Improved Protective Efficacy of a Species-Specific DNA Vaccine Encoding Mycolyl-Transferase Ag85A from Mycobacterium ulcerans by Homologous Protein Boosting

Vaccination with plasmid DNA encoding Ag85A from M. bovis BCG can partially protect C57BL/6 mice against a subsequent footpad challenge with M. ulcerans. Unfortunately, this cross-reactive protection is insufficient to completely control the infection. Although genes encoding Ag85A from M. bovis BCG (identical to genes from M. tuberculosis) and from M. ulcerans are highly conserved, minor sequence differences exist, and use of the specific gene of M. ulcerans could possibly result in a more potent vaccine. Here we report on a comparison of immunogenicity and protective efficacy in C57BL/6 mice of Ag85A from M. tuberculosis and M. ulcerans, administered as a plasmid DNA vaccine, as a recombinant protein vaccine in adjuvant or as a combined DNA prime-protein boost vaccine. All three vaccination formulations induced cross-reactive humoral and cell-mediated immune responses, although species-specific Th1 type T cell epitopes could be identified in both the NH2-terminal region and the COOH-terminal region of the antigens. This partial species-specificity was reflected in a higher—albeit not sustained—protective efficacy of the M. ulcerans than of the M. tuberculosis vaccine, particularly when administered using the DNA prime-protein boost protocol

Increased endothelin-1 and diminished nitric oxide levels in blister fluids of patients with intermediate cold type complex regional pain syndrome type 1

BACKGROUND: In complex regional pain syndrome type 1 (CRPS1) pro-inflammatory mediators and vascular changes play an important role in the sustained development and outcome of the disease. The aim of this study was to determine the involvement of vasoactive substances endothelin-1 (ET-1) and nitric oxide (NO) during early chronic CRPS1. METHODS: Included were 29 patients with CRPS 1 who were diagnosed during the acute stage of their disease and observed during follow-up visits. Disease activity and impairment were determined and artificial suction blisters were made on the CRPS1 and the contralateral extremities for measurements of IL-6, TNF-α, ET-1 and nitrate/nitrite (NOx). RESULTS: The levels of IL-6, TNF-α and ET-1 in blister fluid in the CRPS1 extremity versus the contralateral extremity were significantly increased and correlated with each other, whereas NOx levels were decreased. CONCLUSION: The NOx/ET-1 ratio appears to be disturbed in the intermediate stage of CRPS, resulting in vasoconstriction and consequently in a diminished tissue blood distribution

A prospective open label 2-8 year extension of the randomised controlled ICON trial on the long-term efficacy and safety of occipital nerve stimulation in medically intractable chronic cluster headache

BACKGROUND: We demonstrated in the randomised controlled ICON study that 48-week treatment of medically intractable chronic cluster headache (MICCH) with occipital nerve stimulation (ONS) is safe and effective. In L-ICON we prospectively evaluate its long-term effectiveness and safety. METHODS: ICON participants were enrolled in L-ICON immediately after completing ICON. Therefore, earlier ICON participants could be followed longer than later ones. L-ICON inclusion was stopped after the last ICON participant was enrolled in L-ICON and followed for ≥2 years by completing six-monthly questionnaires on attack frequency, side effects, subjective improvement and whether they would recommend ONS to others. Primary outcome was the change in mean weekly attack frequency 2 years after completion of the ICON study compared to baseline. Missing values for log-transformed attack-frequency were imputed for up to 5 years of follow-up. Descriptive analyses are presented as (pooled) geometric or arithmetic means and 95% confidence intervals. FINDINGS: Of 103 eligible participants, 88 (85%) gave informed consent and 73 (83%) were followed for ≥2 year, 61 (69%) ≥ 3 year, 33 (38%) ≥ 5 years and 3 (3%) ≥ 8.5 years. Mean (±SD) follow-up was 4.2 ± 2.2 years for a total of 370 person years (84% of potentially 442 years). The pooled geometric mean (95% CI) weekly attack frequency remained considerably lower after one (4.2; 2.8-6.3), two (5.1; 3.5-7.6) and five years (4.1; 3.0-5.5) compared to baseline (16.2; 14.4-18.3). Of the 49/88 (56%) ICON ≥50% responders, 35/49 (71%) retained this response and 15/39 (38%) ICON non-responders still became a ≥50% responder for at least half the follow-up period. Most participants (69/88; 78% [0.68-0.86]) reported a subjective improvement from baseline at last follow-up and 70/88 (81% [0.70-0.87]) would recommend ONS to others. Hardware-related surgery was required in 44/88 (50%) participants in 112/122 (92%) events (0.35 person-year-1 [0.28-0.41]). We didn't find predictive factors for effectiveness. INTERPRETATION: ONS is a safe, well-tolerated and long-term effective treatment for MICCH. FUNDING: The Netherlands Organisation for Scientific Research, the Dutch Ministry of Health, the NutsOhra Foundation from the Dutch Health Insurance Companies, and Medtronic.</p

A prospective open label 2-8 year extension of the randomised controlled ICON trial on the long-term efficacy and safety of occipital nerve stimulation in medically intractable chronic cluster headache

