Superficial siderosis of the central nervous system

The course of a patient suffering from superficial siderosis of the central nervous system for 37 years is presented and diagnostic and therapeutic approaches are evaluated. The syndrome is clinically defined by slowly progressing deafness, cerebellar ataxia, myelopathy and neuropsychological deficits in combination with recurrent xanthochromia of the cerebrospinal fluid with siderophages. The diagnosis may be confirmed by computed tomography, which shows degeneration of the cerebellar vermis, and by magnetic resonance imaging, demonstrating iron deposits on the surface of brain, brain stem and spinal cord. Therapy should seek to identify and remove the source of bleeding, since pharmacotherapy with iron-depleting drugs is of limited effectiveness.     

Characterization of Human Influenza Virus Variants Selected In Vitro in the Presence of the Neuraminidase Inhibitor GS 4071

An oral prodrug of GS 4071, a potent and selective inhibitor of influenza neuraminidases, is currently under clinical development for the treatment and prophylaxis of influenza virus infections in humans. To investigate the potential development of resistance during the clinical use of this compound, variants of the human influenza A/Victoria/3/75 (H3N2) virus with reduced susceptibility to the neuraminidase inhibitor GS 4071 were selected in vitro by passaging the virus in MDCK cells in the presence of inhibitor. After eight passages, variants containing two amino acid substitutions in the hemagglutinin (A28T in HA1 and R124M in HA2) but no changes in the neuraminidase were isolated. These variants exhibited a 10-fold reduction in susceptibility to GS 4071 and zanamivir (GG167) in an in vitro plaque reduction assay. After 12 passages, a second variant containing these hemagglutinin mutations and a Lys substitution for the conserved Arg292 of the neuraminidase was isolated. The mutant neuraminidase enzyme exhibited high-level (30,000-fold) resistance to GS 4071, but only moderate (30-fold) resistance to zanamivir and 4-amino-Neu5Ac2en, the amino analog of zanamivir. The mutant enzyme had weaker affinity for the fluorogenic substrate 2′-(4-methylumbelliferyl)-α-d-N-acetylneuraminic acid and lower enzymatic activity compared to the wild-type enzyme. The viral variant containing the mutant neuraminidase did not replicate as well as the wild-type virus in culture and was 10,000-fold less infectious than the wild-type virus in a mouse model. These results suggest that although the R292K neuraminidase mutation confers high-level resistance to GS 4071 in vitro, its effect on viral virulence is likely to render this mutation of limited clinical significance.Influenza virus infections remain a serious seasonal health concern and the potential of severe pandemics due to the emergence of new influenza strains, such as the H5N1 “bird flu” recently identified in Hong Kong (39), provides additional impetus to develop potent and effective antiviral agents (24). At present, only amantadine and, in some countries, rimantadine are approved for the treatment and prophylaxis of influenza A infections. However, the usefulness of these two compounds is limited by their lack of activity against influenza B viruses and their rapid selection of drug-resistant mutants which remain transmissible and pathogenic (10, 25).The influenza neuraminidase, which is expressed on the virus surface, has long been considered a valid target for antiviral therapy. This enzyme, which cleaves terminal sialic acid residue from glycoconjugates, is essential for virus proliferation and infectivity (3, 17, 19, 27, 28). The observation that the structural and catalytic amino acids which line the enzyme active site are highly conserved among different influenza