Time Course Of Progression Research Articles

Correcting 4sU induced quantification bias in nucleotide conversion RNA-seq data.

Nucleoside analogues like 4-thiouridine (4sU) are used to metabolically label newly synthesized RNA. Chemical conversion of 4sU before sequencing induces T-to-C mismatches in reads sequenced from labelled RNA, allowing to obtain total and labelled RNA expression profiles from a single sequencing library. Cytotoxicity due to extended periods of labelling or high 4sU concentrations has been described, but the effects of extensive 4sU labelling on expression estimates from nucleotide conversion RNA-seq have not been studied. Here, we performed nucleotide conversion RNA-seq with escalating doses of 4sU with short-term labelling (1h) and over a progressive time course (up to 2h) in different cell lines. With high concentrations or at later time points, expression estimates were biased in an RNA half-life dependent manner. We show that bias arose by a combination of reduced mappability of reads carrying multiple conversions, and a global, unspecific underrepresentation of labelled RNA emerging during library preparation and potentially global reduction of RNA synthesis. We developed a computational tool to rescue unmappable reads, which performed favourably compared to previous read mappers, and a statistical method, which could fully remove remaining bias. All methods developed here are freely available as part of our GRAND-SLAM pipeline and grandR package.

The differential diagnosis of medical and psychogenic disease in primary care.

Diagnosis and management of psychogenic diseases such as conversion disorder, somatic symptom disorder (SSD), illness anxiety disorder, falsehood disorder, and psychotic disorder require an elaborate biopsychosocial approach and are often challenging. Herein, we propose the following points to differentiate medical diseases from these psychogenic diseases: correspondence between symptoms and objective findings or activities of daily living (ADL) impairment; placebo effect; clear provocative or palliative factors; progressive time course; paroxysmal or intermittent symptoms; unfamiliar but not strange expressions; symptoms worsen during sleep or rest.

A fact‐finding survey of medical care provided to neuromuscular disease patients at the National Center of Neurology and Psychiatry in Japan

AbstractSubjectThe aim of the present study was to conduct a fact‐finding survey of medical care practices that are provided to neuromuscular diseases (NMDs) patients and to identify the placement rate and timing of implementation for each of the diseases.MethodAll 3756 NMD patients who were admitted to the Neurology ward between April 2015 and March 2020 were included. This was a retrospective survey of specific medical care practices (percutaneous endoscopic gastrostomy (PEG) and tracheotomy) implemented.ResultsThe results showed that 325 patients (8.7%) had PEG placements, and 78 patients (2.1%) had tracheotomies. When the course of each disease from onset to medical care was examined, the diseases for which medical care was received soon after onset were MND, MSA, DLB, and progressive supranuclear palsy, whereas muscular dystrophy, myopathy, and Parkinson's disease (PD) were diseases with a relatively long time between disease onset and medical care. Discussion: In conducting the fact‐finding survey on medical care practices for NMD, the following were taken into consideration: (i) difficulty in conducting the investigation due to NMD being a rare disease; (ii) existence of a difference in age of onset and progression of the diseases; and (iii) differences in treatment environments due to disparities in treatment policies among medical institutions providing medical care and local support systems.ConclusionsThe course of medical care provision for NMD patients varied depending on the disease, and the difference in the time course of progression of symptoms greatly impacted patients' decision making.

Mystery of changing choroidal thickness.

Mystery of changing choroidal thickness.

Sleep affects higher-level categorization of speech sounds, but not frequency encoding

Sleep can increase consolidation of new knowledge and skills. It is less clear whether sleep plays a role in other aspects of experience-dependent neuroplasticity, which underlie important human capabilities such as spoken language processing. Theories of sensory learning differ in their predictions; some imply rapid learning at early sensory levels, while other propose a slow, progressive timecourse such that higher-level categorical representations guide immediate, novice learning, while lower-level sensory changes do not emerge until later stages. In this study, we investigated the role of sleep across both behavioural and physiological indices of auditory neuroplasticity. Forty healthy young human adults (23 female) who did not speak a tonal language participated in the study. They learned to categorize non-native Mandarin lexical tones using a sound-to-category training paradigm, and were then randomly assigned to a Nap or Wake condition. Polysomnographic data were recorded to quantify sleep during a 3 h afternoon nap opportunity, or equivalent period of quiet wakeful activity. Measures of behavioural performance accuracy revealed a significant improvement in learning the sound-to-category training paradigm between Nap and Wake groups. Conversely, a neural index of fine sound encoding fidelity of speech sounds known as the frequency-following response (FFR) suggested no change due to sleep, and a null model was supported, using Bayesian statistics. Together, these results support theories that propose a slow, progressive and hierarchical timecourse for sensory learning. Sleep's effect may play the biggest role in the higher-level learning, although contributions to more protracted processes of plasticity that exceed the study duration cannot be ruled out.

