Background: Among the numerous therapeutic approaches used in the treatment of interstitial cystitis/bladder pain syndrome (IC/BPS) few have been assessed with a sufficient level of evidence. The ...safety and efficacy of pentosan polysulfate sodium (PPS) has been shown in several open-label and comparative clinical trials with different populations including two meta-analyses. In the context of the approval procedure of PPS for the treatment of IC/BPS by the European Medicines Agency we updated the findings of the previous analyses by incorporating the results of the latest studies.
Method: Relevant studies based on a systematic review of PubMed/Medline and the Cochrane Library in June 2018 were identified. For completeness control, clinical trial registries were also searched. Only randomized, placebo-controlled clinical trials providing sufficient information to estimate at least one relevant effect size measure to compare the efficacy of PPS versus placebo were included in the analysis.
Results: Of the studies identified in the literature search, six randomized placebo-controlled studies met the pre-defined eligibility criteria. Analyses showed no indication of heterogeneity or publication bias. Treatment with PPS led to a statistically significant improvement in the patient's overall response assessment (p < .001), pain (p = .009) and urgency (p = .005).
Conclusions: Our meta-analyses confirmed the results of preceding meta-analyses showing that PPS is efficacious compared to placebo in the treatment of bladder pain, urinary urgency and frequency of micturition and thus an evident option for the treatment of IC/BPS symptoms.
Abstract
Two years since the outbreak of the novel coronavirus SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) pandemic, there remain few clinically effective drugs to complement ...vaccines. One is the anticoagulant, heparin, which in 2004 was found able to inhibit invasion of SARS-CoV (CoV-1) and which has been employed during the current pandemic to prevent thromboembolic complications and moderate potentially damaging inflammation. Heparin has also been shown experimentally to inhibit SARS-CoV-2 attachment and infection in susceptible cells. At high therapeutic doses however, heparin increases the risk of bleeding and prolonged use can cause heparin-induced thrombocytopenia, a serious side effect. One alternative, with structural similarities to heparin, is the plant-derived, semi-synthetic polysaccharide, pentosan polysulfate (PPS). PPS is an established drug for the oral treatment of interstitial cystitis, is well-tolerated, and exhibits weaker anticoagulant effects than heparin. In an established Vero cell model, PPS and its fractions of varying molecular weights inhibited invasion by SARS-CoV-2. Intact PPS and its size-defined fractions were characterized by molecular weight distribution and chemical structure using nuclear magnetic resonance spectroscopy and liquid chromatography–mass spectrometry, then employed to explore the structural basis of interactions with SARS-CoV-2 spike protein receptor-binding domain (S1 RBD) and the inhibition of Vero cell invasion. PPS was as effective as unfractionated heparin, but more effective in inhibiting cell infection than low-molecular-weight heparin (on a weight/volume basis). Isothermal titration calorimetry and viral plaque-forming assays demonstrated size-dependent binding to S1 RBD and inhibition of Vero cell invasion, suggesting the potential application of PPS as a novel inhibitor of SARS-CoV-2 infection.
Herpes simplex virus has been implicated in the pathophysiology of vestibular neuritis. In this placebo-controlled trial, a course of methylprednisolone initiated within three days after the onset of ...vestibular neuritis resulted in improved vestibular function at one year, whereas valacyclovir had no effect.
A course of methylprednisolone is likely to have a long-term benefit.
Vestibular neuritis is the second most common cause of peripheral vestibular vertigo (the first being benign paroxysmal positional vertigo). It accounts for 7 percent of the patients who present at outpatient clinics specializing in the treatment of dizziness
1
and has an incidence of about 3.5 per 100,000 population.
2
The key signs and symptoms of vestibular neuritis are the acute onset of sustained rotatory vertigo, postural imbalance with Romberg's sign (i.e., falls, with the eyes closed, toward the affected ear), horizontal spontaneous nystagmus (toward the unaffected ear) with a rotational component, and nausea. Caloric testing (irrigation of the ear with warm . . .
PURPOSE: To report a possible association of glaucoma with Parkinson’s disease and Alzheimer’s disease.
