Computing a rectilinear shortest path amid splinegons in plane

We reduce the problem of computing a rectilinear shortest path between two given points s and t in the splinegonal domain \calS to the problem of computing a rectilinear shortest path between two points in the polygonal domain. As part of this, we define a polygonal domain \calP from \calS and transform a rectilinear shortest path computed in \calP to a path between s and t amid splinegon obstacles in \calS. When \calS comprises of h pairwise disjoint splinegons with a total of n vertices, excluding the time to compute a rectilinear shortest path amid polygons in \calP, our reduction algorithm takes O(n + h \lg{n}) time. For the special case of \calS comprising of concave-in splinegons, we have devised another algorithm in which the reduction procedure does not rely on the structures used in the algorithm to compute a rectilinear shortest path in polygonal domain. As part of these, we have characterized few of the properties of rectilinear shortest paths amid splinegons which could be of independent interest

The positive predictive value of asymmetrical skin creases in the diagnosis of pathological developmental dysplasia of the hip

Aims The aim of this study was to identify the association between asymmetrical skin creases of the thigh, buttock or inguinal region and pathological developmental dysplasia of the hip (DDH). Patients and Methods Between 1 January 1996 and 31 December 2016, all patients referred to our unit from primary or secondary care with risk factors for DDH were assessed in a “one stop” clinic. All had clinical and sonographic assessment by the senior author (RWP) with the results being recorded prospectively. The inclusion criteria for this study were babies and children referred with asymmetrical skin creases. Those with a neurological cause of DDH were excluded. The positive predictive value (PPV) for pathological DDH was calculated. Results A total of 105 patients met the inclusion criteria. There were 71 girls and 34 boys. Only two were found to have pathological DDH. Both also had unilateral limited abduction of the hip in flexion and a positive Galeazzi sign with apparent leg-length discrepancy. Thus, if the specialist examination of a patient with asymmetrical skin creases was normal, the PPV for DDH was 0%. Conclusion Isolated asymmetrical skin creases are an unreliable clinical sign in the diagnosis of pathological DDH. Greater emphasis should be placed on the presence of additional clinical signs to guide radiological screening in babies and children

Role of cellular senescence and NOX4-mediated oxidative stress in systemic sclerosis pathogenesis.

Systemic sclerosis (SSc) is a systemic autoimmune disease characterized by progressive fibrosis of skin and numerous internal organs and a severe fibroproliferative vasculopathy resulting frequently in severe disability and high mortality. Although the etiology of SSc is unknown and the detailed mechanisms responsible for the fibrotic process have not been fully elucidated, one important observation from a large US population study was the demonstration of a late onset of SSc with a peak incidence between 45 and 54 years of age in African-American females and between 65 and 74 years of age in white females. Although it is not appropriate to consider SSc as a disease of aging, the possibility that senescence changes in the cellular elements involved in its pathogenesis may play a role has not been thoroughly examined. The process of cellular senescence is extremely complex, and the mechanisms, molecular events, and signaling pathways involved have not been fully elucidated; however, there is strong evidence to support the concept that oxidative stress caused by the excessive generation of reactive oxygen species may be one important mechanism involved. On the other hand, numerous studies have implicated oxidative stress in SSc pathogenesis, thus, suggesting a plausible mechanism in which excessive oxidative stress induces cellular senescence and that the molecular events associated with this complex process play an important role in the fibrotic and fibroproliferative vasculopathy characteristic of SSc. Here, recent studies examining the role of cellular senescence and of oxidative stress in SSc pathogenesis will be reviewed

