Hereditary leiomyomatosis and renal cell cancer presenting as metastatic kidney cancer at 18 years of age: implications for surveillance

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an autosomal dominant syndrome characterized by skin piloleiomyomas, uterine leiomyomas and papillary type 2 renal cancer caused by germline mutations in the fumarate hydratase (FH) gene. Previously, we proposed renal imaging for FH mutation carriers starting at the age of 20 years. However, recently an 18-year-old woman from a Dutch family with HLRCC presented with metastatic renal cancer. We describe the patient and family data, evaluate current evidence on renal cancer risk and surveillance in HLRCC and consider the advantages and disadvantages of starting surveillance for renal cancer in childhood. We also discuss the targeted therapies administered to our patient

Genome Haploidisation with Chromosome 7 Retention in Oncocytic Follicular Thyroid Carcinoma

Contains fulltext : 108012.pdf (publisher's version ) (Open Access)BACKGROUND: Recurrent non-medullary thyroid carcinoma (NMTC) is a rare disease. We initially characterized 27 recurrent NMTC: 13 papillary thyroid cancers (PTC), 10 oncocytic follicular carcinomas (FTC-OV), and 4 non-oncocytic follicular carcinomas (FTC). A validation cohort composed of benign and malignant (both recurrent and non-recurrent) thyroid tumours was subsequently analysed (n = 20). METHODS: Data from genome-wide SNP arrays and flow cytometry were combined to determine the chromosomal dosage (allelic state) in these tumours, including mutation analysis of components of PIK3CA/AKT and MAPK pathways. RESULTS: All FTC-OVs showed a very distinct pattern of genomic alterations. Ten out of 10 FTC-OV cases showed near-haploidisation with or without subsequent genome endoreduplication. Near-haploidisation was seen in 5/10 as extensive chromosome-wide monosomy (allelic state [A]) with near-haploid DNA indices and retention of especially chromosome 7 (seen as a heterozygous allelic state [AB]). In the remaining 5/10 chromosomal allelic states AA with near diploid DNA indices were seen with allelic state AABB of chromosome 7, suggesting endoreduplication after preceding haploidisation. The latter was supported by the presence of both near-haploid and endoreduplicated tumour fractions in some of the cases. Results were confirmed using FISH analysis. Relatively to FTC-OV limited numbers of genomic alterations were identified in other types of recurrent NMTC studied, except for chromosome 22q which showed alterations in 6 of 13 PTCs. Only two HRAS, but no mutations of EGFR or BRAF were found in FTC-OV. The validation cohort showed two additional tumours with the distinct pattern of genomic alterations (both with oncocytic features and recurrent). CONCLUSIONS: We demonstrate that recurrent FTC-OV is frequently characterised by genome-wide DNA haploidisation, heterozygous retention of chromosome 7, and endoreduplication of a near-haploid genome. Whether normal gene dosage on especially chromosome 7 (containing EGFR, BRAF, cMET) is crucial for FTC-OV tumour survival is an important topic for future research. MICROARRAYS: Data are made available at GEO (GSE31828)

Disturbance Alters the Phylogenetic Composition and Structure of Plant Communities in an Old Field System

The changes in phylogenetic composition and structure of communities during succession following disturbance can give us insights into the forces that are shaping communities over time. In abandoned agricultural fields, community composition changes rapidly when a field is plowed, and is thought to reflect a relaxation of competition due to the elimination of dominant species which take time to re-establish. Competition can drive phylogenetic overdispersion, due to phylogenetic conservation of ‘niche’ traits that allow species to partition resources. Therefore, undisturbed old field communities should exhibit higher phylogenetic dispersion than recently disturbed systems, which should be relatively ‘clustered’ with respect to phylogenetic relationships. Several measures of phylogenetic structure between plant communities were measured in recently plowed areas and nearby ‘undisturbed’ sites. There was no difference in the absolute values of these measures between disturbed and ‘undisturbed’ sites. However, there was a difference in the ‘expected’ phylogenetic structure between habitats, leading to significantly lower than expected phylogenetic diversity in disturbed plots, and no difference from random expectation in ‘undisturbed’ plots. This suggests that plant species characteristic of each habitat are fairly evenly distributed on the shared species pool phylogeny, but that once the initial sorting of species into the two habitat types has occurred, the processes operating on them affect each habitat differently. These results were consistent with an analysis of correlation between phylogenetic distance and co-occurrence indices of species pairs in the two habitat types. This study supports the notion that disturbed plots are more clustered than expected, rather than ‘undisturbed’ plots being more overdispersed, suggesting that disturbed plant communities are being more strongly influenced by environmental filtering of conserved niche traits