The effect of COVID-19 on routine diabetes care and mortality in people with diabetes

The effect of COVID-19 on routine diabetes care and mortality in people with diabetes

Natural History of Cricopharyngeus Muscle Dysfunction Symptomatology.

Cricopharyngeus muscle dysfunction (CPMD) is a common cause for progressive dysphagia and can lead to dietary restriction, reduced nutrition, weight loss, and pneumonia. There is a continuum between small, non-obstructive cricopharyngeus bars representing mild disease and severely obstructive bars or Zenker's diverticulum forming late-stage disease, but the natural history of untreated CPMD and the associated time course for progression is unknown. Retrospective longitudinal cohort study from a tertiary outpatient dysphagia centre. Patients diagnosed with CPMD by fluoroscopy and either awaiting surgical treatment or electing non-operative management were evaluated through prospectively collected Eating Assessment Tool-10 (EAT-10) and Functional Oral Intake Scale (FOIS). Review of available imaging identified degree of CPMD. We identified 174 patients with CPMD diagnosed between July 1, 2016, and June 30, 2020; 52 patients had serial Eating Assessment Tool (EAT-10) measures obtained at time of diagnosis and follow up appointment without operative treatment. Mean EAT-10 scores increased from 17.1 to 20.6 (3.5 ± 8.1 points, p = 0.002) points. This change was related to those with a Zenker's diverticulum rather than an isolated cricopharyngeus bar. Dietary outcomes measured by FOIS were stable. While some patients showed fluoroscopic progression of bar size, no patients developed a Zenker's diverticulum from a pre-existing bar in this population. Our data indicate patients with a cricopharyngeus bar do not decline in subjective dysphagia score or diet tolerance, however those with a Zenker's diverticulum worsen over time. This has implications for treatment timing and counselling patients but also reflects a need to understand the pathophysiology behind CPMD and the subset of patients who show progression.

RE: Mesocycle Progression in Hypertrophy: Volume Versus Intensity

RE: Mesocycle Progression in Hypertrophy: Volume Versus Intensity

Proteinuria Reduction as a Surrogate End Point in Trials of IgA Nephropathy.

IgA nephropathy (IgAN) is an important cause of ESKD for which there are no approved therapies. A challenge for evaluating treatments for IgAN is the usual long time course for progression to ESKD. The aim of this Kidney Health Initiative project was to identify surrogate end points that could serve as reliable predictors of a treatment's effect on long-term kidney outcomes in IgAN and be used as a basis for approval. Proteinuria was identified as the most widely recognized and well studied risk factor for progression to ESKD in IgAN. The workgroup performed a critical review of the data on proteinuria reduction as a surrogate end point for a treatment's effect on progression to ESKD in IgAN. Epidemiologic data indicate a strong and consistent relationship between the level and duration of proteinuria and loss of kidney function. Trial-level analyses of data from 13 controlled trials also show an association between treatment effects on percent reduction of proteinuria and treatment effects on a composite of time to doubling of serum creatinine, ESKD, or death. We conclude that data support the use of proteinuria reduction as a reasonably likely surrogate end point for a treatment's effect on progression to ESKD in IgAN. In the United States, reasonably likely surrogate end points can be used as a basis for accelerated approval of therapies intended to treat serious or life-threatening conditions, such as IgAN. The clinical benefit of products approved under this program would need to be verified in a postmarketing confirmatory trial.

