Genetic diversity and antigenic polymorphism in Plasmodium falciparum: extensive serological cross-reactivity between allelic variants of merozoite surface protein 2

Diversity in the surface antigens of malaria parasites is generally assumed to be a mechanism for immune evasion, but there is little direct evidence that this leads to evasion of protective immunity. Here we show that alleles of the highly polymorphic merozoite surface protein 2 (MSP-2) can be grouped (within the known dimorphic families) into distinct serogroups; variants within a serogroup show extensive serological cross-reactivity. Cross-reactive epitopes are immunodominant, and responses to them may be boosted at the expense of responses to novel epitopes (original antigenic sin). The data imply that immune selection explains only some of the diversity in the msp-2 gene and that MSP-2 vaccines may need to include only a subset of the known variants in order to induce pan-reactive antibodies.     

High frequency of circulating gamma delta T cells with dominance of the v(delta)1 subset in a healthy population

TCR gamma delta(+) cells constitute <5% of all circulating T cells in healthy, adult Caucasians, and V(delta)1(+) cells constitute a minority of these cells. In contrast to TCR alpha beta(+) cells, their repertoire is selected extrathymically by environmental antigens. Although increased frequencies of V(delta)1(+) cells are found in several diseases, their function remains obscure. Here we show that the frequency of peripheral blood gamma delta T cells in healthy West Africans is about twice that of Caucasians, mainly due to a 5-fold increase in V(delta)1(+) cells, which is consequently the dominant subset. No age dependency of V(delta)1 frequencies was identified and the V(delta)1(+) cells in the African donors did not show preferential V(gamma) chain usage. Analysis of the CDR3 region size did not reveal any particular skewing of the V(delta)1 repertoire, although oligoclonality was more pronounced in adults compared to children. The proportions of CD8(+), CD38(+) and CD45RA(hi)CD45RO(-) cells within the V(delta)1(+) subset were higher in the African than in the European donors, without obvious differences in expression of activation markers. No significant correlations between levels of V(delta)1(+) cells and environmental antigens or immunological parameters were identified. Taken together, the evidence argues against a CDR3-restricted, antigen-driven expansion of V(delta)1(+) cells in the African study population. Our study shows that high frequencies of TCR gamma delta(+) cells with dominance of the V(delta)1(+) subset can occur at the population level in healthy people, raising questions about the physiological role of V(delta)1(+) T cells in the function and regulation of the immune system.     

Biochemical and Hematologic Parameters for Children in the Middle Belt of Ghana

Reference values derived from developed countries are used in many countries in Africa for interpretation of laboratory results obtained during routine healthcare and clinical trials. Use of locally derived reference values has been recommended. The purpose of the study was to establish age- and sex-specific reference values for children in the middle belt of Ghana. Reference values were determined for 21 biochemical and 18 hematologic parameters by using Clinical and Laboratory Standards Institute C28-A3 guidelines in a sample of 1,442 healthy children. Hemoglobin, hematocrit, mean cell volume, erythrocytes, urea, and creatinine were lower when compared with values from northern countries but alanine aminotransferase, aspartate aminotransferase, and total bilirubin were higher. A panel of locally relevant age- and sex-specific reference values was established for commonly used biochemical and hematologic tests in children in the middle part of Ghana. This will help in interpretation of laboratory results for clinical management of patients, screening, and safety monitoring during clinical trials.     

Does radical cure of asymptomatic Plasmodium falciparum place adults in endemic areas at increased risk of recurrent symptomatic malaria?

A cohort of 197 adults in Kassena-Nankana District (northern Ghana) was radically cured of malaria parasites to study subsequent incidence of malaria infection. During the following 20 weeks of the malaria transmission season, 49% experienced clinical attacks associated with Plasmodium falciparum parasitaemia. In a group of 202 adults identically followed-up 1 year later without being treated, only 38% experienced such episodes (log-rank test for equality of survivor functions, P=0.035). Clinical attacks in radically cured individuals presented with lower parasite densities but more symptoms. Randomized studies are needed to test the hypothesis that radical cure of P. falciparum enhances the risk and severity of subsequent clinical malaria attacks.     

Hydralazine-associated Amenorrhea in a Premenopausal Patient With Chronic Kidney Disease: A Case Report and Review of Literature

Purpose

Several antihypertensive medications have been associated with various forms of sexual dysfunction. We present a case report of a premenopausal patient with hydralazine-associated amenorrhea.

