Malfunctions

A persistent boast of the historical approach to functions is that functional properties are normative. The claim is that a token trait retains its functional status even when it is defective, diseased, or damaged and consequently unable to perform the relevant task. This is because historical functional categories are defined in terms of some sort of historical success -- success in natural selection, typically -- which imposes a norm upon the performance of descendent tokens. Descendents thus are supposed to perform the associated task even when they cannot. The conceit, then, is that malfunctions are explicable in terms of historical success. The aim of this paper is to challenge this conceit. My thesis is that the historical approach to functions lacks the resources with which to account for the possibility of malfunctions. If functional types are defined in terms of historical success, then tokens that lack the defining property due to defect, and tokens that have lost the defining property due to disease or damage, are excluded from the functional category. Historically based malfunctions, in consequence, are impossible. The historical approach is no better than its non-historical competitors in accounting for the presumed normativity of functional properties.     

Cancer therapy design based on pathway logic

MOTIVATION: Cancer encompasses various diseases associated with loss of cell cycle control, leading to uncontrolled cell proliferation and/or reduced apoptosis. Cancer is usually caused by malfunction(s) in the cellular signaling pathways. Malfunctions occur in different ways and at different locations in a pathway. Consequently, therapy design should first identify the location and type of malfunction to arrive at a suitable drug combination. RESULTS: We consider the growth factor (GF) signaling pathways, widely studied in the context of cancer. Interactions between different pathway components are modeled using Boolean logic gates. All possible single malfunctions in the resulting circuit are enumerated and responses of the different malfunctioning circuits to a 'test' input are used to group the malfunctions into classes. Effects of different drugs, targeting different parts of the Boolean circuit, are taken into account in deciding drug efficacy, thereby mapping each malfunction to an appropriate set of drugs.     

Adverse Events in Robotic Surgery: A Retrospective Study of 14 Years of FDA Data

BackgroundUse of robotic systems for minimally invasive surgery has rapidly increased during the last decade. Understanding the causes of adverse events and their impact on patients in robot-assisted surgery will help improve systems and operational practices to avoid incidents in the future.MethodsBy developing an automated natural language processing tool, we performed a comprehensive analysis of the adverse events reported to the publicly available MAUDE database (maintained by the U.S. Food and Drug Administration) from 2000 to 2013. We determined the number of events reported per procedure and per surgical specialty, the most common types of device malfunctions and their impact on patients, and the potential causes for catastrophic events such as patient injuries and deaths.ResultsDuring the study period, 144 deaths (1.4% of the 10,624 reports), 1,391 patient injuries (13.1%), and 8,061 device malfunctions (75.9%) were reported. The numbers of injury and death events per procedure have stayed relatively constant (mean = 83.4, 95% confidence interval (CI), 74.2–92.7 per 100,000 procedures) over the years. Surgical specialties for which robots are extensively used, such as gynecology and urology, had lower numbers of injuries, deaths, and conversions per procedure than more complex surgeries, such as cardiothoracic and head and neck (106.3 vs. 232.9 per 100,000 procedures, Risk Ratio = 2.2, 95% CI, 1.9–2.6). Device and instrument malfunctions, such as falling of burnt/broken pieces of instruments into the patient (14.7%), electrical arcing of instruments (10.5%), unintended operation of instruments (8.6%), system errors (5%), and video/imaging problems (2.6%), constituted a major part of the reports. Device malfunctions impacted patients in terms of injuries or procedure interruptions. In 1,104 (10.4%) of all the events, the procedure was interrupted to restart the system (3.1%), to convert the procedure to non-robotic techniques (7.3%), or to reschedule it (2.5%).ConclusionsDespite widespread adoption of robotic systems for minimally invasive surgery in the U.S., a non-negligible number of technical difficulties and complications are still being experienced during procedures. Adoption of advanced techniques in design and operation of robotic surgical systems and enhanced mechanisms for adverse event reporting may reduce these preventable incidents in the future.     

Diagnostic analysis

This paper presents an application of sensitivity analysis to the problem of diagnosing malfunctions in a class of continuous physiological systems. The technique leads to a computational algorithm for determining which parameters in a system have deviated from their nominal values and to what extent.     

