Brain-derived neurotrophic factor genetic polymorphism (rs6265) is protective against chemotherapy-associated cognitive impairment in patients with early-stage breast cancer

Background

Brain-derived neurotrophic factor (BDNF), a neurotrophin that regulates neuronal function and development, is implicated in several neurodegenerative conditions. Preliminary data suggest that a reduction of BDNF concentrations may lead to postchemotherapy cognitive impairment. We hypothesized that a single nucleotide polymorphism (rs6265) of the BDNF gene may predispose patients to cognitive impairment. This study aimed to evaluate the effect of BDNF gene polymorphism on chemotherapy-associated cognitive impairment.

Methods

Overall, 145 patients receiving chemotherapy for early-stage breast cancer (mean age: 50.8 ± 8.8 y; 82.1% Chinese) were recruited. Patients'' cognitive functions were assessed longitudinally using the validated Functional Assessment of Cancer Therapy–Cognitive Function (v.3) and an objective computerized tool, Headminder. Genotyping was performed using Sanger sequencing. Logistic regression was used to evaluate the association between BDNF Val66Met polymorphism and cognition after adjusting for ethnicity and clinically important covariates.

Results

Of the 145 patients, 54 (37%) reported cognitive impairment postchemotherapy. The Met/Met genotype was associated with statistically significant lower odds of developing cognitive impairment (odds ratio [OR] = 0.26; 95% CI: 0.08–0.92; P = .036). The Met carriers were less likely to experience impairment in the domains of verbal fluency (OR = 0.34; 95% CI: 0.12–0.90; P = .031) and multitasking ability (OR = 0.37; 95% CI: 0.15–0.91; P = .030) compared with the Val/Val homozygote. No associations were observed between Headminder and the BDNF Val66Met polymorphism.

Conclusions

This is the first study to provide evidence that carriers of the BDNF Met allele are protected against chemotherapy-associated cognitive impairment. Further studies are required to validate the findings.     

Quality assessment by expert opinion in melanoma pathology: experience of the Pathology Panel of the Dutch Melanoma Working Party

Some cutaneous melanocytic lesions are notoriously difficult to diagnose by histopathology. For that reason, the Pathology Panel of the Dutch Melanoma Working Party was instituted and is regularly approached to provide an expert opinion on problem cases. In order to identify the most common diagnostic problems, 1069 consecutive referral cases of submitted lesions (1992 to 1994 inclusive) were analysed. About 60 per cent of the requests came from small laboratories, with up to three consultant pathologists. Two-thirds of the lesions reviewed concerned women and nearly 50 per cent of the patients were 30 years of age or younger. In 8 per cent of the cases, the referring pathologists felt unable to make a confident diagnosis; in 14 per cent, melanoma was suspected; and in 12 per cent, a differential diagnosis only had been formulated. The panel felt able to provide an unequivocal diagnosis in 93 per cent of the requests. Of the 158 lesions classified as ‘invasive melanoma’ by the referring pathologists, 22 were considered to be benign by the panel. Conversely, 108 invasive melanomas (panel diagnosis) had originally been considered as benign lesions, dysplastic naevi or melanoma in situ. These high numbers of discordancies reflect the intrinsic difficulty of the differential diagnoses in this selected material submitted to the panel. Diagnostic difficulties were most often encountered with Spitz naevi and dysplastic naevi. Although the rate of overdiagnosis and underdiagnosis is quite high, in the majority of cases the diagnosis of the referring pathologist matched the diagnosis of the panel. This may reflect a proper awareness of difficult melanocytic lesions in pathology practice. The activities of the Pathology Panel of the Dutch Melanoma Working Party contribute to the improvement of the quality of diagnosis in cutaneous melanocytic lesions, as they increase the number of unequivocal diagnoses and reduce the number of incorrect diagnoses. On the basis of the systematic comparison of the diagnosis by the referring pathologist and the panel, postgraduate teaching and quality control can be more focused on specific diagnostic problems. © 1997 John Wiley & Sons, Ltd.     

