Lentiviral vector delivery of parkin prevents dopaminergic degeneration in an alpha-synuclein rat model of Parkinson's disease

Parkinson's disease (PD) is characterized by a progressive loss of midbrain dopamine neurons and the presence of cytoplasmic inclusions called Lewy bodies. Mutations in several genes including alpha-synuclein and parkin have been linked to familial PD. The loss of parkin's E3-ligase activity leads to dopaminergic neuronal degeneration in early-onset autosomal recessive juvenile parkinsonism, suggesting a key role of parkin for dopamine neuron survival. To evaluate the potential neuroprotective role of parkin in the pathogenesis of PD, we tested whether overexpression of wild-type rat parkin could protect against the toxicity of mutated human A30P alpha-synuclein in a rat lentiviral model of PD. Animals overexpressing parkin showed significant reductions in alpha-synuclein-induced neuropathology, including preservation of tyrosine hydroxylase-positive cell bodies in the substantia nigra and sparing of tyrosine hydroxylase-positive nerve terminals in the striatum. The parkin-mediated neuroprotection was associated with an increase in hyperphosphorylated alpha-synuclein inclusions, suggesting a key role for parkin in the genesis of Lewy bodies. These results indicate that parkin gene therapy may represent a promising candidate treatment for PD.     

Laparoscopic colorectal surgery—Are we being honest with our patients?

PURPOSE: A survey was undertaken to assess the impact of laparoscopy on the practice of colorectal surgery. METHODS: A total of 1,520 questionnaires were mailed to all members of the American Society of Colon and Rectal Surgeons; 635 (42 percent) surgeons responded, 50 percent, and indicated that one questionnaire represented their entire group practice. RESULTS: Two hundred seventy-eight (47 percent) respondents currently perform laparoscopic colorectal surgery; 62 percent (171) use the laparoscope for 20 percent of their bowel resections. Conversely, only 6 percent (16) use the laparoscope in over 50 percent of resections. The percentage of surgeons who perform various procedures were right colectomy, 78 percent; left colectomy, 57 percent; stoma creations, 52 percent; anterior resection, 44 percent; Hartmann's closure, 42 percent; abdominoperineal resection, 27 percent; rectopexy, 18 percent; and total colectomy, 14 percent. If the preoperative diagnosis is known to be carcinoma, 196 (71 percent) surgeons attempted laparoscopic colorectal surgery, but 55 percent of surgeons (108) operated only for early lesions and 35 percent (68) only for palliation. To enable the procedure to be laparoscopically performed, 87 percent (243) of surgeons stated that they have changed their practice to include routine use of ureteral stents (23 percent), preoperative colonoscopic marking of small lesions (40 percent), or intraoperative colonoscopy. Despite increased use of endoscopy, there were 18 patients in whom the wrong segment of colon was removed. Moreover, nine patients had early local recurrence after resection of colon cancer, nine had early local recurrence after rectal cancer resection, and five had early port-site recurrence. Although 255 (40 percent) surgeons surveyed would themselves undergo laparoscopic colorectal surgery for a rectal villous adenoma, only 38 (6 percent) would have a laparoscopic anterior resection for cancer. CONCLUSIONS: Several important problems exist including early port-site recurrence and a dual surgical standard. Although many surgeons are eager to practice laparoscopic colorectal surgery on their patients with carcinoma, they are reluctant to have the new technique applied to themselves.Read at the meeting of The American Society of Colon and Rectal Surgeons, Orlando, Florida, May 8 to 13, 1994.     

Atypical antioxidant activity of non-phenolic amino-coumarins

Coumarin compounds have been described as anti-inflammatories, and chemotherapeutic agents as well as antioxidants. However, the origin of the antioxidant activity of non phenolic coumarins remains obscure. In the present report, we demonstrate that non-phenolic 7-dialkyl-aminocoumarins may also have significant antioxidant properties against free radicals derived from 2,2′-azobis(2-amidinopropane) dihydrochloride under aerobic conditions. This atypical behaviour is due to the presence of traces of very reactive hydroxycinnamic acid-type compounds. Changing functional groups at the C-3 and C-4 positions shifts the reactivity of the compounds from peroxyl to alkoxyl free radicals. Kinetic and theoretical studies based on Density Functional Theory support the formation of reactive hydroxycinnamic acid and directly link the antioxidant behaviour of the compounds to hydrogen atom transfer.

