A neuroanatomical approach to examining changes in cognition: the long-term effects of chronic cocaine use

Cognitive deficits exhibited by human cocaine users have been shown to predict outcome of therapeutic treatments, so understanding the structural basis of these deficits is clinically important. Longitudinal cognitive assessments were made, using touch-screen based tasks, in two groups of rhesus monkeys: a chronic cocaine self-administration group, and a control water self-administration group. Structural changes in regions of the prefrontal cortex over time were determined by measuring changes in the volumes of gray matter from magnetic resonance images taken pre- and post-treatment. Linear regressions were run to correlate changes in cognition with structural changes over time. A positive correlation was observed between changes in visual working memory performance and changes in structure in the dorsolateral prefrontal cortex, area 8, area 10, and area 12 in the cocaine group, but not in the control group. In human studies, it is impossible to know if structural changes are a direct result of cocaine use or result from differences prior to drug use or other factors. The structural differences identified in this study strongly support a link between cocaine use and cognitive deficits, and will guide post-mortem studies into possible neurobiological mechanisms underlying the observed anatomical changes

Analysis of ligation and DNA binding by Escherichia coli DNA ligase (LigA).

NAD+-dependent DNA ligases are essential enzymes in bacteria, with the most widely studied of this class of enzymes being LigA from Escherichia coli. NAD+-dependent DNA ligases comprise several discrete structural domains, including a BRCT domain at the C-terminus that is highly-conserved in this group of proteins. The over-expression and purification of various fragments of E. coli LigA allowed the investigation of the different domains in DNA-binding and ligation by this enzyme. Compared to the full-length protein, the deletion of the BRCT domain from LigA reduced in vitro ligation activity by 3-fold and also reduced DNA binding. Using an E. coli strain harbouring a temperature-sensitive mutation of ligA, the over-expression of protein with its BRCT domain deleted enabled growth at the non-permissive temperature. In gel-mobility shift experiments, the isolated BRCT domain bound DNA in a stable manner and to a wider range of DNA molecules compared to full LigA. Thus, the BRCT domain of E. coli LigA can bind DNA, but it is not essential for DNA nick-joining activity in vitro or in vivo

Combined treatment of adenoid cystic carcinoma with cetuximab and IMRT plus C12 heavy ion boost: ACCEPT [ACC, Erbitux® and particle therapy]

<p>Abstract</p> <p>Background</p> <p>Local control in adjuvant/definitive RT of adenoid cystic carcinoma (ACC) is largely dose-dependent leading to the establishment of particle therapy in this indication. However, even modern techniques leave space for improvement of local control by intensification of local treatment. Radiation sensitization by exploitation of high EGFR-expression in ACC with the EGFR receptor antibody cetuximab seems promising.</p> <p>Methods/design</p> <p>The ACCEPT trial is a prospective, mono-centric, phase I/II trial evaluating toxicity (primary endpoint: acute and late effects) and efficacy (secondary endpoint: local control, distant control, disease-free survival, overall survival) of the combined treatment with IMRT/carbon ion boost and weekly cetuximab in 49 patients with histologically proven (≥R1-resected, inoperable or Pn+) ACC. Patients receive 18 GyE carbon ions (6 fractions) and 54 Gy IMRT (2.0 Gy/fraction) in combination with weekly cetuximab throughout radiotherapy.</p> <p>Discussion</p> <p>The primary objective of ACCEPT is to evaluate toxicity and feasibility of cetuximab and particle therapy in adenoid cystic carcinoma.</p> <p>Trial Registration</p> <p>Clinical Trial Identifier: <a href="http://www.clinicaltrials.gov/ct2/show/NCT01192087">NCT 01192087</a></p> <p>EudraCT number: 2010 - 022425 - 15</p

Disease control and functional outcome in three modern combined organ preserving regimens for locally advanced squamous cell carcinoma of the head and neck (SCCHN)