Impaired structural remodelling of pulmonary arteries in newborns with congenital diaphragmatic hernia: a histological study of 29 cases

Congenital diaphragmatic hernia (CDH) is associated in many cases with lung hypoplasia and pulmonary hypertension (PH). The pathogenetic mechanisms underlying the pulmonary hypertension in CDH are not completely understood. In order to alleviate the pulmonary hypertension, new therapeutic modalities have been introduced including extracorporeal membrane oxygenation (ECMO). This paper reports a study of the histology of the lungs of 29 CDH autopsy cases, with special attention to the pulmonary arteries, and relating the findings to gestational age and ECMO treatment. Formalin-fixed and paraffin-embedded specimens were stained with haematoxylin and eosin (H&E) and elastic van Gieson (EvG) stains, followed by morphometric measurements of the arterial media and adventitia. As expected, there was a significant decrease in adventitial percentage and total wall thicknesses of small pulmonary arteries with an external diameter less than or equal to 150 µm in term control newborns compared with pre-term controls ( p=0·0004 and 0·05). In CDH newborns, all the measured values of the arterial wall remained significantly higher. The increase of adventitial thickness also affected the supernumerary arteries in CDH neonates. CDH newborns subjected to ECMO treatment showed a significantly thinner arterial adventitia than CDH cases who did not receive ECMO ( p=0·0001), the former approaching normal values. These results indicate that in CDH, there is failure of the normal arterial remodelling processes occurring in the perinatal period. The adventitial thickening, which has been reported previously in term CDH patients only, was related in the present study to differences in gestational ages. This appears to be partially reversed by ECMO treatment, thus constituting one of the mechanisms by which ECMO treatment aids in alleviating the associated PH in CDH newborns. Copyright © 1999 John Wiley & Sons, Ltd.     

Desmopressin for the prevention of bleeding in percutaneous kidney biopsy: efficacy and hyponatremia

International Urology and Nephrology - Desmopressin is used to reduce bleeding complications for kidney biopsies with azotemia but little is known about desmopressin-induced hyponatremia in these...     

Host genetics of Bordetella pertussis infection in mice: significance of Toll-like receptor 4 in genetic susceptibility and pathobiology

The susceptibility to and the severity of Bordetella pertussis infections in infants and children varies widely, suggesting that genetic differences between individuals influence the course of infection. We have previously identified three novel loci that influence the severity of whooping cough by using recombinant congenic strains of mice: Bordetella pertussis susceptibility loci 1, 2, and 3 (Bps1, -2, and -3). Because these loci could not account for all genetic differences between mice, we extended our search for additional susceptibility loci. We therefore screened 11 inbred strains of mice for susceptibility to a pertussis infection after intranasal infection. Susceptibility was defined by the number of bacteria in the lungs, being indicative of the effect between the clearance and replication of bacteria. The most resistant (A/J) and the most susceptible (C3H/HeJ) strains were selected for further genetic and phenotypic characterization. The link between bacterial clearance and chromosomal location was investigated with 300 F2 mice, generated by crossing A/J and C3H/HeJ mice. We found a link between the delayed clearance of bacteria from the lung and a large part of chromosome 4 in F2 mice with a maximum log of the odds score of 33.6 at 65.4 Mb, which is the location of Tlr4. C3H/HeJ mice carry a functional mutation in the intracellular domain of Tlr4. This locus accounted for all detectable genetic differences between these strains. Compared to A/J mice, C3H/HeJ mice showed a delayed clearance of bacteria from the lung, a higher relative lung weight, and increased body weight loss. Splenocytes from infected C3H/HeJ mice produced almost no interleukin-1beta (IL-1beta) and tumor necrosis factor alpha (TNF-alpha) upon ex vivo restimulation with B. pertussis compared to A/J mice and also showed a delayed gamma interferon (IFN-gamma) production. TNF-alpha expression in the lungs 3 days after infection was increased fivefold compared to uninfected controls in A/J mice and was not affected in C3H/HeJ mice. In conclusion, Tlr4 is a major host factor explaining the differences in the course of infection between these inbred strains of mice. Functional Tlr4 is essential for an efficient IL-1-beta, TNF-alpha, and IFN-gamma response; efficient clearance of bacteria from the lung; and reduced lung pathology.     

