The chemistry of multi-protic drugs Part 1: a potentiometric, multi-wavelength UV and NMR pH titrimetric study of the micro-speciation of SKI-606

The application of a combination of potentiometric, spectrophotometric and nuclear magnetic resonance (NMR) pH titrimetric methodology to measure the macroscopic and to calculate the microscopic protonation constants of SKI-606, a multi-protic compound is described. This compound is currently under evaluation as a candidate drug for the treatment of cancer. SKI-606 was found to have four protonatable sites in the pH range 1–12. Two of these were well separated (Δlog K > 3), whereas the other two overlapped to form a di-protic system. Protonation at only two of the sites yielded a change in the UV spectrum, but the protonation at all four sites could be monitored by NMR. The microscopic equilibrium constants were calculated from the NMR data, which were used in combination with the potentiometric macroscopic constants to calculate the distribution of micro-species.     

Exploring the Relationship Between Surgical Capacity and Output in Ghana: Current Capacity Assessments May Not Tell the Whole Story

Objective

Capacity assessments serve as surrogates for surgical output in low- and middle-income countries where detailed registers do not exist. The relationship between surgical capacity and output was evaluated in Ghana to determine whether a more critical interpretation of capacity assessment data is needed on which to base health systems strengthening initiatives.

Methods

A standardized surgical capacity assessment was performed at 37 hospitals nationwide using WHO guidelines; availability of 25 essential resources and capabilities was used to create a composite capacity score that ranged from 0 (no availability of essential resources) to 75 (constant availability) for each hospital. Data regarding the number of essential operations performed over 1 year, surgical specialties available, hospital beds, and functional operating rooms were also collected. The relationship between capacity and output was explored.

Results

The median surgical capacity score was 37 [interquartile range (IQR) 29–48; range 20–56]. The median number of essential operations per year was 1480 (IQR 736–1932) at first-level hospitals; 1545 operations (IQR 984–2452) at referral hospitals; and 11,757 operations (IQR 3769–21,256) at tertiary hospitals. Surgical capacity and output were not correlated (p?>?0.05).

Conclusions

Contrary to current understanding, surgical capacity assessments may not accurately reflect surgical output. To improve the validity of surgical capacity assessments and facilitate maximal use of available resources, other factors that influence output should also be considered, including demand-side factors; supply-side factors and process elements; and health administration and management factors.

     

Life-threatening Oro-facial infections

SummaryFour cases of oro-facial infection leading to life-threatening complications are reported. Although all had been treated with antibiotics prior to consultation, lack of surgical intervention had allowed the infection to progress. These cases are a reminder that acute spreading odontogenic infection can be life-threatening. Definitive treatment includes airway management, adequate resuscitation and optimization of pre-existing medical conditions prior to removal of the source of infection and drainage of pus. High dose intravenous antibiotics should be administered, with the initial choice of antibiotics modified in the light of subsequent bacteriological reports. The treatment of all odontogenic infections must include removal of the focus of infection, and drainage of pus.     

Using the Behavior Change Technique Taxonomy v1 to conceptualize the clinical content of Breaking Free Online: a computer-assisted therapy program for substance use disorders

Background

In recent years, research within the field of health psychology has made significant progress in terms of advancing and standardizing the science of developing, evaluating and reporting complex behavioral change interventions. A major part of this work has involved the development of an evidence-based Behavior Change Technique Taxonomy v1 (BCTTv1), as a means of describing the active components contained within such complex interventions. To date, however, this standardized approach derived from health psychology research has not been applied to the development of complex interventions for the treatment of substance use disorders (SUD). Therefore, this paper uses Breaking Free Online (BFO), a computer-assisted therapy program for SUD, as an example of how the clinical techniques contained within such an intervention might be mapped onto the BCTTv1.

Method

The developers of BFO were able to produce a full list of the clinical techniques contained within BFO. Exploratory mapping of the BCTTv1 onto the clinical content of the BFO program was conducted separately by the authors of the paper. This included the developers of the BFO program and psychology professionals working within the SUD field. These coded techniques were reviewed by the authors and any discrepancies in the coding were discussed between all authors until an agreement was reached.

Results

The BCTTv1 was mapped onto the clinical content of the BFO program. At least one behavioral change technique was found in 12 out of 16 grouping categories within the BCTTv1. A total of 26 out of 93 behavior change techniques were identified across the clinical content of the program.

Conclusion

This exploratory mapping exercise has identified the specific behavior change techniques contained within BFO, and has provided a means of describing these techniques in a standardized way using the BCTTv1 terminology. It has also provided an opportunity for the BCTTv1 mapping process to be reported to the wider SUD treatment community, as it may have real utility in the development and evaluation of other psychosocial and behavioral change interventions within this field.

