On malfunctioning software

Artefacts do not always do what they are supposed to, due to a variety of reasons, including manufacturing problems, poor maintenance, and normal wear-and-tear. Since software is an artefact, it should be subject to malfunctioning in the same sense in which other artefacts can malfunction. Yet, whether software is on a par with other artefacts when it comes to malfunctioning crucially depends on the abstraction used in the analysis. We distinguish between “negative” and “positive” notions of malfunction. A negative malfunction, or dysfunction, occurs when an artefact token either does not (sometimes) or cannot (ever) do what it is supposed to. A positive malfunction, or misfunction, occurs when an artefact token may do what is supposed to but, at least occasionally, it also yields some unintended and undesirable effects. We argue that software, understood as type, may misfunction in some limited sense, but cannot dysfunction. Accordingly, one should distinguish software from other technical artefacts, in view of their design that makes dysfunction impossible for the former, while possible for the latter

Bisfosfonatos y Patología Oral I: aspectos generales y preventivos

Los bisfosfonatos constituyen un grupo de fármacos capaces de modular el recambio óseo y disminuir su remodelado cuando existe una reabsorción excesiva. Por ello están indicados en numerosas patologías óseas como la osteoporosis postmenopáusica o la osteolisis asociada al cáncer de mama o al mieloma múltiple. En los últimos años y a raíz de su utilización masiva se han ido publicando numerosos casos de complicaciones asociadas a su uso. Entre los posibles efectos adversos más importantes se encuentran los orales, con la aparición de ulceraciones y sobre todo los casos de osteonecrosis de los maxilares asociados a esta terapéutica. En esta revisión analizamos las características generales de estos medicamentos y su mecanismo de actuación, así como los efectos adversos descritos, especialmente los orales y maxilofaciales, haciendo una referencia especial sobre la prevención de la osteonecrosis de los maxilares, a la luz de los casos descritos en la literatura médica y odontológica. El protocolo preventivo refuerza el papel fundamental del odontólogo en la prevención efectiva de este proceso antes, durante y después del tratamiento.Bisphosphonates constitute a group of drugs capable of modulating bone turnover, and reduce its remodelling when an excessive resorption occurs. This is why they are indicated in a large group of bone diseases like postmenopausal osteoporosis or osteolisis associated with breast cancer or multiple myeloma. Over the last years and due to their extensive use, many cases of complications associated with their use have been published. Among the most important possible adeverse effects are the oral ones, with the appearance of ulcerations and, especially, osteonecrosis of the jaws associated with this therapy. In this paper, we have analyzed the general characteristics of these drugs and their mechanisms of action as well as the described adverse effects, especially oral and maxillofacial has been made special reference regarding the prevention of osteonecrosis of the jaws, hightened by cases described in medical and odontological literature. The preventive protocol backs up the fundamental role of the odontologist in the effective prevention of this process before, during and after the treatment

Amino acids in the development of Prodrugs

Although drugs currently used for the various types of diseases (e.g., antiparasitic, antiviral, antibacterial, etc.) are effective, they present several undesirable pharmacological and pharmaceutical properties. Most of the drugs have low bioavailability, lack of sensitivity, and do not target only the damaged cells, thus also affecting normal cells. Moreover, there is the risk of developing resistance against drugs upon chronic treatment. Consequently, their potential clinical applications might be limited and therefore, it is mandatory to find strategies that improve those properties of therapeutic agents. The development of prodrugs using amino acids as moieties has resulted in improvements in several properties, namely increased bioavailability, decreased toxicity of the parent drug, accurate delivery to target tissues or organs, and prevention of fast metabolism. Herein, we provide an overview of models currently in use of prodrug design with amino acids. Furthermore, we review the challenges related to the permeability of poorly absorbed drugs and transport and deliver on target organs.NV acknowledges support from Fundação para a Ciência e Tecnologia (FCT, Lisbon, Portugal) and FEDER (European Union), award number IF/00092/2014/CP1255/CT0004. NV also thanks FCT for the IF position and Fundação Manuel António da Mota (FMAM, Porto, Portugal) and Pfizer (Portugal) for support for the Nuno Vale Research Group. The contents of this report are solely the responsibility of the authors and do not necessarily represent the official views of the FCT, FMAM and Pfizer