METHODS: Retrospective chart review (observational case series). The ophthalmologic charts of ...49 patients with Alzheimer’s disease and of 38 patients with Parkinson’s disease were reviewed to determine the occurrence rate of glaucoma among these patients.
RESULTS: Glaucomatous visual field defects or cup-to-disk ratios of 0.8 or greater were recorded in 12 patients with Alzheimer’s disease (24.5%) and in 9 patients with Parkinson’s disease (23.7%).
CONCLUSION: Patients with Alzheimer’s disease and Parkinson’s disease may have an increased occurrence rate of glaucoma.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
The discovery of 4′-azidocytidine (3) (R1479) ( J. Biol. Chem. 2006, 281, 3793 ; Bioorg. Med. Chem. Lett. 2007, 17, 2570 ) as a potent inhibitor of RNA synthesis by NS5B (EC50 = 1.28 μM), the RNA ...polymerase encoded by hepatitis C virus (HCV), has led to the synthesis and biological evaluation of several monofluoro and difluoro derivatives of 4′-azidocytidine. The most potent compounds in this series were 4′-azido-2′-deoxy-2′,2′-difluorocytidine and 4′-azido-2′-deoxy-2′-fluoroarabinocytidine with antiviral EC50 of 66 nM and 24 nM in the HCV replicon system, respectively. The structure−activity relationships within this series were discussed, which led to the discovery of these novel nucleoside analogues with the most potent compound, showing more than a 50-fold increase in antiviral potency as compared to 4′-azidocytidine (3).
To provide a bridge between in vivo and in vitro studies of
eukaryotic translation initiation, we have developed a
reconstituted translation initiation system using components
from the yeast ...Saccharomyces cerevisiae. We have purified
a minimal set of initiation factors (eIFs) that, together with
yeast 80S ribosomes, GTP, and initiator methionyl-tRNA, are
sufficient to assemble active initiation complexes on a minimal
mRNA template. The kinetics of various steps in the pathway
of initiation complex assembly and the formation of the first
peptide bond in vitro have been explored. The formation of active
initiation complexes in this system is dependent on ribosomes,
mRNA, Met-tRNAi, GTP hydrolysis, eIF1, eIF1A, eIF2,
eIF5, and eIF5B. Our data indicate that eIF1 and eIF1A both
facilitate the binding of the
eIF2bull GTPbull Met-tRNAi complex to the 40S
ribosomal subunit to form the 43S complex. eIF5 stimulates a
step after 43S complex formation, consistent with its proposed
role in activating GTP hydrolysis by eIF2 upon initiation codon
recognition. The presence of eIF5B is required for the joining
of the 40S and 60S subunits to form the 80S initiation complex.
The step at which each of these factors acts in this reconstituted
system is in agreement with previous data from in vivo studies
and work using reconstituted mammalian systems, indicating that
the system recapitulates fundamental events in translation
initiation in eukaryotic cells. This system should allow us
to couple powerful yeast genetic and molecular biological
experiments with in vitro kinetic and biophysical experiments,
yielding a better understanding of the molecular mechanics of
this central, complex process.
Previous studies suggest that MR imaging is capable of providing accurate data on knee joint cartilage volume and thickness in vitro, but the reproducibility of these data in living subjects has not ...been analyzed rigorously. Our aim was therefore to determine the in vivo reproducibility of volume and thickness measurements from replicated data sets, applying three-dimensional (3D) postprocessing methods.
Eight healthy volunteers were imaged six times at a resolution of 2 x 0.31 x 0.31 mm with a fat-suppressed fast low-angle shot 3D sequence, the knee being repositioned in between replicated examinations. Three-dimensional reconstructions of the articular cartilage surfaces were obtained from sagittal data sets, and the cartilage volumes were calculated. The thickness distribution was analyzed throughout the joint surfaces independent of the section orientation, using a previously validated 3D minimal-distance algorithm.
