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Rationale: Inhaled nitric oxide (iNO) has been shown to result in benefits in moderate to vigorous physical activity (MVPA) in patients with fibrotic interstitial lung disease (f-ILD) receiving supplemental oxygen in two independent trials. Objective: This phase III randomized, double-blind, placebo-controlled study sought to validate the benefit of ambulatory iNO in patients with f-ILD requiring supplemental oxygen. Methods: Patients with f-ILD receiving supplemental long-term oxygen were randomized in a 1:1 fashion to iNO at 45 μg/kg ideal body weight per hour or placebo for 16 weeks. The primary outcome was the change from baseline to Week 16 in MVPA assessed by accelerometry. Secondary outcomes included overall activity, 6-minute-walk distance and patient-reported outcomes. Results: 145 patients were enrolled; 75 were assigned to receive iNO and 70 placebo. The changes from baseline in MVPA at 16 weeks were −9.2 min/d (standard error, 3.51) in the iNO45 group and −3.7 min/d (3.76) in the placebo group (difference, 5.5; P = 0.265). No statistically significant differences between the two treatment arms were found for any of the secondary outcomes. A subgroup analysis of patients with an intermediate or high probability of pulmonary hypertension on echocardiography did not demonstrate any benefit. The most common adverse events reported were respiratory tract infections, but the therapy was generally very well tolerated. Conclusions: There was no demonstrable benefit to iNO in patients with f-ILD receiving supplemental oxygen in daily physical activity assessed by actigraphy, a potential novel clinical trial endpoint. Clinical trial registered with (NCT 03267108). [ABSTRACT FROM AUTHOR]

In order to improve the wear and frictional behavior of the aluminum metal matrix composites, carbon nanotube, and fly ash were added as reinforcements. Powder metallurgy technique was used to fabricate the hybrid metal matrix composites. Experimentations were carried out using pin on disc type wear test rig. The analyzed experimental results showed that, in comparison to the pure aluminum and mono reinforcement combination, the wear loss and coefficient of friction of hybrid metal matrix composites were greatly reduced. It was noted that compared to pure aluminum wear loss was decreased to 89.58%, 86.97%, 83.3% by adding 0.25, 0.5, 0.75 wt% carbon nanotube (CNT), respectively. By the addition of 4, 8 and 16 wt% FA to pure Al wear loss was decreased to 83.85%, 89.58%, and 78.12%, respectively. It was also noted that compared to Al/8 wt% FA mono reinforced composites, wear loss was decreased to 77%, 71.26%, and 53.22% with the addition of 0.25, 0.5, 0.75 wt% CNT, respectively. With the addition of 4, 8, 16 wt% FA, wear loss decreased to 81%, 88%, and 75% over Al/0.25 wt% CNT composites, respectively. The microstructural study of the worn‐out surfaces revealed low abrasive and adhesive wear by the presence of carbon nanotubes and fly ash in aluminum metal matrix. The reinforcing mechanisms of the wear and frictional properties were also discussed. [ABSTRACT FROM AUTHOR]

Pulmonary hypertension (PH) associated with interstitial lung disease (ILD) is an attractive target for clinical trials of PH medications. There are many factors that need to be considered to prime such studies for success. The patient phenotype most likely to respond to the intervention requires weighing the extent of the parenchymal lung disease against the severity of the hemodynamic impairment. The inclusion criteria should not be too restrictive, thus enabling recruitment. The trial should be of sufficient duration to meet the chosen endpoint which should reflect how the patient feels, functions, or survives. This paper summarizes prior studies in PH-ILD and provides a framework of the type of studies to be considered. Inclusion criteria, clinical trial endpoints, and pharmacovigilance in the context of PH-ILD trials are also addressed. Through lessons learnt from prior studies, suggestions and guidance for future clinical trials in PH-ILD are also provided. [ABSTRACT FROM AUTHOR]

Pulmonary hypertension (PH) has been linked to worse outcomes in chronic lung diseases. The presence of PH in the setting of underlying Interstitial Lung Disease (ILD) is strongly associated with decreased exercise and functional capacity, an increased risk of hospitalizations and death. Examining the scope of this issue and its impact on patients is the first step in trying to define a roadmap to facilitate and encourage future research in this area. The aim of our working group is to strengthen the communities understanding of PH due to lung diseases and to improve the care and quality of life of affected patients. This introductory statement provides a broad overview and lays the foundation for further in‐depth papers on specific topics pertaining to PH‐ILD. [ABSTRACT FROM AUTHOR]