Acute Migraine Therapy: New Drugs and New Approaches

The conceptual shift of our understanding of migraine from a vascular disorder to a brain disorder has dramatically altered the approach to the development of new medicines in the field. Current pharmacologic treatments of acute migraine consist of nonspecific and relatively specific agents. Migraine-specific drugs comprise two classes, the ergot alkaloid derivatives and the triptans, serotonin 5-HT1B/1D receptor agonists. The ergots, consisting of ergotamine and dihydroergotamine (DHE), are the oldest specific antimigraine drugs available and are considered relatively safe and effective. Ergotamine has been used less extensively because of its adverse effects; DHE is better tolerated. The triptan era, beginning in the 1990s, was a period of considerable change, although these medicines retained vasoconstrictor actions. New methods of delivering older drugs include orally inhaled DHE and the transdermal formulation of sumatriptan, both currently under study. Novel medicines being developed are targeted at neural sites of action. Serotonin 5-HT1F receptor agonists have proven effective in phase II studies and have no vascular actions. Calcitonin gene-related peptide (CGRP) receptor antagonists are another promising nonvasoconstrictor approach to treating acute migraine. Olcegepant (BIBN4096BS) and telcagepant (MK-0974) have been shown to be safe and effective in phase I, II, and (for telcagepant) phase III clinical trials. Other targets under investigation include glutamate (AMPA/kainate), TRPV1, prostanoid EP4, and nitric oxide synthase. With new neural targets and the potential for therapeutic advances, the next era of antimigraine medications is near

An in vitro collagen perfusion wound biofilm model; with applications for antimicrobial studies and microbial metabolomics

BackgroundThe majority of in vitro studies of medically relevant biofilms involve the development of biofilm on an inanimate solid surface. However, infection in vivo consists of biofilm growth on, or suspended within, the semi-solid matrix of the tissue, whereby current models do not effectively simulate the nature of the in vivo environment. This paper describes development of an in vitro method for culturing wound associated microorganisms in a system that combines a semi-solid collagen gel matrix with continuous flow of simulated wound fluid. This enables culture of wound associated reproducible steady state biofilms under conditions that more closely simulate the dynamic wound environment. To demonstrate the use of this model the antimicrobial kinetics of ceftazidime, against both mature and developing Pseudomonas aeruginosa biofilms, was assessed. In addition, we have shown the potential application of this model system for investigating microbial metabolomics by employing selected ion flow tube mass spectrometry (SIFT-MS) to monitor ammonia and hydrogen cyanide production by Pseudomonas aeruginosa biofilms in real-time. ResultsThe collagen wound biofilm model facilitates growth of steady-state reproducible Pseudomonas aeruginosa biofilms under wound like conditions. A maximum biofilm density of 1010 cfu slide-1 was achieved by 30 hours of continuous culture and maintained throughout the remainder of the experiment. Treatment with ceftazidime at a clinically relevant dose resulted in a 1.2 – 1.6 log reduction in biofilm density at 72 hours compared to untreated controls. Treatment resulted in loss of complex biofilm architecture and morphological changes to bacterial cells, visualised using confocal microscopy. When monitoring the biofilms using SIFT-MS, ammonia and hydrogen cyanide levels peaked at 12 hours at 2273 ppb (±826.4) and 138 ppb (±49.1) respectively and were detectable throughout experimentation. ConclusionsThe collagen wound biofilm model has been developed to facilitate growth of reproducible biofilms under wound-like conditions. We have successfully used this method to: (1) evaluate antimicrobial efficacy and kinetics, clearly demonstrating the development of antimicrobial tolerance in biofilm cultures; (2) characterise volatile metabolite production by P. aeruginosa biofilms, demonstrating the potential use of this method in metabolomics studies

Treatment of migraine attacks based on the interaction with the trigemino-cerebrovascular system

Primary headaches such as migraine are among the most prevalent neurological disorders, affecting up to one-fifth of the adult population. The scientific work in the last decade has unraveled much of the pathophysiological background of migraine, which is now considered to be a neurovascular disorder. It has been discovered that the trigemino-cerebrovascular system plays a key role in migraine headache pathophysiology by releasing the potent vasodilator calcitonin gene-related peptide (CGRP). This neuropeptide is released in parallel with the pain and its concentration correlates well with the intensity of the headache. The development of drugs of the triptan class has provided relief for the acute attacks but at the cost of, mainly cardiovascular, side effects. Thus, the intention to improve treatment led to the development of small CGRP receptor antagonists such as olcegepant (BIBN4096BS) and MK-0974 that alleviate the acute migraine attack without acute side events. The purpose of this review is to give a short overview of the pathological background of migraine headache and to illustrate the mechanisms behind the actions of triptans and the promising CGRP receptor blockers

Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018.

Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes. The mission of the NCCD is to provide a widely accepted nomenclature on cell death in support of the continued development of the field