In the volunteers, the coefficient of variation for replicated volume measurements ranged from 1.3% (patella) to 3.4% (lateral tibia), and the standard deviation of the individual cartilage volumes ranged from +/- 16% (lateral tibia) to +/- 22% (femur). The intraclass correlation coefficient ranged from .959 (lateral tibia) to .995 (patella). The interobserver evaluation was similar to the interscan reproducibility. The mean interscan deviation of the maximal cartilage thickness interval ranged from 0.1 to 0.3 cartilage thickness intervals (of 0.5 mm); only in rare cases did we record deviations greater than one thickness interval.
MR imaging can be used to determine cartilage volume and thickness in the knee joints of living subjects with high precision, provided that a fat-suppressed gradient-echo sequence with adequate resolution and 3D digital image processing are used.
To document the time course of retinal dysfunction by scotopic electroretinography (ERG) and by quantitative morphology in eyes of the DBA/2NNia substrain of mouse (DBA) with inherited angle-closure ...glaucoma.
DBA and control C57BL/6J (C57) mice were studied by ERG recordings from 5 to 15 months of age, and by morphology from 1 to 14 months of age. Scotopic ERGs were simultaneously recorded from both eyes of dark-adapted anesthetized mice. Changes in the central neuronal retina were evaluated by quantitative morphometry performed on serial semithin sections of Epon-embedded eyes.
When compared with normal C57 mice, DBA mice showed significant reductions of the a-wave and b-wave amplitudes by 7 to 8 months, and the decline continued as the animals aged. The b-wave implicit time in DBA mice showed a gradual prolongation beginning at 8 months of age, when compared with C57 mice. Logistic regression analyses revealed significant correlations in a- and b-wave amplitude reductions between ipsilateral and contralateral eyes of DBA mice at ages when ERG parameters were greatly altered. Morphologically, thinning of the whole retina was already evident in DBA mice at 4 months of age, but loss of ganglion cells and thinning of the outer plexiform layer were first seen in 7- to 8-month-old animals. These changes progressed to the end of the 13-month period studied.
Progressive thinning of the outer retinal layers in DBA mice was found to correlate with decreases in ERG a- and b-wave amplitudes, both occurring from the age of 7 to 8 months onward. Similarities with the findings in human late-stage glaucomatous retinopathy indicate the relevance of this animal model in further glaucoma research.
To evaluate the clinical use of a test battery of short-wavelength automated perimetry (SWAP), frequency-doubling technology (FDT) perimetry, and pattern-electroretinography (PERG) in patients with ...definite primary open-angle glaucoma (POAG) but normal results on standard automated perimetry (SAP).
Prospective, comparative, observational case series.
Thirty-six patients with POAG with standard visual field defects in one eye and normal standard visual fields in the contralateral eye and 36 normal controls were enrolled.
SWAP, PERG, FDT, and SAP were performed in all eyes, and global indices and amplitudes were used for statistical analysis.
When contralateral POAG eyes with asymmetric glaucomatous damage was compared, a paired
t test showed significant differences in SAP mean deviation (MD) (
P < 0.0001), SWAP-MD (
P = 0.0003), FDT-MD (
P = 0.0008), and PERG amplitudes (
P < 0.0001). When comparing between POAG eyes with normal results on SAP and normal controls, Student’s
t test showed significant differences for SWAP-MD (
P < 0.0001), FDT-MD (
P = 0.0006), PERG N1P1-amplitude (
P = 0.0486) and P1N2-amplitude (
P < 0.0001); receiver operating characteristic analysis revealed promising accuracy for SWAP-MD of 73.6% (
P < 0.0001). SWAP-MD (
P < 0.0001) and FDT-MD (
P < 0.0001) correlated significantly with SAP-MD and with each other (range,
P < 0.0001 to
P = 0.0020). Regression analysis revealed that PERG P1N2-amplitude could improve the power of SWAP-MD from 73.6% to detect early POAG in eyes with normal results on SAP to an accuracy of 81.9%.
A test battery of SWAP-MD and PERG P1N2-amplitude could detect glaucomatous optic neuropathy in POAG eyes with normal standard visual fields, whereas FDT-MD and SWAP-MD significantly correlated with each other and with SAP-MD. All tests were able to detect the eye with the more severe glaucomatous optic neuropathy in patients with asymmetric POAG.
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