The nature of nurture in a wild mammal's fitness

Genetic variation in fitness is required for the adaptive evolution of any trait but natural selection is thought to erode genetic variance in fitness. This paradox has motivated the search for mechanisms that might maintain a population''s adaptive potential. Mothers make many contributions to the attributes of their developing offspring and these maternal effects can influence responses to natural selection if maternal effects are themselves heritable. Maternal genetic effects (MGEs) on fitness might, therefore, represent an underappreciated source of adaptive potential in wild populations. Here we used two decades of data from a pedigreed wild population of North American red squirrels to show that MGEs on offspring fitness increased the population''s evolvability by over two orders of magnitude relative to expectations from direct genetic effects alone. MGEs are predicted to maintain more variation than direct genetic effects in the face of selection, but we also found evidence of maternal effect trade-offs. Mothers that raised high-fitness offspring in one environment raised low-fitness offspring in another environment. Such a fitness trade-off is expected to maintain maternal genetic variation in fitness, which provided additional capacity for adaptive evolution beyond that provided by direct genetic effects on fitness.     

Intraoperative radiation therapy as part of breast conserving therapy of early breast cancer—Results of one-year follow-up

Aim

The aim of this study was to assess the therapeutic effect of intraoperative radiotherapy, describe the method, and examine the occurrence of side effects and quality of life.

Background

Breast conserving therapy has recently become a standard treatment modality in patients with early invasive cancer. Radiotherapy, along with surgery, is an integral part of such treatment. The important thing of radiotherapy is to deliver a high dose to the tumour bed. One of the methods is the intraoperative radiotherapy.

Materials and methods

The analysis comprised sixty Tis-T2N0-1A breast cancer patients treated with breast conserving surgery. Patients’ mean age was 57 years (range: 32–73 years). Intraoperative radiation therapy was delivered in the operating theatre during surgery and involved a single dose of 10 Gy with an electron beam of 4, 6, 9 or 12 MeV. After that, all patients were treated with whole breast irradiation. During one year observation photos and side effects examination were made.

Results

Physical and imaging examinations performed during a one-year follow-up revealed no local or distant relapse and good tolerance of IORT. Acute mild responses to the radiotherapy occurred in 23.3% of patients. Based on the examination, a good and very good cosmetic effect was found in 78.3%, with 83.3% of patients evaluating their treatment effects in the same way.

Conclusions

Due to its exceptional physical and radiobiological properties, intraoperative radiation therapy can be a good alternative to other methods of boosting dose to the post-operative site in management of low stage breast cancer, enabling a precise therapy to the tumour bed.     

Neuropeptide Y, B-type natriuretic peptide, substance P and peptide YY are novel substrates of fibroblast activation protein-α

Fibroblast activation protein-α (FAP) is a cell surface-expressed and soluble enzyme of the prolyl oligopeptidase family, which includes dipeptidyl peptidase 4 (DPP4). FAP is not generally expressed in normal adult tissues, but is found at high levels in activated myofibroblasts and hepatic stellate cells in fibrosis and in stromal fibroblasts of epithelial tumours. FAP possesses a rare catalytic activity, hydrolysis of the post-proline bond two or more residues from the N-terminus of target substrates. α(2)-antiplasmin is an important physiological substrate of FAP endopeptidase activity. This study reports the first natural substrates of FAP dipeptidyl peptidase activity. Neuropeptide Y, B-type natriuretic peptide, substance P and peptide YY were the most efficiently hydrolysed substrates and the first hormone substrates of FAP to be identified. In addition, FAP slowly hydrolysed other hormone peptides, such as the incretins glucagon-like peptide-1 and glucose-dependent insulinotropic peptide, which are efficient DPP4 substrates. FAP showed negligible or no hydrolysis of eight chemokines that are readily hydrolysed by DPP4. This novel identification of FAP substrates furthers our understanding of this unique protease by indicating potential roles in cardiac function and neurobiology.     

Traditional Chinese medicine herbs - are they safe for psoriatic patients?

Although traditional Chinese medicine (TCM) relies on remedies of natural origin, its use is not always safe as it can have not only beneficial but also deleterious effects. Psoriatic patients, disappointed by conventional treatment and unaware of the potential side effects of TCM preparations, are increasingly reaching for non-traditional therapeutic methods. This review presents brief characteristics of selected Chinese herbs self-prescribed by psoriatic patients. It is important that dermatologists should be able to recognize any potential hazards connected with current or previous taking of these herbs by their patients.     

Very low levels of direct additive genetic variance in fitness and fitness components in a red squirrel population

A trait must genetically correlate with fitness in order to evolve in response to natural selection, but theory suggests that strong directional selection should erode additive genetic variance in fitness and limit future evolutionary potential. Balancing selection has been proposed as a mechanism that could maintain genetic variance if fitness components trade off with one another and has been invoked to account for empirical observations of higher levels of additive genetic variance in fitness components than would be expected from mutation–selection balance. Here, we used a long‐term study of an individually marked population of North American red squirrels (Tamiasciurus hudsonicus) to look for evidence of (1) additive genetic variance in lifetime reproductive success and (2) fitness trade‐offs between fitness components, such as male and female fitness or fitness in high‐ and low‐resource environments. “Animal model” analyses of a multigenerational pedigree revealed modest maternal effects on fitness, but very low levels of additive genetic variance in lifetime reproductive success overall as well as fitness measures within each sex and environment. It therefore appears that there are very low levels of direct genetic variance in fitness and fitness components in red squirrels to facilitate contemporary adaptation in this population.     