Sequence of joint tissue inflammation during rheumatoid arthritis development

ObjectiveSubclinical joint inflammation in patients with arthralgia is predictive for progression to rheumatoid arthritis (RA). However, the time course of progression for bone marrow edema (osteitis), synovitis, and/or tenosynovitis is unsettled. This longitudinal study assessed the course of magnetic resonance imaging (MRI)-detected subclinical joint inflammation during progression to RA.MethodsPatients that progressed from clinically suspect arthralgia (CSA) to RA underwent 1.5-T MRI of the metacarpophalangeal (MCP), wrist, and metatarsophalangeal (MTP) joints at presentation with arthralgia and at first identification of synovitis assessed through physical examination (n = 31). MRIs were evaluated for osteitis, synovitis, tenosynovitis, and erosions by two readers, blinded for clinical data and order in time. To estimate changes in MRI scores between the asymptomatic state and CSA onset, scores of MRI features at CSA baseline were compared with scores from age-matched symptom-free persons.ResultsAt presentation with CSA, synovitis and tenosynovitis scores were higher than scores from age-matched symptom-free persons (p = 0.004 and p = 0.001, respectively). Anti-citrullinated protein antibody (ACPA)-positive arthralgia patients also had increased osteitis scores (p = 0.04). Median duration between presentation with arthralgia and RA development was 17 weeks. During progression to RA, synovitis and osteitis increased significantly (p = 0.001 and p = 0.036, respectively) in contrast to tenosynovitis and erosion scores. This pattern was similar in both ACPA subsets, although statistical significance was reached for synovitis and osteitis in ACPA-negative but not ACPA-positive RA.ConclusionIncreased tenosynovitis and synovitis scores at CSA onset and the increase in synovitis and osteitis during progression to RA suggest an ‘outside-in’ temporal relationship of arthritis development, in particular for ACPA-negative RA. For ACPA-positive RA, further studies are needed.

Stress perception differentially regulates the inflammatory response in the CNS to a neurotropic viral pathogen

Abstract Intranasal application of neurotropic vesicular stomatitis virus (VSV) replicates in olfactory receptor neurons and then rapidly invades the olfactory bulb (OB). VSV has an established time course of progression through discrete brain regions and of onset and recovery from encephalitis. Coincident with viral progression is a bimodal brain cytokine response composed of multiple chemokines and cytokines responsible for the prominent neuroinflammatory response. Stress can have significant, but poorly understood, effects on immune function and even less is known on how stress perception may impact immune competency. Therefore, VSV infected mice were exposed to either controllable (modeled by escapable foot shock, ES) or uncontrollable (modeled by inescapable foot shock, IS) stress prior to infection and for 1–3 days post infection (PI). OB cytokine responses were initially blunted and then amplified and dysregulated at days 1 and 3 PI, respectively. With time, dysregulated responses in ES mice were associated with increased pathogenecity. Ingenuity Pathways Analysis (IPA) identified miRNA146a as an upstream regulator of this response and qPCR found elevated OB levels (~5 fold) in ES versus IS cohorts at day 1 PI. Surprisingly, brains from mice that had long ago cleared VSV still contained an infiltrate containing CD103+ cells, a marker associated with long-term brain T resident memory cells. To our knowledge, this is the first time that stress perception has been shown to differentially modulate neuroinflammation. Our data also suggest the microRNA likely responsible for the observed stress-induced changes in the antiviral immune response to a neurotropic viral pathogen.

Clinical Predictors for Mild Cognitive Impairment Progression in a Korean Cohort.

Background and PurposePatients with mild cognitive impairment (MCI) and their caregivers are concerned with the likelihood and time course of progression to dementia. This study was performed to identify the clinical predictors of the MCI progression in a Korean registry, and investigated the effects of medications without evidence, frequently prescribed in clinical practice.MethodsUsing a Korean cohort that included older adults with MCI who completed at least one follow-up visit, clinical characteristics and total medical expenses including prescribed medications were compared between two groups: progressed to dementia or not. Cox proportional hazards regression analysis was conducted.ResultsDuring the mean 1.42±0.72 years, 215 (27.63%) of 778 participants progressed to dementia. The best predictors were age [hazard ratio (HR), 1.036; 95% confidence interval (CI), 1.006–1.067; p=0.018], apolipoprotein ε4 allele (HR, 2.247; 95% CI, 1.512–3.337; p<0.001), Clinical Dementia Rating scale-sum of boxes scores (HR, 1.367; 95% CI, 1.143–1.636; p=0.001), Instrumental Activities of Daily Living scores (HR, 1.035; 95% CI, 1.003–1.067; p=0.029), and lower Mini-Mental State Examination scores (HR, 0.892; 95% CI, 0.839–0.949; p<0.001). Total medical expenses were not different.ConclusionsOur data are in accordance with previous reports about clinical predictors for the progression from MCI to dementia. Total medical expenses were not different between groups with and without progression.