<p>Abstract</p> <p>Purpose</p> <p>To report our experience on disease control and functional outcome using three modern combined-modality approaches for definitive radiochemotherapy of locally advanced SCCHN with modern radiotherapy techniques: radiochemotherapy (RChT), radioimmunotherapy (RIT) with cetuximab, or induction chemotherapy with docetaxel, cisplatin, and 5-FU (TPF) combined with either RChT or RIT.</p> <p>Methods</p> <p>Toxicity and outcome was retrospectively analysed in patients receiving definitive RChT, RIT, or induction chemotherapy followed by RChT or RIT between 2006 and 2009. Outcome was estimated using Kaplan-Meier analyses, toxicity was analysed according to CTCAE v 3.0.</p> <p>Results</p> <p>Thirty-eight patients were treated with RChT, 38 patients with RIT, 16 patients received TPF followed by either RChT or RIT. Radiotherapy was mostly applied as IMRT (68%). Long-term toxicity was low, only one case of grad III dysphagia requiring oesophageal dilatation, no case of either xerostomia ≥ grade II or cervical plexopathy were observed. Median overall survival (OS) was 25.7 months (RChT) and 27.7 months (RIT), median locoregional progression-free survival (PFS) was not reached yet. Subgroup analysis showed no significant differences between TPF, RChT, and RIT despite higher age and co-morbidities in the RIT group. Results suggested improved OS, distant and overall PFS for the TPF regimen.</p> <p>Conclusion</p> <p>Late radiation effects in our cohort are rare. No significant differences in outcome between RChT and RIT were observed. Adding TPF suggests improved progression-free and overall survival, impact of TPF on locoregional PFS was marginal, therefore radiotherapeutic options for intensification of local treatment should be explored.</p

RadioImmunotherapy for adenoid cystic carcinoma: a single-institution series of combined treatment with cetuximab

<p>Abstract</p> <p>Background</p> <p>Local control in adjuvant/definitive RT of adenoid cystic carcinoma (ACC) is largely dose-dependent. However, some clinical situations do not allow application of tumouricidal doses (i.e. re-irradiation) hence radiation sensitization by exploitation of high endothelial growth factor receptor (EGFR)-expression in ACC seems beneficial. This is a single-institution experience of combined radioimmunotherapy (RIT) with the EGFR-inhibitor cetuximab.</p> <p>Methods</p> <p>Between 2006 and 2010, 9 pts received RIT for advanced/recurrent ACC, 5/9 pts as re-irradiation. Baseline characteristics as well as treatment parameters were retrieved to evaluate efficacy and toxicity of the combination regimen were evaluated. Control rates (local/distant) and overall survival were calculated using Kaplan-Meier estimation.</p> <p>Results</p> <p>Median dose was 65 Gy, pts received a median of 6 cycles cetuximab. RIT was tolerated well with only one °III mucositis/dysphagia. Overall response/remission rates were high (77,8%); 2-year estimate of local control was 80% hence reaching local control levels comparable to high-dose RT. Progression-free survival (PFS) at 2 years and median overall survival were only 62,5% and 22,2 mo respectively.</p> <p>Conclusion</p> <p>While local control and treatment response in RIT seems promising, PFS and overall survival are still hampered by distant failure. The potential benefit of RIT with cetuximab warrants exploration in a prospective controlled clinical trial.</p

Phase II study of induction chemotherapy with TPF followed by radioimmunotherapy with Cetuximab and intensity-modulated radiotherapy (IMRT) in combination with a carbon ion boost for locally advanced tumours of the oro-, hypopharynx and larynx - TPF-C-HIT