Relevant antioxidant properties of non-phenolic 7-dialkyl-aminocoumarins against free radicals derived from 2,2′-azobis(2-amidinopropane) dihydrochloride under aerobic conditions have been experimentally and theoretically demonstrated.     

Semi-automatic detection of myocardial trabeculation using cardiovascular magnetic resonance: correlation with histology and reproducibility in a mouse model of non-compaction

Background

The definition of left ventricular (LV) non-compaction is controversial, and discriminating between normal and excessive LV trabeculation remains challenging. Our goal was to quantify LV trabeculation on cardiovascular magnetic resonance (CMR) images in a genetic mouse model of non-compaction using a dedicated semi-automatic software package and to compare our results to the histology used as a gold standard.

Methods

Adult mice with ventricular non-compaction were generated by conditional trabecular deletion of Nkx2–5. Thirteen mice (5 controls, 8 Nkx2–5 mutants) were included in the study. Cine CMR series were acquired in the mid LV short axis plane (resolution 0.086?×?0.086x1mm³) (11.75 T). In a sub set of 6 mice, 5 to 7 cine CMR were acquired in LV short axis to cover the whole LV with a lower resolution (0.172?×?0.172x1mm3). We used semi-automatic software to quantify the compacted mass (M_c), the trabeculated mass (M_t) and the percentage of trabeculation (M_t/M_c) on all cine acquisitions_. After CMR all hearts were sliced along the short axis and stained with eosin, and histological LV contouring was performed manually, blinded from the CMR results, and M_t, M_c and M_t/M_c were quantified. Intra and interobserver reproducibility was evaluated by computing the intra class correlation coefficient (ICC).

Results

Whole heart acquisition showed no statistical significant difference between trabeculation measured at the basal, midventricular and apical parts of the LV. On the mid-LV cine CMR slice, the median M_t was 0.92 mg (range 0.07–2.56 mg), M_c was 12.24 mg (9.58–17.51 mg), M_t/M_c was 6.74% (0.66–17.33%). There was a strong correlation between CMR and the histology for M_t, M_c and M_t/ M_c with respectively: r²?=?0.94 (p?<?0.001), r²?=?0.91 (p?<?0.001), r²?=?0.83 (p?<?0.001). Intra- and interobserver reproducibility was 0.97 and 0.8 for M_t; 0.98 and 0.97 for M_c; 0.96 and 0.72 for M_t/M_c, respectively and significantly more trabeculation was observed in the M_c Mutant mice than the controls.

Conclusion

The proposed semi-automatic quantification software is accurate in comparison to the histology and reproducible in evaluating M_c, M_t and M_t/ M_c on cine CMR.

     

Biologics for treating axial spondyloarthritis

Introduction: Spondyloarthritis (SpA) encompasses a heterogeneous group of diseases sharing genetic, immunological, clinical and imaging features. Axial spondyloarthritis (axSpA) refers to a subgroup characterised predominately by inflammation of the axial skeleton with subsequent symptoms of chronic (often inflammatory) back pain and sacroiliitis. There is a strong association with the major histocompatibility complex (MHC) class I allele human leukocyte antigen (HLA) B27. In the last decade, there has been significant progress in earlier detection of the disease and the molecular mechanisms involved in its pathogenesis. The subsequent introduction of anti-tumour necrosis factor (TNF) has revolutionised the treatment of patients with axSpA.

Areas covered: In this article, we review the current biologic therapies for axSpA, the emergence of biosimilars, predictors of response, primary and secondary failure and new biologics on the horizon.

Expert opinion: There have been significant advances in the treatment of axSpA. Beyond the clear efficacy of anti-TNF inhibition, IL-17 offers an alternative therapeutic target and there is promise from inhibition of the IL-17/IL-23 pathway and small molecules, such as Janus kinase (JAK) inhibitors. Biosimilars have offered greater affordability and choice within this increasingly growing field of therapeutics.