BACKGROUND: We demonstrated in the randomised controlled ICON study that 48-week treatment of medically intractable chronic cluster headache (MICCH) with occipital nerve stimulation (ONS) is safe and effective. In L-ICON we prospectively evaluate its long-term effectiveness and safety. METHODS: ICON participants were enrolled in L-ICON immediately after completing ICON. Therefore, earlier ICON participants could be followed longer than later ones. L-ICON inclusion was stopped after the last ICON participant was enrolled in L-ICON and followed for ≥2 years by completing six-monthly questionnaires on attack frequency, side effects, subjective improvement and whether they would recommend ONS to others. Primary outcome was the change in mean weekly attack frequency 2 years after completion of the ICON study compared to baseline. Missing values for log-transformed attack-frequency were imputed for up to 5 years of follow-up. Descriptive analyses are presented as (pooled) geometric or arithmetic means and 95% confidence intervals. FINDINGS: Of 103 eligible participants, 88 (85%) gave informed consent and 73 (83%) were followed for ≥2 year, 61 (69%) ≥ 3 year, 33 (38%) ≥ 5 years and 3 (3%) ≥ 8.5 years. Mean (±SD) follow-up was 4.2 ± 2.2 years for a total of 370 person years (84% of potentially 442 years). The pooled geometric mean (95% CI) weekly attack frequency remained considerably lower after one (4.2; 2.8-6.3), two (5.1; 3.5-7.6) and five years (4.1; 3.0-5.5) compared to baseline (16.2; 14.4-18.3). Of the 49/88 (56%) ICON ≥50% responders, 35/49 (71%) retained this response and 15/39 (38%) ICON non-responders still became a ≥50% responder for at least half the follow-up period. Most participants (69/88; 78% [0.68-0.86]) reported a subjective improvement from baseline at last follow-up and 70/88 (81% [0.70-0.87]) would recommend ONS to others. Hardware-related surgery was required in 44/88 (50%) participants in 112/122 (92%) events (0.35 person-year-1 [0.28-0.41]). We didn't find predictive factors for effectiveness. INTERPRETATION: ONS is a safe, well-tolerated and long-term effective treatment for MICCH. FUNDING: The Netherlands Organisation for Scientific Research, the Dutch Ministry of Health, the NutsOhra Foundation from the Dutch Health Insurance Companies, and Medtronic.</p

Research Report 2008–2009

The NHMRC Clinical Trials Centre at the University of Sydney runs large multicentre investigator-initiated clinical trials, takes part in trials of national and international collaborative trial groups and contributes expertise to trials run by others. It also: • undertakes research into trial methods and is recognised through publications as a leader in trial methodology • reviews and synthesises evidence from completed trials, and is at the forefront of developments in methods, such as prospective meta-analysis • advises on trial design and operation, and randomises patients and analyses data for other groups conducting trials, particularly through its Outreach program • takes a lead in proposing new directions for trial research in Australia, particularly with regard to integrating clinical trials with national policy and clinical practice • offers placements for postgraduate students in all of these areas • runs short courses in the design and conduct of clinical trials as part of its undertaking to train people for Australian medical research. Core funding is provided by the NHMRC, and specific projects are funded by government, public and private institutions and the pharmaceutical industry. The CTC is at two sites in Camperdown in inner Sydney — the Medical Foundation Building on Parramatta Road and on Mallett Street. This report covers the CTC’s achievements for the biennium 2008–200

Prevalence of post-traumatic neuropathic pain after digital nerve repair and finger amputation

Introduction: Post-traumatic neuropathic pain is a major factor affecting the quality of life after finger trauma and is reported with considerable variance in the literature. This can partially be attributed to the different methods of determining neuropathic pain. The Douleur Neuropathique 4 (DN4) has been validated to be a reliable and non-invasive tool to assess the presence of neuropathic pain. This study investigated the prevalence of neuropathic pain after finger amputation or digital nerve repair using the DN4 questionnaire. Methods: Patients with finger amputation or digital nerve repair were identified between 2011 and 2018 at our institution. After a minimal follow-up of 12 months, the short form DN4 (S-DN4) was used to assess neuropathic pain. Results: A total of 120 patients were included: 50 patients with 91 digital amputations and 70 patients with 87 fingers with digital nerve repair. In the amputation group, 32% of the patients had pain, and 18% had neuropathic pain. In the digital nerve repair group, 38% of the patients had pain, and 14% had neuropathic pain. Secondly, of patient-, trauma-, and treatment-specific factors, only the time between trauma and surgery had a significant negative influence on the prevalence of neuropathic pain in patients with digital nerve repair. Conclusion: This study shows that persistent pain and neuropathic pain are common after finger trauma with nerve damage. One of the significant prognostic factors in developing neuropathic pain is treatment delay between trauma and time of digital nerve repair, which is of major clinical relevance for surgical planning of these injuries.</p

The detached dust shells of AQ And, U Ant, and TT Cyg

Detached circumstellar dust shells are detected around three carbon variables using Herschel-PACS. Two of them are already known on the basis of their thermal CO emission and two are visible as extensions in IRAS imaging data. By model fits to the new data sets, physical sizes, expansion timescales, dust temperatures, and more are deduced. A comparison with existing molecular CO material shows a high degree of correlation for TT Cyg and U Ant but a few distinct differences with other observables are also found.Comment: Letter accepted for publication on the A&A Herschel Special Issu

Pain-related changes in cutaneous innervation of patients suffering from bortezomib-induced, diabetic or chronic idiopathic axonal polyneuropathy

Consistent associations between the severity of neuropathic pain and cutaneous innervation have not been described. We collected demographic and clinical data, McGill Pain Questionnaires (MPQ) and skin biopsies processed for PGP9.5 and CGRP immunohistochemistry from patients with bortezomib-induced peripheral neuropathy (BiPN; n = 22), painful diabetic neuropathy (PDN; n = 16), chronic i