Clinical course of homozygous familial hypercholesterolemia during childhood: report on 4 unrelated patients with homozygous or compound heterozygous mutations in theLDLR gene

Natural history of the disease in 4 unrelated Polish children with homozygous familial hypercholesterolemia (FH) is described. Their phenotypic homozygosity was established by identification of known LDLR gene mutations on both alleles, respectively: p.G592E & p.G592E in Patient 1; p.G592E & p.C667Y in Patient 2; p.S177L & p.R350X in Patient 3; and p.G592E & deletion in the promoter region, exons 1 and 2 in Patient 4. Heterozygosity of the mutations was revealed in all patients' mothers and fathers (obligatory heterozygotes) and in 1 out of 4 siblings studied. FH was diagnosed at the age of 4 months to 9 years by cholesterol screening among family members of patients with early cardiovascular disease episodes. At the time of FH detection, the children were asymptomatic. Only in 2, some skin eruptions were found. Antihyperlipidemic therapy was started, including a lipid-lowering diet, cholestyramine, and HMG-CoA inhibitors if necessary. No cardiovascular symptoms appeared during the observation up to the age of 18, 20, 19, and 17 years, respectively. An increase in external carotid artery diameter was found in a patient at the age of 9 years, and LDL-apheresis was introduced in his therapy. We conclude that the analysis of LDLR gene mutations in the studied FH children made it possible to identify 4 presymptomatic FH homozygotes and to introduce early appropriate treatment. Multicenter analysis of such persons would finally determine if the early lipid-lowering procedures can significantly reduce the risk of premature cardiovascular disease in homozygous FH.     

Site-specific conjugation of a cytotoxic drug to an antibody improves the therapeutic index

Antibody-drug conjugates enhance the antitumor effects of antibodies and reduce adverse systemic effects of potent cytotoxic drugs. However, conventional drug conjugation strategies yield heterogenous conjugates with relatively narrow therapeutic index (maximum tolerated dose/curative dose). Using leads from our previously described phage display-based method to predict suitable conjugation sites, we engineered cysteine substitutions at positions on light and heavy chains that provide reactive thiol groups and do not perturb immunoglobulin folding and assembly, or alter antigen binding. When conjugated to monomethyl auristatin E, an antibody against the ovarian cancer antigen MUC16 is as efficacious as a conventional conjugate in mouse xenograft models. Moreover, it is tolerated at higher doses in rats and cynomolgus monkeys than the same conjugate prepared by conventional approaches. The favorable in vivo properties of the near-homogenous composition of this conjugate suggest that our strategy offers a general approach to retaining the antitumor efficacy of antibody-drug conjugates, while minimizing their systemic toxicity.     

Clinical presentation of extraintestinal infections caused by non-typhoid Salmonella serotypes among patients at the University Hospital in Cracow during an 7-year period

The most characteristic finding in non-typhoid salmonella (NTS) infection is acute food related outbreaks of gastroenteritis, which is usually benign and self-limiting. However, more serious extraintestinal findings, such as bacteraemia and focal infections localized to any organ may appear. The objective of this paper is to describe the most important characteristic of the extraintestinal infections due to NTS serotypes observed in University Hospital, in Cracow between January 2000 and December 2006. To do so, we reviewed the clinical presentations, risk groups, complications and outcomes of in-patients, in which extraintestinal non-typhoid Salmonella serotypes were isolated, applying a clinomicrobiological protocol. Out of 30 patients with either bacteraemias (n = 22) or focal salmonella infections (n = 8), 12 had malignancies, 17 had immune dysfunction state, 9 had gastrointestinal disorders and 8 had chronic heart, pulmonary or kidney disease. Four of these patients (13%) who had hematological malignancies (2), renal transplantation (1) and pulmonary disease (1) died. Regarding the clinical picture, primary bacteraemia and focal infections occurred with similar frequency (33.3% and 26.7%, respectively); the remaining were bacteraemias secondary to gastroenteritis. The incidence rate (mean 0.30/1000 hospital admission/year) increased steadily from 0.19/1000 to 0.32/1000 hospital admission during the study period. From 30 Salmonella isolates from extraintestinal samples collected, only four isolates were resistant to ampicillin, ciprofloxacin or trimethoprim-sulfamethoxazole. This finding indicate that multidrug resistance does not represent a serious problem among NTS serotypes collected from the our medical center as monitored over a period of 7 years. Given this presentation, clinicians need to have a high index of suspicion and to consider preemptive therapy, especially in elderly patients who are likely to develop severe immunosuppression following interventions.     

Forest floor vegetation response to nitrogen deposition in Europe

Chronic nitrogen (N) deposition is a threat to biodiversity that results from the eutrophication of ecosystems. We studied long‐term monitoring data from 28 forest sites with a total of 1,335 permanent forest floor vegetation plots from northern Fennoscandia to southern Italy to analyse temporal trends in vascular plant species cover and diversity. We found that the cover of plant species which prefer nutrient‐poor soils (oligotrophic species) decreased the more the measured N deposition exceeded the empirical critical load (CL) for eutrophication effects (P = 0.002). Although species preferring nutrient‐rich sites (eutrophic species) did not experience a significantly increase in cover (P = 0.440), in comparison to oligotrophic species they had a marginally higher proportion among new occurring species (P = 0.091). The observed gradual replacement of oligotrophic species by eutrophic species as a response to N deposition seems to be a general pattern, as it was consistent on the European scale. Contrary to species cover changes, neither the decrease in species richness nor of homogeneity correlated with nitrogen CL exceedance (ExCL_empN). We assume that the lack of diversity changes resulted from the restricted time period of our observations. Although existing habitat‐specific empirical CL still hold some uncertainty, we exemplify that they are useful indicators for the sensitivity of forest floor vegetation to N deposition.