Flagellum Malfunctions Trigger Metaboly as an Escape Strategy in Euglena gracilis

Euglenoids present the ability to alter the shape of their bodies, a process referred to as metaboly. Metaboly is usually used by phagotrophic cells to engulf their prey. However, Euglena gracilis is osmotrophic and photosynthetic. Though metaboly was discovered centuries ago, it remains unclear why E. gracilis undergo metaboly and what causes them to deform, and some consider metaboly to be a functionless ancestral vestige. Here, we discover that flagellum malfunctions trigger metaboly and metaboly is a smart escape strategy adopted by E. gracilis when the proper rotation and beating of the flagellum are hindered by restrictions including surface obstruction, sticking, resistance, or limited space. Metaboly facilitates escape in five ways: (i) detaching the body from the surface; (ii) enlarging the space between flagellum and the restricting surface which restores beating and rotation of the flagellum; (iii) decreasing the torque of viscous resistance for rotation of the body; (iv) decreasing the length of the body; and (v) crawling backwards on a surface or swimming backwards if the flagellum completely malfunctions or has broken off. Our findings suggest that metaboly plays a key role in enabling E. gracilis to escape from harmful conditions when flagellar functions are impaired or absent.     

Anomalies in the development and functioning of the reproductive system in Siberian sturgeon, <Emphasis Type="Italic">Acipenser baerii</Emphasis> Brandt (Acipenseridae), from the Yenisei River

Based upon long-term studies, the alterations in the development and functioning of the reproductive system in the Yenisei River Siberian sturgeon are analyzed. Primary attention is paid to the malfunctions of gametogenesis during trophoplasmatic growth of the oocytes. Some anomalies were revealed for the first time in the studied population. However, these anomalies are typical for other populations of this species. These anomalies are not species-specific and may be found in other representatives of the family Acipenseridae.     

T-wave Oversensing with Inappropriate Therapy in Remote Monitoring

T-wave oversensing can cause inappropriate implantable cardioverter-defibrillator (ICD) therapies that are difficult to correct. Remote monitoring allows follow-up of ICD patients without visiting the hospital and can help in early detection of any malfunctions. We describe the case of a patient who experienced inappropriate antitachycardia pacing therapy due to T-wave oversensing; the problem was promptly detected by remote monitoring and corrected by device reprogramming.     

To die or not to die: DNA repair in neurons

One of the critical emerging problems in modern pathobiology is how cells govern the decision to live or die, and the cost of making such a decision. Nowhere are these questions more poignant than in deciphering the tissue-specific responses to DNA damage. Mutations in DNA repair enzymes, malfunctions in cell cycle regulation, and genetic instability are associated with most somatic cancers. However, in many hereditary diseases arising from mutations in DNA repair proteins, the same dominant mutations that cause cancer in dividing cells are often associated with cell death in terminally differentiated neurons. Context dependent differences in the response to DNA damage are used to make fundamental choices as to cell fate, and are likely to shed light on the mechanisms underlying human disease.     

Heat shock responses for understanding diseases of protein denaturation

Extracellular stresses induce heat shock response and render cells resistant to lethal stresses. Heat shock response involves induction of heat shock proteins (Hsps). Recently the roles of Hsps in neurodegenerative diseases and cancer are attracting increasing attention and have accelerated the study of heat shock response mechanism. This review focuses on the stress sensing steps, molecules involved in Hsps production, diseases related to Hsp malfunctions, and the potential of proteomics as a tool for understanding the complex signaling pathways relevant to these events.     

The cornified envelope: a model of cell death in the skin

The epidermis functions as a barrier against the environment by means of several layers of terminally differentiated, dead keratinocytes - the cornified layer, which forms the endpoint of epidermal differentiation and death. The cornified envelope replaces the plasma membrane of differentiating keratinocytes and consists of keratins that are enclosed within an insoluble amalgam of proteins, which are crosslinked by transglutaminases and surrounded by a lipid envelope. New insights into the molecular mechanisms and the physiological endpoints of cornification are increasing our understanding of the pathological defects of this unique form of programmed cell death, which is associated with barrier malfunctions and ichthyosis.     

