Lack of association between VAP-1/SSAO activity and corneal neovascularization in a rabbit model

The aim of this study is to determine the efficacy of a potent and specific vascular adhesive protein-1/semicarbazide-sensitive amine oxidase (VAP-1/SSAO) inhibitor, LJP 1207, as a potential antiangiogenic and anti-inflammatory agent in the therapy of corneal neovascularization. Corneal neovascularization was induced with intrastromal suturing in rabbits (n = 20). Topical treatment with VAP-1/SSAO inhibitor LJP 1207 (n = 5, 4 times a day), bevacizumab (n = 5, daily), their combination (n = 5) and vehicle only (n = 5, 4 times a day) were applied postoperatively for 2 weeks. The development and extent of corneal neovascularization were evaluated by digital image analysis. At the end of the observation period, the level of corneal and serum VAP-1/SSAO activity was measured fluorometrically and radiochemically. The corneal VAP-1/SSAO activity was significantly elevated in the suture-challenged vehicle-treated group (3,075 ± 1,009 pmol/mg/h) as compared to unoperated controls (464.2 ± 135 pmol/mg/h, p < 0.001). Treatment with LJP 1207 resulted in slower early phase neovascularization compared to vehicle-treated animals (not significant). At days 7–14, there was no significant difference in the extent of corneal neovascularization between inhibitor- and vehicle-treated corneas, even though inhibitor treatment caused a normalization of corneal VAP-1/SSAO activity (885 ± 452 pmol/mg/h). Our results demonstrate that the significant elevation of VAP-1/SSAO activity due to corneal injury can be prevented with VAP-1/SSAO inhibitor LJP 1207 treatment. However, normalization of VAP-1/SSAO activity in this model does not prevent the development of corneal neovascularization.     

Cerebrovascular hemodynamic changes in multiple sclerosis patients during head-up tilt table test: effect of high-dose intravenous steroid treatment

Demyelination in multiple sclerosis (MS) may cause damage to the vegetative nervous system. Our objective was to examine cerebral autoregulation assessed via blood pressure and cerebral blood flow velocity fluctuations during head-up tilt table testing. We also investigated the effects of high-dose intravenous corticosteroid treatment. Transcranial Doppler registration of middle cerebral artery blood flow velocity and continuous blood pressure and heart rate monitoring were performed at rest and during tilt table testing in 30 MS patients. Ten age-matched healthy subjects were also examined as controls. Correlations between mean arterial blood pressure (MBP) and cerebral blood flow velocity (CBF) fluctuations were averaged, yielding the correlation coefficient index Mx. For a subgroup of 11 patients with acute exacerbations, results were also evaluated before and after methylprednisolone treatment (1 g/day intravenously for 5 days). No significant differences in the autoregulatory indices were seen between patients and controls, or between pre- and post-steroid results. Modeling CBF velocity changes associated with a 1-mmHg increase in MBP, significant differences (p < 0.05) were detected in patients vs. controls, and also after vs. before steroid administration. We conclude that cerebrovascular autoregulation impairments are detectable in early phase MS. Corticosteroid treatment has a significant effect on hemodynamic changes in acute exacerbations.     

Trends in prevalence and characteristics of post-neonatal cerebral palsy cases: A European registry-based study

The present paper aims to analyze trends over time in prevalence of cerebral palsy of post-neonatal origin, to investigate whether changes are similar according to severity and to describe the disability profile by etiology. Post-neonatal cases, birth years 1976 to 1998, were identified from the Surveillance of Cerebral Palsy in Europe collaboration (19 population-based registries). A recognized causal event occurring between 28 days and 24 months of age was considered to define the cases. Trends in prevalence were explored using graphical methods (Lowess and Cusum control chart) and modeled with negative binomial regressions. Over the study period, 404 cases were identified as post-neonatal cases (5.5% of the total). Mean prevalence rate was 1.20 per 10,000 live births (95% CI [1.08–1.31]). A significant downward trend was observed (p = 0.001), with an accentuated decrease in the 1990s. The prevalence of severe cases which account for around one third of the total also significantly decreased over time (p < 0.001). In 46% of cases, an infectious aetiology was reported; the corresponding prevalence significantly decreased since 1989. No significant decrease was observed for the rate of cases due to a vascular episode or of traumatic origin. Our results emphasize the need of large population-based surveillance systems to reliably monitor trends in prevalence in rare subgroups of children like those with acquired cerebral palsy. The decrease of the overall prevalence as well as those of the most severe cases may be partly due to public health actions targeted to prevent such events.     