Rationale: Patients with fibrotic interstitial lung disease often progress to the point of requiring supplemental oxygen. This is invariably accompanied by an impaired quality of life and limitations on activities of daily living. Objectives: This study aimed to assess the improvement in physical activity in patients with interstitial lung disease requiring supplemental oxygen treated with pulsed inhaled nitric oxide via INOpulse (Bellerophon Therapeutics). In addition, it sought to explore the safety and clinical benefits of INOpulse on multiple patient-reported outcomes. Methods: Ambulatory patients with fibrotic lung disease on supplemental oxygen were randomized in a 2:1 ratio to inhaled nitric oxide at 45 μg/kg ideal body weight/h (iNO45) or placebo for 4 months (3 months after baseline) of blinded treatment. The study assessed multiple exploratory efficacy endpoints, including moderate to vigorous physical activity as measured by actigraphy and patient-reported outcomes using the University of California San Diego shortness of breath questionnaire and the St. George's Respiratory Questionnaire (SGRQ). Results: A total of 44 patients (30 iNO45 and 14 placebo) were enrolled. A placebo-corrected clinical benefit of 12.3 min/d increase in MVPA was observed in the iNO45 group. Clinically meaningful beneficial trends were observed for the University of California San Diego shortness of breath questionnaire (6.05 points) and the SGRQ total (3.75) scores, as well as the SGRQ activity (5.84), and SGRQ impact (6.30) domains. Conclusions: INOpulse was well tolerated and associated with maintenance of physical activity and improved symptomatology in patients with interstitial lung disease who require supplemental oxygen. Further validation of this beneficial effect warrants further study in a phase-3 trial that is currently underway. [ABSTRACT FROM AUTHOR]

A 46-year-old man presented with worsening vision in the context of long-standing optic disc changes, bilateral sensorineural hearing loss, chronic aseptic meningitis, rash, arthralgia and raised inflammatory markers. The differential diagnoses of neoplasia, infection and inflammation are discussed. We highlight a condition that can present to adult neurologists, with successful diagnosis leading to targeted treatments that transform patient outcomes. This case was presented at the Association of British Neurologists Annual Meeting 2020 as a Clinicopathological Conference (CPC). [ABSTRACT FROM AUTHOR]

The parasitic protist Trypanosoma brucei is the causative agent of Human African Trypanosomiasis, also known as sleeping sickness. The parasite enters the blood via the bite of the tsetse fly where it is wholly reliant on glycolysis for the production of ATP. Glycolytic enzymes have been regarded as challenging drug targets because of their highly conserved active sites and phosphorylated substrates. We describe the development of novel small molecule allosteric inhibitors of trypanosome phosphofructokinase (PFK) that block the glycolytic pathway resulting in very fast parasite kill times with no inhibition of human PFKs. The compounds cross the blood brain barrier and single day oral dosing cures parasitaemia in a stage 1 animal model of human African trypanosomiasis. This study demonstrates that it is possible to target glycolysis and additionally shows how differences in allosteric mechanisms may allow the development of species-specific inhibitors to tackle a range of proliferative or infectious diseases. Glycolytic enzymes are challenging drug targets due to their highly conserved active sites and phosphorylated substrates. Here, the authors identify fast acting allosteric inhibitors of Trypanosoma brucei phosphofructokinase that block trypanosome glycolysis and provide cure evidence in murine model. [ABSTRACT FROM AUTHOR]