neuraminidase types and subtypes (reviewed in reference 6) suggests that inhibitors of this enzyme would be active against a broad range of influenza viruses.Based on information gained from crystallographic studies of influenza neuraminidases complexed with sialic acid or the transition state analog Neu5Ac2en (2, 41, 43), several potent and selective inhibitors of the influenza neuraminidases have been synthesized (15, 16, 43). Two of these, GS 4071 ([3R,4R,5S]-4-acetamido-5-amino-3-[1-ethylpropoxy]1-cyclohexene-1-carboxylic acid), in the form of its oral prodrug GS 4104, and zanamivir (GG167, 4-guanidino-Neu5Ac2en) are currently under clinical development for the prophylaxis and treatment of influenza virus infections. Both compounds have demonstrated efficacy against influenza A and B viruses in vitro (13, 23, 40, 43, 45), in animal models of influenza virus infection (23, 31, 32, 34), and in experimental influenza virus infection in humans (11, 12, 14) when GS 4104 is taken orally and zanamivir is delivered topically to the respiratory tract as an inhalant.Although the development of resistance to zanamivir in animals or people treated with the drug has not been reported, influenza variants resistant to zanamivir due to mutations within their hemagglutinin or neuraminidase genes have been selected in vitro (1, 7, 8, 20, 38). In general, zanamivir-resistant hemagglutinin mutants have been easier to generate than neuraminidase mutations. These hemagglutinin mutants commonly contain amino acid substitutions in or near the sialic acid binding site and are believed to make the virus replication less dependent on neuraminidase activity (7, 20, 33). However, these mutations likely only affect the in vitro, not the in vivo, susceptibility to zanamivir (29).The most common neuraminidase mutation which arises in vitro under selective pressure of zanamivir has been that of the conserved Glu119 residue in the neuraminidase active site (1, 7, 38). Mutations of Glu119, which interacts with the guanidino side chain of zanamivir but not with the natural substrate (43), cause a 100-fold reduction in the sensitivity of the enzyme to zanamivir (1, 7, 38). Viruses containing mutations at this position remain infectious (8) and capable of inducing a febrile response in ferrets (5). Recently, a Lys substitution for the conserved Arg at position 292 has also been reported for a variant selected in the presence of zanamivir (8). The neuraminidase containing this mutation exhibited only a 10-fold reduction in sensitivity to zanamivir. A reassortant virus containing the mutant neuraminidase was 500-fold less infectious than wild-type virus in mice (8).In this report, we describe the first in vitro isolation and characterization of variants of a human influenza virus, A/Victoria/3/75 (H3N2), selected in the presence of GS 4071. In contrast with the experience with amantadine and rimantadine, with which drug-resistant variants can be selected after one or two passages in culture (26), variants with decreased susceptibility to GS 4071 did not readily occur. In the eighth passage, a variant containing two mutations in the stalk region of the hemagglutinin was isolated. This variant exhibited a minor decrease in susceptibility to neuraminidase inhibitors in general. A second variant, containing a conservative substitution of a Lys for an Arg at amino acid 292 of the neuraminidase enzyme active site, was isolated later in the selection process. This mutation caused a marked decrease in the susceptibility of the virus and the sensitivity of the enzyme to GS 4071. However, this mutation also adversely affected neuraminidase enzyme activity, compromised the ability of the virus to replicate in tissue culture, and reduced the infectivity of the virus 10,000-fold in mice.     