Malfunctioning of adipocytes in obesity is linked to quantitative surfaceome changes

Increased triglyceride accumulation in adipocytes caused by a misbalance between energy intake and energy consumption, results in increased adipocyte size, excess adipose tissue, increased body weight and ultimately, obesity. It is well established that enlarged adipocytes exhibit malfunctions that contribute to whole body insulin resistance, a key factor for the development of type 2 diabetes. However, the underlying molecular cause for dysfunctional adipocyte behavior and signaling is poorly understood. Since the adipocyte cell surface proteome, or surfaceome, represents the cellular signaling gateway to the microenvironment, we studied the contribution of this subproteome to adipocyte malfunctions in obesity. By using the chemoproteomic Cell Surface Capture (CSC) technology, we established surfaceome maps of primary adipocytes derived from different mouse models for metabolic disorders. Relative quantitative comparison between these surfaceome maps revealed a set of cell surface glycoproteins with modulated location-specific abundance levels. RNAi mediated targeting of a subset of the detected obesity modulated cell surface glycoproteins in an in vitro model system provided functional evidence for their role in adiponectin secretion and the lipolytic activity of adipocytes. Thus, we conclude that the identified cell surface glycoproteins which exhibit obesity induced abundance changes and impact adipocyte function at the same time contribute to adipocyte malfunction in obesity. The regulation of their concerted activities could improve adipocyte function in obesity.     

The 2-bodied continuous cardiac output catheter

Continuous cardiac output (CCO) pulmonary artery catheters (PACs) are used in cardiac surgical patients for hemodynamic monitoring. This is an invasive technique; therefore, it has well-known mechanical and infectious complications related to its use. Associated problems, more commonly noticed, are catheter malfunctions and malpositions. We present a case in which a CCO catheter appeared to have a double body on radiologic diagnosis. This resulted in extra radiography for rechecking and careful clinical reevaluation of the monitored data.     

The neuronal primary cilium: Driver of neurogenesis and memory formation in the hippocampal dentate gyrus?

Considerable attention has recently been focused on the postnatal persistence of neurogenesis in the dentate gyrus of the hippocampus and the roles of signals from the primary cilium in the different functions of an increasing number of tissues and their malfunctions. Here we summarize the evidence that ties sonic hedgehog-triggered proliferogenic signaling from the primary cilia on granule cell progenitors in the adult dentate subgranular zone to maintain a pool of new “blank slate” dentate granule cells. These can be recruited to bundle and encode novel inputs flowing from various regions of the brain into the dentate gyrus via the entorhinal cortex without altering and erasing the synaptic patterns from previous inputs inscribed on older granule cells.     

Vascular endothelium in cancer

The vascular endothelium plays an essential role during organogenesis and in tissue homeostasis. Growing evidence also supports its essential and complex role in tumour biology and cancer progression. In particular, excessive proliferation and transformation or dysfunction of endothelial cells leads to pathological (lymph)angiogenesis or vascular malfunctions, which are hallmarks of neoplastic and malignant disorders. Reciprocal interactions between endothelial cells and the local tumour microenvironment may regulate tumour progression and resistance to anti-cancer therapies in a tumour-type-specific manner. This work was supported by Cancer Research UK.     

Malfunctions within the Cbl interactome uncouple receptor tyrosine kinases from destructive transport

Proteins of the Cbl family are adaptor molecules and ubiquitin ligases with major functions in the regulation, intracellular transport and degradation of receptor tyrosine kinases (RTKs). Due to this central role, mutations that cause malfunctions of Cbl or their associated proteins - termed the Cbl interactome - easily lead to the transformation of affected cells and eventually the development of cancer. This review intends to give an overview on the mechanisms of Cbl-mediated cell transformation in light of the dysregulated intracellular trafficking of RTKs.     

Comparative Performance of Three Brands of Lightweight Global Positioning System Collars

ABSTRACT Recent miniaturization and weight reductions of Global Positioning System (GPS) collars have opened up deployment opportunities on a new array of terrestrial animal species, but the performance of lightweight (<90 g) GPS collars has not been evaluated. I examined the success of 42 GPS collars from 3 manufacturers (Televilt/TVP Positioning, AB, Lindesburg, Sweden; Sirtrack Ltd., Havelock North, New Zealand; H.A.B.I.T [HABIT] Research Ltd., Victoria, BC, Canada) in stationary, open-sky conditions and during deployments on brushtail possums (Trichosurus vulpecula), a nocturnal arboreal marsupial. I assessed performance of these collars in terms of technical malfunctions, fix-success rates, battery longevity, and aspects of location quality. Technical malfunctions occurred in >50% of HABIT and Televilt collars, whereas all Sirtrack collars operated normally. Fix-success rates for all brands were significantly higher during stationary tests than when deployed on brushtail possums. HABIT and Televilt brands functioned poorly in field conditions, with success rates of 16.2% and 2.1%, respectively. Sirtrack collars had the highest fix rate when deployed (64.8%). I modified several HABIT collars by changing the GPS antenna location, with a resultant substantial increase in field fix success (92.6%). Most collars ceased working before they reached 50% of their manufacturer-estimated life expectancy. Suboptimal placement of GPS antenna, combined with short satellite acquisition times and long fix intervals, were a likely cause of low fix-success rates and premature battery failures. Researchers wanting to employ lightweight GPS collars must be aware of current limitations and should carefully consider prospects of low fix rates and limited battery lives before deciding whether these units are capable of meeting study objectives.     