6-Phosphofructokinase-1-kinase (PFK) tetramers catalyse the phosphorylation of fructose 6-phosphate (F6P) to fructose 1,6-bisphosphate (F16BP). Vertebrates have three PFK isoforms (PFK-M, PFK-L, and PFK-P). This study is the first to compare the kinetics, structures, and transcript levels of recombinant human PFK isoforms. Under the conditions tested PFK-M has the highest affinities for F6P and ATP (K0.5ATP 152 μM; K0.5F6P 147 μM), PFK-P the lowest affinities (K0.5ATP 276 μM; K0.5F6P 13333 μM) PFK-L demonstrates a mixed picture of high ATP affinity and low F6P affinity (K0.5ATP 160 μM; K0.5 F0.5F6P 1360 μM). PFK-M is more resistant to ATP inhibition compared with PFK-L and PFK-P (respectively, 23%, 31%, 50% decreases in specificity constants). GTP is an alternate phospho donor. Interface 2, which regulates the inactive dimer to active tetramer equilibrium, differs between isoforms, resulting in varying tetrameric stability. Under the conditions tested PFK-M is less sensitive to fructose 2,6-bisphosphate (F26BP) allosteric modulation than PFK-L or PFK-P (allosteric constants [K0.5ATP+F26BP/K0.5ATP] 1.10, 0.92, 0.54, respectively). Structural analysis of two allosteric sites reveals one may be specialised for AMP/ADP and the other for smaller/flexible regulators (citrate or phosphoenolpyruvate). Correlations between PFK-L and PFK-P transcript levels indicate that simultaneous expression may expand metabolic capacity for F16BP production whilst preserving regulatory capabilities. Analysis of cancer samples reveals intriguing parallels between PFK-P and PKM2 (pyruvate kinase M2), and simultaneous increases in PFK-P and PFKFB3 (responsible for F26BP production) transcript levels, suggesting prioritisation of metabolic flexibility in cancers. Our results describe the kinetic and transcript level differences between the three PFK isoforms, explaining how each isoform may be optimised for distinct roles. [ABSTRACT FROM AUTHOR]

Background: The interstitial lung diseases include a variety of disorders, many of which are characterized by fibrotic changes (fILD). Of the fILDs, Idiopathic pulmonary fibrosis is the most common. Pulmonary hypertension (PH) frequently complicates fILD and is associated with impaired functional capability, lower physical activity, and significantly reduced life expectancy. There is no proven treatment for patients with fILD-PH. We report results from the first cohort of a phase 2b/3 trial with pulsed inhaled nitric oxide (iNO) in patients with fILD-PH.Methods: Subjects in cohort 1 were randomized to iNO 30 μg/kg ideal body weight/h (iNO30) or placebo for 8 weeks of blinded treatment; subjects then transitioned to open-label extension (OLE) on iNO30 followed by dose escalation to iNO45 then iNO75. Activity monitoring was used to assess changes in daily activity. Safety and efficacy were evaluated.Results: Twenty-three patients were randomized to iNO30 and 18 to placebo. During blinded treatment, iNO30 subjects showed an average improvement in moderate/vigorous physical activity (MVPA) and remained stable in overall activity. Placebo subjects showed an average drop of 26% in MVPA and a 12% drop in overall activity. The iNO group had an improvement in oxygen saturation. During OLE, subjects maintained their activity levels including placebo subjects who transitioned from a decline to a maintenance in all activity parameters. Inhaled nitric oxide at all doses (30, 45, and 75) was safe and well tolerated.Conclusions: Treatment with iNO30 demonstrated clinically and statistically significant benefit in MVPA and clinically significant benefit in overall activity. In the OLE, higher doses of iNO were also safe and well tolerated while showing maintenance in activity parameters. [ABSTRACT FROM AUTHOR]

Progressive multifocal leukoencephalopathy is a rare demyelinating disorder of the CNS, caused by John Cunningham virus, that occurs in those with impaired immune systems. Existing treatment options are ineffective or unproven. This article reviews research into novel therapies: immune checkpoint-blocking antibodies (nivolumab and pembrolizumab), allogenic BK virus-specific T cell treatment and filgrastim. Results for these therapies in small clinical trials are promising, but further research is required to assess efficacy fully. [ABSTRACT FROM AUTHOR]