Bisphosphonates and Oral Pathology I : general and preventive aspects

Los bisfosfonatos constituyen un grupo de fármacos capaces de modular el recambio óseo y disminuir su remodelado cuando existe una reabsorción excesiva. Por ello están indicados en numerosas patologías óseas como la osteoporosis postmenopáusica o la osteolisis asociada al cáncer de mama o al mieloma múltiple. En los últimos años y a raíz de su utilización masiva se han ido publicando numerosos casos de complicaciones asociadas a su uso. Entre los posibles efectos adversos más importantes se encuentran los orales, con la aparición de ulceraciones y sobre todo los casos de osteonecrosis de los maxilares asociados a esta terapéutica. En esta revisión analizamos las características generales de estos medicamentos y su mecanismo de actuación, así como los efectos adversos descritos, especialmente los orales y maxilofaciales, haciendo una referencia especial sobre la prevención de la osteonecrosis de los maxilares, a la luz de los casos descritos en la literatura médica y odontológica. El protocolo preventivo refuerza el papel fundamental del odontólogo en la prevención efectiva de este proceso antes, durante y después del tratamiento

Bisphosphonates and Oral Pathology II. Osteonecrosis of the jaws : Review of the literature before 2005

Bisphosphonates are bone-turnover modulating drugs which are used in the management of a number of bone diseases ranging from osteoporosis to neoplasic pathology-associated osteolysis. In the last years a number of cases of osteonecrosis of the jaws associated with these drugs have been reported. In this review we analyze the cases published in the literature indexed from 2003 to December 2005. During this period 246 cases were reported, being more frequently associated with women in the sixth decade of life. More frequently associated bisphosphonates were the nitrogenated bisphosphonates (pamidronate, zolendronic acid) and the most common oral antecedent was a dental extraction. Nevertheless more than 25% of the cases were spontaneous. The most frequent site was the mandible and most of the cases presented clinical evidence of bone exposure and pain. Different treatments have been proposed with different antibiotic therapies with or without surgery, showing in general terms an uncertain prognosis with low healing rates

Carbidopa Alters Tryptophan Metabolism in Breast Cancer and Melanoma Cells Leading to the Formation of Indole-3-Acetonitrile, a Pro-Proliferative Metabolite

Carbidopa is used for the treatment of Parkinson's disease (PD) as an inhibitor of DOPA decarboxylase, and PD patients taking carbidopa have a lower incidence of various tumors, except for breast cancer and melanoma. Recently, it was shown that carbidopa inhibits tryptophan-2,3-dioxygenase (TDO) and kynureninase enzymes. In the present study, the effect of carbidopa on the viability and metabolic profile of breast cancer MCF-7 and melanoma A375 cells was investigated. Carbidopa was not effective in inhibiting MCF-7 and A375 proliferation. Liquid chromatography and mass spectrometry revealed a new compound, identified as indole-3-acetonitrile (IAN), which promoted a concentration-dependent increase in the viability of both cell lines. The results suggest that treatment with carbidopa may alter tryptophan (Trp) metabolism in breast cancer and melanoma leading to the formation of a pro-proliferative Trp metabolite, which may contribute to its failure in reducing breast cancers and melanoma incidence in PD patients taking carbidopa.This work was financed by FEDER—Fundo Europeu de Desenvolvimento Regional funds through the COMPETE 2020—Operational Programme for Competitiveness and Internationalisation (POCI), Portugal 2020, and by Portuguese funds through FCT, in the framework of the project “Institute for Research and Innovation in Health Sciences” (POCI-01-0145-FEDER-007274).” NV thanks FCT for IF position, Fundação Manuel António da Mota (FMAM, Portugal) for support. The contents of this report are solely the responsibility of the authors and do not necessarily represent the official views of the FCT and FMAMinfo:eu-repo/semantics/publishedVersio