痔核の時間的進行経過の検討

痔核の時間的進行経過の検討

Successful arrest of photoreceptor and vision loss expands the therapeutic window of retinal gene therapy to later stages of disease

Inherited retinal degenerations cause progressive loss of photoreceptor neurons with eventual blindness. Corrective or neuroprotective gene therapies under development could be delivered at a predegeneration stage to prevent the onset of disease, as well as at intermediate-degeneration stages to slow the rate of progression. Most preclinical gene therapy successes to date have been as predegeneration interventions. In many animal models, as well as in human studies, to date, retinal gene therapy administered well after the onset of degeneration was not able to modify the rate of progression even when successfully reversing dysfunction. We evaluated consequences of gene therapy delivered at intermediate stages of disease in a canine model of X-linked retinitis pigmentosa (XLRP) caused by a mutation in the Retinitis Pigmentosa GTPase Regulator (RPGR) gene. Spatiotemporal natural history of disease was defined and therapeutic dose selected based on predegeneration results. Then interventions were timed at earlier and later phases of intermediate-stage disease, and photoreceptor degeneration monitored with noninvasive imaging, electrophysiological function, and visual behavior for more than 2 y. All parameters showed substantial and significant arrest of the progressive time course of disease with treatment, which resulted in long-term improved retinal function and visual behavior compared with control eyes. Histology confirmed that the human RPGR transgene was stably expressed in photoreceptors and associated with improved structural preservation of rods, cones, and ON bipolar cells together with correction of opsin mislocalization. These findings in a clinically relevant large animal model demonstrate the long-term efficacy of RPGR gene augmentation and substantially broaden the therapeutic window for intervention in patients with RPGR-XLRP.

Toward an Understanding of the Neural Circuitry of Major Depressive Disorder Through the Clinical Response to Deep Brain Stimulation of Different Anatomical Targets

Deep brain stimulation has been proposed as a treatment for treatment-resistant depression. To date, multiple brain targets have been tested in single case studies and case series. The target regions with the most evidence to support their use are the subcallosal cingulate, ventral capsule/ventral striatum, nucleus accumbens, and medial forebrain bundle. Treatment effects of stimulation at each target share some commonalities, including similar response and remission rates, a relatively slow and progressive time course of treatment response, with a comparatively fast depressive relapse after discontinuation of stimulation. Response is maintained over time, and in some cases improves over years. Similarities may be at least partially attributable to overlap in white matter pathways between targets. Careful attention to mood and somatic effects seen with acute stimulation may differentiate primary vs. secondary treatment effects and mechanisms between the target regions. Understanding which symptoms are primarily affected, and the time course of response and relapse, will shed light on the biological mechanisms underlying DBS effects and depression pathology.

AIDS and HIV Infection after Thirty Years.

AIDS and HIV Infection after Thirty Years.

Primary Hepatic Lymphoma: A Diagnosis to Remember

We present 2 cases of PHL presenting to our hospital in the last 6 months. Both cases had similarities in that they had a rapidly progressive time course of less than 8 weeks and radiology failed to illustrate the normal disease pattern. Both were elderly men presenting with jaundice, rare presentations of PHL. One patient was interesting in that he had a bicytopenic blood picture, a common manifestation of PHL, whilst his lactate dehydrogenase was normal. The other had a past history of hepatitis B, interesting for its possible association with PHL. Whilst one patient died prior to treatment, the other was successfully treated with aggressive multidrug chemotherapy. A liver biopsy is essential in any patient where there is a high index of suspicion for PHL based on a bicytopenic blood picture, abnormal liver function tests or radiology. If diagnosed early enough, chemotherapy has proven a successful treatment. doi: http://dx.doi.org/10.4021/ jmc345w