Trypanosomatids possess glycosome organelles that contain much of the glycolytic machinery, including phosphofructokinase (PFK). We present kinetic and structural data for PFK from three human pathogenic trypanosomatids, illustrating intriguing differences that may reflect evolutionary adaptations to differing ecological niches. The activity of Leishmania PFK – to a much larger extent than Trypanosoma PFK – is reliant on AMP for activity regulation, with 1 mm AMP increasing the L. infantum PFK (LiPFK) kcat/K0.5F6P value by 10‐fold, compared to only a 1.3‐ and 1.4‐fold increase for T. cruzi and T. brucei PFK, respectively. We also show that Leishmania PFK melts at a significantly lower (> 15 °C) temperature than Trypanosoma PFKs and that addition of either AMP or ATP results in a marked stabilization of the protein. Sequence comparisons of Trypanosoma spp. and Leishmania spp. show that divergence of the two genera involved amino acid substitutions that occur in the enzyme's 'reaching arms' and 'embracing arms' that determine tetramer stability. The dramatic effects of AMP on Leishmania activity compared with the Trypanosoma PFKs may be explained by differences between the T‐to‐R equilibria for the two families, with the low‐melting Leishmania PFK favouring the flexible inactive T‐state in the absence of AMP. Sequence comparisons along with the enzymatic and structural data presented here also suggest there was a loss of AMP‐dependent regulation in Trypanosoma species rather than gain of this characteristic in Leishmania species and that AMP acts as a key regulator in Leishmania governing the balance between glycolysis and gluconeogenesis. [ABSTRACT FROM AUTHOR]

PML should be considered in patients with neurological symptoms following MM and in those who are immunosuppressed. Symptoms are diverse and often rapidly progressing. Prompt referral and early involvement of the multidisciplinary team are crucial. [ABSTRACT FROM AUTHOR]

Rhabdomyolysis is the combination of symptoms (myalgia, weakness and muscle swelling) and a substantial rise in serum creatine kinase (CK) >50 000 IU/L; there are many causes, but here we specifically address exertional rhabdomyolysis. The consequences of this condition can be severe, including acute kidney injury and requirement for higher level care with organ support. Most patients have 'physiological' exertional rhabdomyolysis with no underlying disease; they do not need investigation and should be advised to return to normal activities in a graded fashion. Rarely, exertional rhabdomyolysis may be the initial presentation of underlying muscle disease, and we review how to identify this much smaller group of patients, who do require investigation. [ABSTRACT FROM AUTHOR]

Eukaryotic ATP-dependent phosphofructokinases (PFKs) are often considered unidirectional enzymes catalysing the transfer of a phospho moiety from ATP to fructose 6-phosphate to produce ADP and fructose 1,6-bisphosphate. The reverse reaction is not generally considered to occur under normal conditions and has never been demonstrated for any eukaryotic ATP-dependent PFKs, though it does occur in inorganic pyrophosphate-dependent PFKs and has been experimentally shown for bacterial ATP-dependent PFKs. The evidence is provided via two orthogonal assays that all three human PFK isoforms can catalyse the reverse reaction in vitro, allowing determination of kinetic properties. Additionally, the reverse reaction was shown possible for PFKs from three clinically important trypanosomatids; these enzymes are contained within glycosomes in vivo. This compartmentalisation may facilitate reversal, given the potential for trypanosomatids to have an altered ATP/ADP ratio in glycosomes compared with the cytosol. The kinetic properties of each trypanosomatid PFK were determined, including the response to natural and artificial modulators of enzyme activity. The possible physiological relevance of the reverse reaction in trypanosomatid and human PFKs is discussed. [ABSTRACT FROM AUTHOR]

Pulmonary hypertension (PH) and its subset, pulmonary arterial hypertension (PAH), are rare diseases with a significant unmet need. Between the 1980s and 2010s, the 5-year survival rate for PAH after diagnosis improved from 34% to 65%,1,2 but remains unacceptably low. Since the introduction of vasodilator therapy, 3,4 important advances have been made in the understanding of the disease pathophysiology and development of targeted therapies. There are now 14 US Food and Drug Administration (FDA)-approved therapies that target 3 distinct pathways that contribute to PAH, and additional therapeutic targets are currently under investigation in phase 1, 2, and 3 clinical trials.5 However, there have been major challenges in PH medication development to date, including: 1) only one medication approved for pediatric PAH; 2) focusing on vasodilator therapy rather than targeting the underlying pathogenesis of the disease; 3) no medications approved for PH World Health Organization (WHO) Groups 2, 3, and 5; and 4) several recent high-profile clinical failures after promising preclinical studies. The focus and goal of the PH research community should be directed at identifying new options and solutions for patients. The field must ensure that the approaches used for clinical trials to develop orphan drugs maximize the scarce resources available for recruiting subjects, and are directed toward making safe and effective therapies available in a timely manner. Therefore, there is a critical need to coordinate and harmonize innovative approaches within the field, including strengthening translational research to deliver promising candidates and optimize the designs, endpoints, and biomarkers to conduct safe and efficient clinical trials. [ABSTRACT FROM AUTHOR]