Automated pipette failure monitoring using image processing for point-of-care testing devices

Background

The accuracy and precision of liquid handling can be altered by several causes including wearing or failure of parts, and human error. The last cause is crucial since point-of-care testing (POCT) devices can be used by non-experienced users or patients themselves. Therefore it is important to improve the method of informing the users of POCT device malfunctions due to damage of parts or human error.

Methods

In this paper, image-based failure monitoring of the automated pipetting was introduced for POCT devices. An inexpensive, high-performance camera for smartphones was employed in our previous work to resolve various malfunctions such as incorrect insertion of the tip, false positioning of the tip and pump, and improper operation of the pump. The image acquired from the camera was analyzed to detect the malfunctions. In this paper, the reagent volume in the tip was estimated from the image processing to verify the pump operation. First, the color component corresponding to the reagent intrinsic color was extracted to identify the reagent area in the tip before applying the binary image processing. The extracted reagent area was projected horizontally and the support length of the projection image was calculated. As the support length was related to the reagent volume, it was referred to the volume length. The relationship between the measured volume length and the previously measured solution mass was investigated. If we can predict the mass of the solution by the volume length, we will be able to detect the pump malfunction.

Results

The cube of the volume length obtained by the proposed image processing method showed a very linear relationship with the reagent mass in the tip injected by the pumping operation (R²?=?0.996), indicating that the volume length could be utilized to estimate the reagent volume to monitor the accuracy and precision of the pumping operation.

Conclusions

An inexpensive smartphone camera was enough to detect various malfunctions of a POCT device with pumping operation. The proposed image processing could monitor the level of inaccuracy of pumping volume in limited range. The simple image processing such as a fixed threshold and projections was employed for the cost optimization and system robustness. However it delivered the promising results because the imaging condition was highly controllable in the devices.

     

In vitro assessment of anti-inflammatory and anti-arthritic effects of Helicanthes elasticus (Desv.) Danser accessions collected from six different hosts

Arthritis and other rheumatoid or non-rheumatoid joint inflammations are prevalent among people all around the world. The plant-derived drugs and other herbal therapeutic practices are widely used against these malfunctions. Helicanthes elasticus (Desv.) Danser, an endemic hemiparasite was found less exploited for these types of disorders and this plant collected from different hosts might be having differential expression towards such ailments. In order to asses this differential expression, in the present study, methanolic extract of Helicanthes elasticus collected from six different hosts were examined for HRBC membrane stabilization assay for anti-inflammatory responses and the protein denaturation method for anti-arthritic assay. Anti-inflammatory and anti-arthritic potential were observed in H. elasticus growing on different hosts. The hemiparasitic plant obtained from Hevea brasiliensis, Nerium oleander and Anacardium occidentale showed high anti-inflammatory responses whereas those from Nerium oleander had high anti-arthritic efficacy. H. elasticus showed a therapeutically significant effect on arthritis and inflammatory responses in humans and the efficacy of the curative property showed variation with respect to the host plant in which the parasite has hemiparasite found growing.     

Der Epitheliale Natrium Kanal. 15 Jahre Kanalarbeiten

Epithelial sodium channels (ENaCs) are sodium‐conducting ion channels that are located in the apical membrane of various epithelia. They represent the rate‐limiting step for transeptihelial sodium‐ and thereby water‐transport. ENaCs contribute to a variety of physiological processes including the regulation of salt and water homeostasis, blood pressure or the water content of the lung. Further, malfunctions in ENaC regulation contribute to the pathogenesis of diseases like hypertension or pulmonary oedema. This article describes the function and physiology of epithelial sodium channels as well as cellular mechanisms that determine the activity of these ion channels.