The Cat as a Model for Human Obesity and Diabetes

Obesity is the most common nutritional disorder of cats and is a risk factor for diabetes. Similar to developments in obese people, obese cats show peripheral tissue insulin resistance and may demonstrate glucose intolerance when challenged with pharmacological amounts of glucose. However, they compensate well for the insulin resistance and do not show elevated glucose concentrations when monitored during their regular daily routine, including postprandial periods. This is possible because obese cats in the fasted and postprandial state are able to maintain hepatic insulin sensitivity and decrease endogenous glucose production, which allows them to maintain normoglycemia. Also dissimilar to what is seen in many obese humans, cats do not develop atherosclerosis and clinical hypertension. The time course for progression to overt diabetes of obese cats is unknown. One might speculate that diabetes develops when the liver finally becomes insulin resistant and/or insulin secretion becomes too low to overcome increased glucose production. In addition, amyloid, demonstrated to be deposited in islet of chronically obese cats, may contribute to a reduction in insulin secretion by reducing functional β-cell mass.

Primary Hepatic Lymphoma: A Diagnosis to Remember

We present 2 cases of PHL presenting to our hospital in the last 6 months. Both cases had similarities in that they had a rapidly progressive time course of less than 8 weeks and radiology failed to illustrate the normal disease pattern. Both were elderly men presenting with jaundice, rare presentations of PHL. One patient was interesting in that he had a bicytopenic blood picture, a common manifestation of PHL, whilst his lactate dehydrogenase was normal. The other had a past history of hepatitis B, interesting for its possible association with PHL. Whilst one patient died prior to treatment, the other was successfully treated with aggressive multidrug chemotherapy. A liver biopsy is essential in any patient where there is a high index of suspicion for PHL based on a bicytopenic blood picture, abnormal liver function tests or radiology. If diagnosed early enough, chemotherapy has proven a successful treatment. J Med Cases. 2013;4(1):52-55 doi: https://doi.org/10.4021/jmc345w

Kinetic Mechanism and Rate-Limiting Steps of Focal Adhesion Kinase-1

Steady-state kinetic analysis of focal adhesion kinase-1 (FAK1) was performed using radiometric measurement of phosphorylation of a synthetic peptide substrate (Ac-RRRRRRSETDDYAEIID-NH(2), FAK-tide) which corresponds to the sequence of an autophosphorylation site in FAK1. Initial velocity studies were consistent with a sequential kinetic mechanism, for which apparent kinetic values k(cat) (0.052 +/- 0.001 s(-1)), K(MgATP) (1.2 +/- 0.1 microM), K(iMgATP) (1.3 +/- 0.2 microM), K(FAK-tide) (5.6 +/- 0.4 microM), and K(iFAK-tide) (6.1 +/- 1.1 microM) were obtained. Product and dead-end inhibition data indicated that enzymatic phosphorylation of FAK-tide by FAK1 was best described by a random bi bi kinetic mechanism, for which both E-MgADP-FAK-tide and E-MgATP-P-FAK-tide dead-end complexes form. FAK1 catalyzed the betagamma-bridge:beta-nonbridge positional oxygen exchange of [gamma-(18)O(4)]ATP in the presence of 1 mM [gamma-(18)O(4)]ATP and 1.5 mM FAK-tide with a progressive time course which was commensurate with catalysis, resulting in a rate of exchange to catalysis of k(x)/k(cat) = 0.14 +/- 0.01. These results indicate that phosphoryl transfer is reversible and that a slow kinetic step follows formation of the E-MgADP-P-FAK-tide complex. Further kinetic studies performed in the presence of the microscopic viscosogen sucrose revealed that solvent viscosity had no effect on k(cat)/K(FAK-tide), while k(cat) and k(cat)/K(MgATP) were both decreased linearly at increasing solvent viscosity. Crystallographic characterization of inactive versus AMP-PNP-liganded structures of FAK1 showed that a large conformational motion of the activation loop upon ATP binding may be an essential step during catalysis and would explain the viscosity effect observed on k(cat)/K(m) for MgATP but not on k(cat)/K(m) for FAK-tide. From the positional isotope exchange, viscosity, and structural data it may be concluded that enzyme turnover (k(cat)) is rate-limited by both reversible phosphoryl group transfer (k(forward) approximately 0.2 s(-1) and k(reverse) approximately 0.04 s(-1)) and a slow step (k(conf) approximately 0.1 s(-1)) which is probably the opening of the activation loop after phosphoryl group transfer but preceding product release.