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(PH-PF) ON LONG TERM OXYGEN THERAPY B PURPOSE: b Pulmonary fibrosis (PF) is made up of a variety of fibrotic lung diseases, the largest of which is IPF (Idiopathic Pulmonary Fibrosis). Inhaled Nitric Oxide (iNO) at a dose of 30 mcg/kg IBW/hr (Cohort 1) has been demonstrated to improve moderate to vigorous physical activity (MVPA) by 34% (placebo-corrected) in an 8-week controlled trial. [Extracted from the article]

The article presents a case study of progressive hemiparesis in a 75-year-old male patient. He is a right-handed, retired dockyard electrical engineer presented in 2005 with a 35-year history of progressive right leg weakness, and finding it difficult to walk. The patient's clinical examination, including blood, radiology, and neurophysiology, and clinical progress are described. A discussion of other neuronal diseases are also offered.

In keeping with this hypothesis is a study showing that hydrophilic polymer embolization was found in 13% of autopsies,4 with not all patients demonstrating an inflammatory reaction.2 Alternatively, polymer detachment may only occur infrequently, perhaps provoked by protracted device use (as in our patient and previous reports1-3). The precise prevalence of hydrophilic polymer embolization is unknown but is likely to be under-reported due to patients being asymptomatic and not undergoing interval imaging sensitive to hydrophilic polymer embolization. [Extracted from the article]

Transient loss of consciousness (TLOC) in adults is a common presenting symptom to the Acute Receiving Unit, with an epileptic seizure a potential cause. A first ever generalised epileptic seizure is not uncommon, with a lifetime prevalence of approximately one in 20 people. However, as epileptic seizures are only one cause of TLOC, it is important for doctors to be able to distinguish between seizures and the other causes of TLOC. In this article we provide practical advice on how to do this. [ABSTRACT FROM AUTHOR]

Diagnosing stroke is not always straightforward. Stroke mimics such as Todd's paresis or hemiplegic migraine account for between a fifth and a quarter of suspected strokes (depending on the setting in which they are assessed). Stroke chameleons can arise when the tempo of symptom onset is not apoplectic or if the loss of function is not clearly consistent with a deficit within an arterial territory. Thrombolysis and secondary prevention have much to offer patients with stroke chameleons, though those with stroke mimics may be harmed by these treatments and have more to gain from other therapies. [ABSTRACT FROM AUTHOR]

The enzyme glucose oxidase (E.C. 1.1.3.4) was immobilized on collagen - a proteinaceous material found in biological systems as a structural material for a wide variety of cells and membranes. The novel technique of electrocodeposition, which utilizes the principles of electrophoresis, was used to deposit the enzyme-collagen complex on stainless steel helical supports. This technique has been developed in our laboratory. The mechanism of complex formation between collagen and enzyme involves multiple salt linkages, hydrogen bonds and van der Waals interactions. As a first step toward examining its feasible technical use, the kinetic behavior of the collagen-supported glucose oxidase was studied in a batch recycle type reactor and was compared with that for the soluble form. A novel reactor configuration consisting of multiple concentric electrocodeposited helical coils was used. The reactor was found to attain a stable level of activity which was maintained for several months under cyclic testing. The optimum levels of pH and temperature for the immobilized form of the enzyme were the same as those of the soluble enzyme, but the immobilized enzyme was more active than the soluble form at higher temperatures and pH. The values of the Michaelis-Menten parameters indicate that the overall reaction rate of the immobilized enzyme may be partially restricted by bulk and matrix diffusion. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "Effect of BCG Vaccination Against Mycobacterium Tuberculosis Infection in Children: Systematic Review and Meta-Analysis" by A. Roy and colleagues in the August 5, 2014 issue.