Rate of recurrence and malignant transformation in 88 cases with inverted papilloma between 1998–2008

Conclusions The recurrence rate of IP in the current study is comparable to international and national studies. When the primary tumour was located in the frontal or the sphenoid sinus, the tumour seemed more likely to recur. Some recurrences were more than 2 years after primary surgery, suggesting continued need for long-term follow-up. The rate of malignant transformation in inverted papilloma cases has not changed in Denmark.

Objectives Inverted papillomas are benign tumours located in the nasal cavity and paranasal sinuses. They are known for their tendency to recur after surgery and show invasive growth, causing bone remodulation and the association with malignant transformation. The introduction of endoscopic sinus surgery and computer aided sinus surgery over the last decades has made this tumour more approachable with less cosmetic and functional damage. The objective of this study is to establish whether the recurrence rate and the rate of malignant transformation of IP have changed with the application of these new techniques.

Method A retrospective study between 1998–2008 including 88 cases with inverted papilloma.

Results In total, 25.3% had recurrence. Combined surgical approach with endoscope/open approach had the lowest rate of recurrence. A malignant transformation in the postoperative histological examination was found in 8.9%.     

Deletion of Lkb1 in Renal Tubular Epithelial Cells Leads to CKD by Altering Metabolism

Renal tubule epithelial cells are high-energy demanding polarized epithelial cells. Liver kinase B1 (LKB1) is a key regulator of polarity, proliferation, and cell metabolism in epithelial cells, but the function of LKB1 in the kidney is unclear. Our unbiased gene expression studies of human control and CKD kidney samples identified lower expression of LKB1 and regulatory proteins in CKD. Mice with distal tubule epithelial-specific Lkb1 deletion (Ksp-Cre/Lkb1^flox/flox) exhibited progressive kidney disease characterized by flattened dedifferentiated tubule epithelial cells, interstitial matrix accumulation, and dilated cystic-appearing tubules. Expression of epithelial polarity markers β-catenin and E-cadherin was not altered even at later stages. However, expression levels of key regulators of metabolism, AMP-activated protein kinase (Ampk), peroxisome proliferative activated receptor gamma coactivator 1-α (Ppargc1a), and Ppara, were significantly lower than those in controls and correlated with fibrosis development. Loss of Lkb1 in cultured epithelial cells resulted in energy depletion, apoptosis, less fatty acid oxidation and glycolysis, and a profibrotic phenotype. Treatment of Lkb1-deficient cells with an AMP-activated protein kinase (AMPK) agonist (A769662) or a peroxisome proliferative activated receptor alpha agonist (fenofibrate) restored the fatty oxidation defect and reduced apoptosis. In conclusion, we show that loss of LKB1 in renal tubular epithelial cells has an important role in kidney disease development by influencing intracellular metabolism.     

The HLA 8.1 ancestral haplotype is strongly linked to the C allele of -429T>C promoter polymorphism of receptor of the advanced glycation endproduct (RAGE) gene. Haplotype-independent association of the -429C allele with high hemoglobinA1C levels in diabetic patients

Previously we reported on strong linkage disequilibrium (LD) between the mono-S-C4B-RCCX module (mono-S) and the TNF2 allele (both known constituents of the 8.1 ancestral haplotype (8.1 AH)) in two Caucasian populations. The gene for the receptor of advanced glycation endproducts (RAGE) is encoded between the RCCX module and the HLA class II genes in the central MHC region. In order to assess the relationship between the promoter polymorphisms of the RAGE gene and the 8.1 AH, we performed a family study in eight informative families affected with type 1 diabetes mellitus; haplotypes of a RAGE promoter SNP (-429T>C) with the HLA-DQ2, -DR-3(17) and TNF2 alleles, as well as the mono-S genotype were determined. A similar analysis was performed in 82 unrelated patients with type 1 diabetes mellitus, and in unrelated healthy individuals of three different Caucasian populations (Hungarians, Ohioian females, Icelandics). In the diabetic patients clinical correlations were also investigated. Out of the 32 paternal and maternal chromosome 6 from the eight families, 15 different MHC haplotypes were found. Haplotypes containing at least three of the known constituents of the 8.1 AH (HLA-DQ2, -DR17, mono-S, TNF2) were always linked to the RAGE -429C allele. The RAGE -429C allele exhibited highly significant (p<0.0001) LD coefficients to known constituents of the 8.1 AH both in healthy persons and patients with type 1 diabetes. In the group of patients with diabetes we found significantly (p=0.013) higher maximal hemoglobinA1C concentration in the carriers of the RAGE -429C allele, this trait, however was not linked to the 8.1 AH. Our present findings indicate that the RAGE -429C allele can be considered as a candidate member of the 8.1 AH. The results also reveal a spectrum of recombinant MHC haplotypes in addition to the conserved ancestral haplotypes.     