Caffeine, a Risk Factor for Osteoarthritis and Longitudinal Bone Growth Inhibition

Osteoarthritis (OA), the most common chronic rheumatic disease, is mainly characterized by a progressive degradation of the hyaline articular cartilage, which is essential for correct joint function, lubrication, and resistance. Articular cartilage disturbances lead to joint failure, pain, and disability. Hyaline cartilage is also present in the growth plate and plays a key role in longitudinal bone growth. Alterations of this cartilage by diverse pathologies have been related to longitudinal bone growth inhibition (LBGI), which leads to growth retardation. Diet can play a crucial role in processes involved in the OA and LBGI's onset and evolution. Specifically, there is ample evidence pointing to the negative impacts of caffeine consumption on hyaline cartilage. However, its effects on these tissues have not been reviewed. Accordingly, in this review, we summarize all current knowledge in the PubMed database about caffeine catabolic effects on articular and growth plate cartilage. Specifically, we focus on the correlation between OA and LBGI with caffeine prenatal or direct exposure. Overall, there is ample evidence indicating that caffeine intake negatively affects the physiology of both articular and growth plate cartilage, increasing consumers predisposition to suffer OA and LBGI. As a result, caffeine consumption should be avoided for these pathologies

Algorithmic iteration for computational intelligence

Machine awareness is a disputed research topic, in some circles considered a crucial step in realising Artificial General Intelligence. Understanding what that is, under which conditions such feature could arise and how it can be controlled is still a matter of speculation. A more concrete object of theoretical analysis is algorithmic iteration for computational intelligence, intended as the theoretical and practical ability of algorithms to design other algorithms for actions aimed at solving well-specified tasks. We know this ability is already shown by current AIs, and understanding its limits is an essential step in qualifying claims about machine awareness and Super-AI. We propose a formal translation of algorithmic iteration in a fragment of modal logic, formulate principles of transparency and faithfulness across human and machine intelligence, and consider the relevance to theoretical research on (Super)-AI as well as the practical import of our results

DSM-5 insomnia disorder in pregnancy: associations with depression, suicidal ideation, and cognitive and somatic arousal, and identifying clinical cutoffs for detection

STUDY OBJECTIVES: The study had three primary goals. First, we estimated survey-assessed DSM-5 insomnia disorder rates in pregnancy, and described associated sociodemographics, and sleep-wake and mental health symptoms. Second, we derived cutoffs for detecting DSM-5 insomnia disorder using common self-report measures of sleep symptoms. Third, we identified clinically relevant cut-points on measures of nocturnal cognitive and somatic arousal. METHODS: Ninety-nine women (85.9% in the 2nd trimester) completed online surveys including DSM-5 insomnia disorder criteria, the Insomnia Severity Index (ISI), Pittsburgh Sleep Quality Index (PSQI), Presleep Arousal Scale’s Cognitive (PSASC) and Somatic (PSASS) factors, and Edinburgh Postnatal Depression Scale. RESULTS: DSM-5 insomnia disorder rate was 19.2%. Insomnia was associated with depression, suicidality, nocturnal cognitive and somatic arousal, and daytime sleepiness. An ISI scoring method that aligns with DSM-5 criteria yielded excellent metrics for detecting insomnia disorder and good sleep. Regarding quantitative cutoffs, ISI ≥ 10 and ISI ≥ 11 (but not ISI ≥ 15) were supported for detecting DSM-5 insomnia, whereas ISI ≤ 7 and ISI ≤ 9 performed well for detecting good sleep. PSQI cutoff of 5 was supported for detecting insomnia and good sleep. The optimal cutoff for nocturnal cognitive arousal was PSASC ≥ 18, whereas the optimal cutoff for somatic arousal was PSASS ≥ 13. CONCLUSIONS: Insomnia disorder affects a large segment of pregnant women. Empirically derived cutoffs for insomnia, good sleep, cognitive arousal, and somatic arousal may inform case identification and future perinatal sleep research methodology