     

Immunogenicity of the tuberculosis vaccine MVA85A is reduced by coadministration with EPI vaccines in a randomized controlled trial in Gambian infants

New tuberculosis vaccines are urgently needed to curtail the current epidemic. MVA85A is a subunit vaccine that could enhance immunity from BCG vaccination. To determine MVA85A safety and immunogenicity as well as interactions with other routine vaccines administered in infancy, we randomized healthy 4-month-old infants who had received Bacille Calmette-Guérin at birth to receive Expanded Program on Immunization (EPI) vaccines alone, EPI and MVA85A simultaneously, or MVA85A alone. Adverse events were monitored throughout. Blood samples obtained before vaccination and at 1, 4, and 20 weeks after vaccination were used to assess safety and immunogenicity. The safety profile of both low and standard doses was comparable, but the standard dose was more immunogenic and therefore was selected for the second stage of the study. In total, 72 (first stage) and 142 (second stage) infants were enrolled. MVA85A was safe and well tolerated and induced a potent cellular immune response. Coadministration of MVA85A with EPI vaccines was associated with a significant reduction in MVA85A immunogenicity, but did not affect humoral responses to the EPI vaccines. These results provide important information regarding timing of immunizations, which is required for the design of infant efficacy trials with MVA85A, and suggest that modifications to the standard EPI schedule may be required to incorporate a new generation of T cell-inducing vaccines.     

Anti-inflammatory and antioxidant activities of the leaves of Wissadula amplissima var Rostrata

The present study determined the anti-inflammatory activity of Wissadula amplissima var rostrata (Schum. & Thonn.), and calculated the total phenolic content and total antioxidant capacity of the plant in an attempt to justify the traditional uses of the plant in the Ashanti region of Ghana for the management of spider,wasps and bee stings. Powdered dried leaves of Wissadula amplissima were Soxhlet extracted with Petroleum Ether (PWA, yield: 1.46% (w)/(w)); Chloroform (CWA, yield: 1.18% (w)/(w)) and Methanol (MWA, yield: 3.39% (w)/(w)). These fractions were tested for anti-inflammatory activity using carrageenan-induced foot edema in 7 day old chicks. The effect before the induction of inflammation (pre-emptive protocol) paradigm was used for the assessment. Oral administration of PWA, CWA and MWA (30 - 300 mg/kg) dose dependently reduced edema with maximal effects of 68.25±2.03%, 77.83±0.81% and 62.21±2.61% respectively. Similarly the NSAID, Diclofenac (10 - 100 mg/Kg, i.p) and the steroidal anti-inflammatory drug dexamethasone (0.3 - 3 mg/Kg, i.p) used as positive controls, dose-dependently inhibited the edema with maximal effect of 87.96±1.11% and 67.47±3.51% respectively. The potencies exhibited by all three extracts were comparable to that shown by Diclofenac but higher than that of Dexamethasone. Phenols were detected in all three extracts with the highest concentration in the MWA. The extracts also scavenged DPPH with EC(50) values of 0.9784, 0.9096 and 0.2767 for PWA, CWA, MWA respectively. The results of this study give scientific credence to the local use of Wissadula amplissima to modulate inflammation induced by stings of animals.     

Enumeration of Operations Performed for Elderly Patients in Ghana: An Opportunity to Improve Global Surgery Benchmarking

World Journal of Surgery - The Lancet Commission on Global Surgery proposed 5000 operations/100,000 people annually as a benchmark for developing countries but did not define benchmarks for...     

Antitumor and Anti-Pneumocystis Carinii Activities of Novel Bisbenzamidines

Among a library of 17 bisbenzamidines connected with various linkers, compounds with a flexible pentanediamide (10) or hexanediamide (12) linker were the most potent derivatives against rat Pneumocystis carinii (IC₅₀ values of 3 and 2 nM, respectively) and had the highest selectivity index ratios (GI₅₀ of human tumor cells/IC₅₀ of rat P. carinii cells) of >10⁴. Seven compounds caused 50% growth inhibition (GI₅₀) of tumor cells at concentrations of <100 μM while the remaining ten were not cytotoxic. DNA binding affinity (ΔT_m) of the tested compounds did not correlate with either their anti-P. carinii activity or cytotoxicity.     

ESAT-6/CFP-10 fusion protein and peptides for optimal diagnosis of mycobacterium tuberculosis infection by ex vivo enzyme-linked immunospot assay in the Gambia

Overlapping peptides of Mycobacterium tuberculosis antigens ESAT-6 and CFP-10 offer increased specificity over the purified protein derivative skin test when they were used in an ex vivo enzyme-linked immunospot (ELISPOT) assay for gamma interferon detection for the diagnosis of M. tuberculosis infection from recent exposure. We assessed whether equivalent results could be obtained for a fusion protein of the two antigens and whether a combined readout would offer increased sensitivity in The Gambia. We studied the ELISPOT assay results for 488 household contacts of 88 sputum smear-positive tuberculosis (TB) cases. The proportions of subjects positive by each test and by the tests combined were assessed across an exposure gradient, defined according to sleeping proximity to a TB case. Eighty-eight (18%) subjects were positive for CFP-10 peptides, 148 (30%) were positive for ESAT-6 peptides, 161 (33%) were positive for both peptides, and 168 (34%) were positive for the fusion protein; 188 (39%) subjects had either a positive result for a peptide or a positive result for the fusion protein. There was reasonable agreement between the peptide and the protein results (kappa statistic = 0.78) and no significant discordance (P = 0.38). There was a strong correlation between the fusion protein and combined peptide spot counts (r = 0.9), and responses to the peptide and the proteins all increased significantly according to M. tuberculosis exposure. The proportion of subjects positive for either the pool of peptides or the fusion protein offered maximum sensitivity, being significantly higher than the proportion of subjects positive for ESAT-6 peptides alone (P = 0.007). A fusion protein of ESAT-6 and CFP-10 is equivalent to overlapping peptides for the diagnosis of latent M. tuberculosis infection. Use of a combination of peptides and fusion protein offers improved sensitivity.