractive therapeutic approach for human USC, a highly aggressive variant of endometrial cancer.

Bowel loops and eyelid droops.

A patient presented with a small-bowel obstruction associated with signs and symptoms of botulism. Fecal cultures were positive for viable Clostridium botulinum. This case emphasizes the importance of a broad differential diagnosis and doing a complete examination to account for all signs and symptoms.

Axial myopathy due to primary amyloidosis.

A 74-year-old man presented with progressive weakness involving only his back muscles. Serum protein electrophoresis revealed the presence of a monoclonal gammopathy. Muscle biopsy of affected muscles demonstrated amyloid light chain deposition surrounding individual muscle fibers as well as in the walls of blood vessels in association with vasculitis. Selective involvement of axial muscles in isolated amyloid myopathy has not been previously described. We report the occurrence of axial myopathy with associated vasculitis as a presenting feature of primary (AL) amyloidosis. Amyloidosis should be considered in the differential diagnosis of focal myopathies, since the condition may be responsive to chemotherapy.

Simulation of brain death from fulminant de-efferentation.

BACKGROUND: Guillain-Barré syndrome (GBS) classically presents with a subacutely evolving areflexic paralysis, with typical laboratory findings of elevated cerebrospinal fluid protein and abnormal nerve conduction studies. There is now an increasing recognition of GBS variants that differ in clinical presentation, prognosis, electrophysiology and presumed pathogenesis. Fulminant cases of GBS have been reported in which a rapid deterioration evolves to a clinical state resembling "brain death". METHODS: A retrospective analysis of two such cases of fulminant neuropathy are described, that includes the clinical course, electrophysiology and neuropathology where available. RESULTS: We describe two patients that presented with a rapid course of neurological deterioration, lapsing into what resembled a "clinically brain-dead" state that was subsequently ascribed to a fulminant polyneuropathy. Investigations (electrophysiological, pathological) and the clinical course suggested an axonal neuropathy. CONCLUSIONS: A fulminant neuropathy can result in a clinical state resembling "brain death" through diffuse de-efferentation. Although generally attributed to aggressive demyelination with secondary axonal degeneration, a primary axonopathy can also lead to a similar clinical presentation.