<p>Abstract</p> <p>Background</p> <p>Long-term locoregional control in locally advanced squamous cell carcinoma of the head and neck (SCCHN) remains challenging. While recent years have seen various approaches to improve outcome by intensification of treatment schedules through introduction of novel induction and combination chemotherapy regimen and altered fractionation regimen, patient tolerance to higher treatment intensities is limited by accompanying side-effects. Combined radioimmunotherapy with cetuximab as well as modern radiotherapy techniques such as intensity-modulated radiotherapy (IMRT) and carbon ion therapy (C12) are able to limit toxicity while maintaining treatment effects. In order to achieve maximum efficacy with yet acceptable toxicity, this sequential phase II trial combines induction chemotherapy with docetaxel, cisplatin, and 5-FU (TPF) followed by radioimmunotherapy with cetuximab as IMRT plus carbon ion boost. We expect this approach to result in increased cure rates with yet manageable accompanying toxicity.</p> <p>Methods/design</p> <p>The TPF-C-HIT trial is a prospective, mono-centric, open-label, non-randomized phase II trial evaluating efficacy and toxicity of the combined treatment with IMRT/carbon ion boost and weekly cetuximab in 50 patients with histologically proven locally advanced SCCHN following TPF induction chemotherapy. Patients receive 24 GyE carbon ions (8 fractions) and 50 Gy IMRT (2.0 Gy/fraction) in combination with weekly cetuximab throughout radiotherapy. Primary endpoint is locoregional control at 12 months, secondary endpoints are disease-free survival, progression-free survival, overall survival, acute and late radiation effects as well as any adverse events of the treatment as well as quality of life (QoL) analyses.</p> <p>Discussion</p> <p>The primary objective of TPF-C-HIT is to evaluate efficacy and toxicity of cetuximab in combination with combined IMRT/carbon ion therapy following TPF induction in locally advanced SCCHN.</p> <p>Trial Registration</p> <p>Clinical Trial Identifier: <a href="http://www.clinicaltrials.gov/ct2/show/NCT01245985">NCT01245985</a> (clinicaltrials.gov)</p> <p>EudraCT number: 2009 - 016489- 10</p

Stigma in the health clinic and implications for PrEP access and use by adolescent girls and young women : conflicting perspectives in South Africa

DATA AVAILABILITY : Data and materials are available on request from Dr. Wendee Wechsberg at [email protected] : Globally, an urgent need exists to expand access to HIV prevention among adolescent girls and young women (AGYW), but the need is particularly acute in sub-Saharan Africa. Oral pre-exposure prophylaxis (PrEP) offers an effective HIV prevention method. In many countries, however, accessing PrEP necessitates that AGYW visit their local health clinic, where they may face access challenges. Some countries have implemented youth-friendly services to reduce certain challenges in local health clinics, but barriers to access persist, including clinic stigma. However, evidence of clinic stigma toward AGYW, particularly with respect to PrEP service delivery, is still limited. This mixed methods study explores stigma toward AGYW seeking clinic services, in particular PrEP, from the perspective of both clinic staff (clinical and nonclinical) and AGYW who seek services at clinic sites in Tshwane province, South Africa. METHODS : Six focus group discussions were conducted with AGYW (43 total participants) and four with clinic staff (42 total participants) and triangulated with survey data with AGYW (n = 449) and clinic staff (n = 130). Thematic analysis was applied to the qualitative data and descriptive statistics were conducted with the survey data. RESULTS : Four common themes emerged across the qualitative and quantitative data and with both AGYW and clinic staff, although with varying degrees of resonance between these two groups. These themes included (1) clinic manifestations of stigma toward AGYW, (2) concerns about providing PrEP services for AGYW, (3) healthcare providers’ identity as mothers, and (4) privacy and breaches of confidentiality. An additional theme identified mainly in the AGYW data pertained to stigma and access to healthcare. CONCLUSION : Evidence is needed to inform strategies for addressing clinic stigma toward AGYW, with the goal of removing barriers to PrEP services for this group. While awareness has increased and progress has been achieved around the provision of comprehensive, youth-friendly sexual and reproductive health services, these programs need to be adapted for the specific concerns of young people seeking PrEP services. Our findings point to the four key areas noted above where programs seeking to address stigma toward AGYW in clinics can tailor their programming.The Eunice Kennedy Shriver National Institute of Child Health & Human Development of the National Institutes of Health.http://www.biomedcentral.com/bmcpublichealtham2023Medical Microbiolog