The patients’ view: impact of the extent of resection,intraoperative imaging,and awake surgery on health-related quality of life in high-grade glioma patients—results of a multicenter cross-sectional study

Neurosurgical Review - The objective of the present study is to assess the influence of extent of resection (EoR), use of intraoperative imaging, and awake surgery on health-related quality of life...     

5-Jahres-Follow-up von 210 Columbus-Knietotalendoprothesen

Introduction

As part of 10-year documentation using the Columbus system, the interim evaluation was carried out 5 years after implantation with a collection of clinical scores, evaluation of radiological imaging and collection of statistics concerning complications.

Methods

There was a multicentre prospective recruitment of consecutive patients with the indication of implantation of a surface replacement prosthesis (Columbus CR, Deep Dish fixed inlay). Preoperatively, clinical scores were recorded (KSS and Oxford score). Five years postoperatively a new evaluation of clinical scores, the range of motion (ROM) and a radiological check-up including full leg imaging under load was performed. During this period, detailed complication documentation was made.

Results

A total of 210 patients were recruited in five centres. 187 patients were available for examination 5 years after surgery. Cumulative KSS increased from 87.5 (±26.6) preoperatively to 170 (±29.1) 5 years postoperatively. The cumulative KSS improvement was 81.5 (±35.2) points and was highly significant (p?<?0.0001; t?test). The average functional improvement in the Oxford score between the preoperative and 5?year follow-up was 21.7 (±8.8) points and was also highly significant (p?<?0.0001). The ROM improved from 106.3° (±20.2) preoperatively to 114.0° (±12.1) 5 years postoperatively (p?<?0.0001; t test). Five years after implantation, the average mechanical leg axis was 178.0° (±2.1). There was no clinically apparent or native radiologic visible aseptic loosening of the femoral or tibial joint component. There were 33 complications, but no implant-related complications such as inlay dislocation, material fracture or aseptic loosening. In total, 6 revision surgeries were performed during the follow-up period, which corresponds to a survival rate of 97.1% (CI 95%) for the implanted Columbus knee in the present patient collective for 5 years.

Conclusion

The interim analysis at 5 years of long-term observation of the Columbus system provided good clinical and radiographic results.

     

The objective burden in partners of heart failure patients; development and initial validation of the Dutch Objective Burden Inventory.

BACKGROUND: Measures on objective caregiver burden in partners of Heart Failure patients are hardly available and never include HF specific aspects. AIM: The main objective of our study was to develop an inventory that assesses the objective caregiver burden of partners of HF patients, including the full range of potential care giving demands. METHODS: To develop the inventory, six domains of caregiving demands were identified. Items for the domains were generated from the literature, expert opinion and existing scales. The original 50-items self-report inventory was administered to 321 partners of HF patients. Demographic data of HF partners were collected by questionnaire. Clinical data of the HF patients were collected by chart review. RESULTS: Component analysis led to exclusion of 12 original items and to a meaningful four-factor solution with a total explained variance of 43%. The components reflected four different kinds of care giving tasks; personal care, emotional, motivational and practical (treatment related) support. They demonstrated good internal consistency and initial validity was supported by a pattern of meaningful associations with external variables. CONCLUSION: The Objective Burden Inventory is a promising inventory to assess objective care giving tasks performed by HF partners, including emotional and motivational support. It provides information on the caregiver situation that may help to develop effective interventions.     

Genetic replacement of the adenovirus shaft fiber reduces liver tropism in ovarian cancer gene therapy

Approaches to alter the native tropism of adenoviruses (Ads) are beneficial to increase their efficacy and safety profile. Liver tropism is important with regard to potential clinical toxicity in humans. Ad5/3 chimeras in which the Ad5 knob is substituted by the Ad3 knob, such as Ad5/3luc1, have been recently shown to increase infectivity of ovarian cancer cell lines and primary tumor cells, which express low levels of the coxsackie-adenovirus receptor (CAR), without increasing infectivity of liver cells. A novel strategy to address the problem of liver uptake and improve the tumor/liver ratio is genetic replacement of the Ad fiber shaft. Ad5.Ad3.SH.luc1 is an Ad5-based vector that contains the fiber shaft from Ad serotype 3 but the fiber knob from Ad serotype 5. To compare tumor/liver of Ad5.Ad3.SH.luc1 and Ad5/3luc1 in vivo, we created three different tumor and treatment models of ovarian cancer in mice, simulating intraperitoneal and intravenous administration of tumors. Ad5.Ad3.SH.luc1 displayed the lowest liver tropism of all viruses in all models tested. Intravenous administration of all viruses resulted in higher tumor transduction rates compared to intraperitoneal administration. Genetic shortening of the Ad5 fiber shaft significantly increases relative tumor/liver gene transfer. This could improve the effective tumor dose and reduce side effects, thereby increasing the bioavailability of therapeutic agents.