Controlled study of lactoperoxidase gel on oral flora and saliva in irradiated patients with oral cancer

The aim of this study was to determine if radiotherapy induces hyposalivation altering oral microbial flora. The purpose of this placebo-controlled, single-blind study was to determine beneficial effects of a saliva substitute and an oral hygiene product on irradiated patients with oropharyngeal cancer. Eighteen patients were assigned to the test group (Biotène Oral Balance gel [Lacléde Incorporated Healthcare Products, Gardena, CA] and toothpaste used daily), and another 18 were put on a conventional daily regimen (carboxymethylcellulose gel and Oral-B toothpaste [Laclede Pharmaceuticals, Gardena, CA]). Cultures for identifying and quantitating microorganisms, whole unstimulated saliva, and visual analog measurements for comfort were obtained before mucositis occurred and after treatment. Daily use of Biotène products enhanced control of microbial flora, improved salivary flow, and increased oral comfort as compared with control subjects. Four weeks after mucositis, some aerobic isolates disappeared in the test group; periodontal-associated bacteria were markedly decreased in the test group; and candidal species were significantly lowered in the test group. Although baseline saliva was lower in the test group (P = 0.001), after 4 weeks, no difference between groups existed; comfort was greater in the test group (P = 0.007). Use of enzyme-engineered Biotène products that assist in control of the oral microbial flora as well as supporting oral comfort through lubrication appear to be useful aids for irradiated patients with oropharyngeal cancer.     

Effectiveness of antibiotic therapy in pediatric patients with cat scratch disease

Background Appropriate antibiotic treatment of cat scratch disease (CSD) in pediatrics is not well established. Objective The purpose of this study was to evaluate the response rates of antibiotic therapy in pediatrics with CSD. Methods The electronic medical records of a cohort of pediatric patients with confirmed diagnosis of CSD (2006–2016) were reviewed, retrospectively. Data collection included patient demographics, clinical and laboratory results, antibiotic treatment and follow-up evaluations. Results One hundred and seventy-five patients (aged 7.4?±?4.4 years) had confirmed CSD. Azithromycin and trimethoprim/sulfamethoxazole (TMP/SMX) were the largest groups with documented effectiveness at follow-up visits. Resolution and improvement of CSD was observed in 51.4% and 61.5% of patients with azithromycin and TMP/SMX, respectively among those with follow-up assessment. The effectiveness of azithromycin and TMP/SMX was comparable (p?=?0.56). Conclusion Azithromycin and TMP/SMX were most frequently prescribed antibiotics. Azithromycin appeared to be an appropriate option for the treatment of CSD. TMP/SMX may be considered as an alternative antibiotic when azithromycin cannot be used.     

Real-life experience with switching TNF-α inhibitors in ankylosing spondylitis

Background

Published economic evaluations of trastuzumab for the treatment of HER2-positive metastatic breast cancer have arrived at different conclusions regarding the cost-effectiveness of trastuzumab, despite comparative efficacy being demonstrated by a small set of randomised controlled trials (RCTs).

Objectives

This article aims to provide insight into the quality of the evaluations and explore the possible drivers of the conflicting conclusions.

Methods

A systematic literature review was conducted to identify all published economic evaluations that compared the incremental costs and outcomes of trastuzumab versus a comparator.

Results

Fifteen economic evaluations were identified. In the evaluations that estimated efficacy using an RCT, the key drivers of the conclusions regarding cost-effectiveness were: the approach used to estimate overall survival in the control group given crossover to trastuzumab following progression in the trials; the inclusion of treatment beyond progression; inclusion of wastage due to unused vial portions, adverse events, and the cost of HER2 testing. Four evaluations used non-randomised approaches to estimate efficacy, thus introducing the potential for confounding. As a result these evaluations reported relatively optimistic estimates of comparative effectiveness. Finally the evaluations used different thresholds to determine whether treatment with trastuzumab was cost-effective.

Conclusion

There were numerous drivers of the different conclusions regarding the cost-effectiveness of trastuzumab, many of which are due to judgements made by the authors when translating data from RCTs. Many of the potential drivers were not identified by the published systematic reviews of economic evaluations and perhaps more remain unidentified because of inconsistent and limited reporting.