Bordetella pertussis and vaccination: The persistence of a genetically monomorphic pathogen

Before childhood vaccination was introduced in the 1950s, pertussis or whooping cough was a major cause of infant death worldwide. Widespread vaccination of children was successful in significantly reducing morbidity and mortality. However, despite vaccination, pertussis has persisted and, in the 1990s, resurged in a number of countries with highly vaccinated populations. Indeed, pertussis has become the most prevalent vaccine-preventable disease in developed countries with estimated infection frequencies of 1–6%. Recently vaccinated children are well protected against pertussis disease and its increase is mainly seen in adolescents and adults in which disease symptoms are often mild. The etiologic agent of pertussis, Bordetella pertussis, is extremely monomorphic and its ability to persist in the face of intensive vaccination is intriguing. Numerous studies have shown that B. pertussis populations changed after the introduction of vaccination suggesting adaptation. These adaptations did not involve the acquisition of novel genes but small genetic changes, mainly SNPs, and occurred in successive steps in a period of 40 years. The earliest adaptations resulted in antigenic divergence with vaccine strains. More recently, strains emerged with increased pertussis toxin (Ptx) production. Here I argue that the resurgence of pertussis is the compound effect of pathogen adaptation and waning immunity. I propose that the removal by vaccination of naïve infants as the major source for transmission was the crucial event which has driven the changes in B. pertussis populations. This has selected for strains which are more efficiently transmitted by primed hosts in which immunity has waned. The adaptation of B. pertussis to primed hosts involved delaying an effective immune response by antigenic divergence with vaccine strains and by increasing immune suppression through higher levels of Ptx production. Higher levels of Ptx may also benefit transmission by enhancing clinical symptoms. The study of B. pertussis populations has not only increased our understanding of pathogen evolution, but also suggests way to improve pertussis vaccines, underlining the public health significance of population-based studies of pathogens.     

Pertussis in the Netherlands,is the current vaccination strategy sufficient to reduce disease burden in young infants?

Background

Pertussis has resurged in the Netherlands since 1996. Several measures, i.e. acceleration of the schedule, introduction of a preschool acellular pertussis booster and change from an infant whole cell to an acellular pertussis combination vaccine were implemented in the National Immunisation Programme to decrease disease burden, in particular among very young infants who have the highest morbidity and mortality of pertussis. Nevertheless, a large outbreak occurred in 2011–2012.

Methods

1996–2010 was divided in 3-year-periods to assess the impact of the measures taken, using notifications and hospitalisations. These results were compared with 2011–2012. Mean Incidence rates (IRs) per 100,000 were calculated.

Results

Although the measures taken resulted in decreased IRs among the targeted age groups after implementation, overall mean IRs of notifications increased from 32 (1996–2004) to 37 (2005–2010) and 63 (2011–2012). Young infants, not yet vaccinated, did not benefit; during the 2011–2012 outbreak, IR in 0–2-month-olds amounted to 259.6. IR among persons over 9 years of age increased from 6.8 (1996–1999) to 59.1 (2011–2012) For hospitalisations overall mean IRs decreased from 1.95 per 100,000 (1997–2004) to 0.88 (2005–2010) and 0.76 (2011).

Conclusion

The measures taken reduced IRs of notifications and hospitalisations among groups eligible for vaccination, but had no effect on the increasing IRs in adolescents and adults. This trend is also observed in other countries. The high IRs in 2012 in adolescents and adults probably resulted in increased transmission to infants, who are at risk for contracting severe pertussis. Therefore, additional measures to protect this group should be considered.