Raster-scanned carbon ion therapy for malignant salivary gland tumors: acute toxicity and initial treatment response

<p>Abstract</p> <p>Background and purpose</p> <p>To investigate toxicity and efficacy in high-risk malignant salivary gland tumors (MSGT) of the head and neck. Local control in R2-resected adenoid cystic carcinoma was already improved with a combination of IMRT and carbon ion boost at only mild side-effects, hence this treatment was also offered to patients with MSGT and microscopic residual disease (R1) or perineural spread (Pn+).</p> <p>Methods</p> <p>From November 2009, all patients with MSGT treated with carbon ion therapy were evaluated. Acute side effects were scored according to CTCAE v.4.03. Tumor response was assessed according to RECIST where applicable.</p> <p>Results</p> <p>103 patients were treated from 11/2009 to 03/2011, median follow-up is 6 months. 60 pts received treatment following R2 resections or as definitive radiation, 43 patients received adjuvant radiation for R1 and/or Pn+. 16 patients received carbon ion treatment for re-irradiation. Median total dose was 73.2 GyE (23.9 GyE carbon ions + 49,9 Gy IMRT) for primary treatment and 44.9 GyE carbon ions for re-irradiation. All treatments were completed as planned and generally well tolerated with no > CTC°III toxicity. Rates of CTC°III toxicity (mucositis and dysphagia) were 8.7% with side-effects almost completely resolved at first follow-up.</p> <p>47 patients showed good treatment responses (CR/PR) according to RECIST.</p> <p>Conclusion</p> <p>Acute toxicity remains low in IMRT with carbon ion boost also in R1-resected patients and patients undergoing re-irradiation. R2-resected patients showed high rates of treatment response, though follow-up is too short to assess long-term disease control.</p

Indoor Residual Spraying in Combination with Insecticide-Treated Nets Compared to Insecticide-Treated Nets Alone for Protection against Malaria: A Cluster Randomised Trial in Tanzania.

Insecticide-treated nets (ITNs) and indoor residual spraying (IRS) of houses provide effective malaria transmission control. There is conflicting evidence about whether it is more beneficial to provide both interventions in combination. A cluster randomised controlled trial was conducted to investigate whether the combination provides added protection compared to ITNs alone. In northwest Tanzania, 50 clusters (village areas) were randomly allocated to ITNs only or ITNs and IRS. Dwellings in the ITN+IRS arm were sprayed with two rounds of bendiocarb in 2012. Plasmodium falciparum prevalence rate (PfPR) in children 0.5-14 y old (primary outcome) and anaemia in children <5 y old (secondary outcome) were compared between study arms using three cross-sectional household surveys in 2012. Entomological inoculation rate (secondary outcome) was compared between study arms. IRS coverage was approximately 90%. ITN use ranged from 36% to 50%. In intention-to-treat analysis, mean PfPR was 13% in the ITN+IRS arm and 26% in the ITN only arm, odds ratio = 0.43 (95% CI 0.19-0.97, n = 13,146). The strongest effect was observed in the peak transmission season, 6 mo after the first IRS. Subgroup analysis showed that ITN users were additionally protected if their houses were sprayed. Mean monthly entomological inoculation rate was non-significantly lower in the ITN+IRS arm than in the ITN only arm, rate ratio = 0.17 (95% CI 0.03-1.08). This is the first randomised trial to our knowledge that reports significant added protection from combining IRS and ITNs compared to ITNs alone. The effect is likely to be attributable to IRS providing added protection to ITN users as well as compensating for inadequate ITN use. Policy makers should consider deploying IRS in combination with ITNs to control transmission if local ITN strategies on their own are insufficiently effective. Given the uncertain generalisability of these findings, it would be prudent for malaria control programmes to evaluate the cost-effectiveness of deploying the combination.\ud \u