Surveillance of Molecular Markers of Plasmodium falciparum Resistance to Sulphadoxine-Pyrimethamine 5 Years after the Change of Malaria Treatment Policy in Ghana

In 2005, sulphadoxine-pyrimethamine (SP) became the drug of choice for intermittent preventive treatment of Plasmodium falciparum malaria in pregnancy (IPTp) in Ghana. Reports suggest the use of SP by others to treat uncomplicated malaria. Because of the increased use of SP, the prevalence of mutations in the genes, dihydrofolate reductase (dhfr), and dihydropteroate synthetase (dhps), linked to SP resistance in P. falciparum were determined. Blood samples from 945 children with uncomplicated malaria collected at nine sites from 2003 to 2010 were analyzed using polymerase chain reaction and restriction fragment length polymorphism. Prevalence of the dhfr triple and dhfr plus dhps quadruple mutations showed significant increase in trend from 2003 to 2010 (χ² = 18.78, P < 0.001, χ² = 15.11, P < 0.001, respectively). For dhps double mutant G437 + E540 the prevalence was low (1.12%) caused by the very low prevalence of E540. Our findings show the wide use of SP in Ghana and therefore its use for IPTp needs to be closely monitored.     

Long-term Results of Rectal Cancer Surgery with a Systematical Operative Approach

Background

Variabilities of both oncologic and functional outcomes are major problems after rectal cancer treatment. Standardized techniques might produce more consistent surgical quality. This study reports outcomes during a 20-year period resulting from a systematically applied surgical approach.

Methods

Between 1990 and 2010, 368 rectal cancer patients, treated with total mesorectal excision conducted in a standardized, stepwise approach, were prospectively entered into a database. Influence of time period, surgeon, tumor and anastomotic height, and resection type was evaluated with multivariable regression analyses adjusting for age, disease stage, diversion, and (neo)adjuvant treatment. Function outcome questionnaires were sent to 50 patients at least 5 years after surgery.

Results

Five-year overall survival was 76.4 %. Local and distant recurrence rates were 5.2 % and 22.1 %. Anastomotic leakage occurred in 5.4 % of patients treated with low anterior resection (n = 259). Time period, surgeon, tumor and anastomotic height, diversion, and abdominoperineal resection were not independent risk factors for any of these outcome measures. Both preoperative and postoperative radiotherapy were independently associated with increased risk of metastases (P = 0.035, hazard ratio (HR) = 3.04; and P = 0.029, HR = 3.59). Function questionnaires were completed by 38 of 50 patients (76 %). One of 13 nonirradiated patients reported mild fecal incontinence compared with 20 of 25 irradiated patients reporting mostly moderate-severe incontinence (P < 0.001).

Conclusions

Systematically applied surgical dissection results consistently in excellent oncologic outcomes with enhanced function outcomes. The findings suggest that in the presence of highly disciplined surgery, radiotherapy might make a smaller contribution to oncologic outcome, while leading to serious adverse effects.     

Predictors of mortality and cost among surgical patients requiring rapid response team activation

BackgroundPrior studies of rapid response team (RRT) implementation for surgical patients have demonstrated mixed results with respect to reductions in poor outcomes. The aim of this study was to identify predictors of in-hospital mortality and hospital costs among surgical inpatients requiring RRT activation.MethodsWe analyzed data prospectively collected from May 2012 to May 2016 at The Ottawa Hospital. We included patients who were at least 18 years of age, who were admitted to hospital, who received either preoperative or postoperative care, and and who required RRT activation. We created a multivariable logistic regression model to describe mortality predictors and a multivariable generalized linear model to describe cost predictors.ResultsWe included 1507 patients. The in-hospital mortality rate was 15.9%. The patient-related factors most strongly associated with mortality included an Elixhauser Comorbidity Index score of 20 or higher (odds ratio [OR] 3.60, 95% confidence interval [CI] 1.96–6.60) and care designations excluding admission to the intensive care unit and cardiopulmonary resuscitation (OR 3.52, 95% CI 2.25–5.52). The strongest surgical predictors included neurosurgical admission (OR 2.09, 95% CI 1.17–3.75), emergent surgery (OR 2.04, 95% CI 1.37–3.03) and occurrence of 2 or more operations (OR 1.73, 95% CI 1.21–2.46). Among RRT factors, occurrence of 2 or more RRT assessments (OR 2.01, 95% CI 1.44–2.80) conferred the highest mortality. Increased cost was strongly associated with admitting service, multiple surgeries, multiple RRT assessments and medical comorbidity.ConclusionRRT activation among surgical inpatients identifies a population at high risk of death. We identified several predictors of mortality and cost, which represent opportunities for future quality improvement and patient safety initiatives.