Environmental Enrichment Induces Behavioral Recovery and Enhanced Hippocampal Cell Proliferation in an Antidepressant-Resistant Animal Model for PTSD

Background: Post traumatic stress disorder (PTSD) can be considered the result of a failure to recover after a traumatic experience. Here we studied possible protective and therapeutic aspects of environmental enrichment (with and without a running wheel) in Sprague Dawley rats exposed to an inescapable foot shock procedure (IFS). Methodology/Principal Findings: IFS induced long-lasting contextual and non-contextual anxiety, modeling some aspects of PTSD. Even 10 weeks after IFS the rats showed reduced locomotion in an open field. The antidepressants imipramine and escitalopram did not improve anxiogenic behavior following IFS. Also the histone deacetylase (HDAC) inhibitor sodium butyrate did not alleviate the IFS induced immobility. While environmental enrichment (EE) starting two weeks before IFS did not protect the animals from the behavioral effects of the shocks, exposure to EE either immediately after the shock or one week later induced complete recovery three weeks after IFS. In the next set of experiments a running wheel was added to the EE to enable voluntary exercise (EE/VE). This also led to reduced anxiety. Importantly, this behavioral recovery was not due to a loss of memory for the traumatic experience. The behavioral recovery correlated with an increase in cell proliferation in hippocampus, a decrease in the tissue levels of noradrenalin and increased turnover of 5-HT in prefrontal cortex and hippocampus. Conclusions/Significance: This animal study shows the importance of (physical) exercise in the treatment of psychiatri

Early onset MSI-H colon cancer with MLH1 promoter methylation, is there a genetic predisposition?

<p>Abstract</p> <p>Background</p> <p>To investigate the etiology of <it>MLH1 </it>promoter methylation in mismatch repair (MMR) mutation-negative early onset MSI-H colon cancer. As this type of colon cancer is associated with high ages, young patients bearing this type of malignancy are rare and could provide additional insight into the etiology of sporadic MSI-H colon cancer.</p> <p>Methods</p> <p>We studied a set of 46 MSI-H colon tumors cases with <it>MLH1 </it>promoter methylation which was enriched for patients with an age of onset below 50 years (n = 13). Tumors were tested for CIMP marker methylation and mutations linked to methylation: <it>BRAF, KRAS</it>, <it>GADD45A </it>and the <it>MLH1 </it>-93G>A polymorphism. When available, normal colon and leukocyte DNA was tested for <it>GADD45A </it>mutations and germline <it>MLH1 </it>methylation. SNP array analysis was performed on a subset of tumors.</p> <p>Results</p> <p>We identified two cases (33 and 60 years) with <it>MLH1 </it>germline promoter methylation. <it>BRAF </it>mutations were less frequent in colon cancer patients below 50 years relative to patients above 50 years (p-value: 0.044). CIMP-high was infrequent and related to <it>BRAF </it>mutations in patients below 50 years. In comparison with published controls the G>A polymorphism was associated with our cohort. Although similar distribution of the pathogenic A allele was observed in the patients with an age of onset above and below 50 years, the significance for the association was lost for the group under 50 years. <it>GADD45A </it>sequencing yielded an unclassified variant. Tumors from both age groups showed infrequent copy number changes and loss-of-heterozygosity.</p> <p>Conclusion</p> <p>Somatic or germline <it>GADD45A </it>mutations did not explain sporadic MSI-H colon cancer. Although germline <it>MLH1 </it>methylation was found in two individuals, locus-specific somatic <it>MLH1 </it>hypermethylation explained the majority of sporadic early onset MSI-H colon cancer cases. Our data do not suggest an intrinsic tendency for CpG island hypermethylation in these early onset MSI-H tumors other than through somatic mutation of <it>BRAF</it>.</p

Therapeutic Validity and Effectiveness of Preoperative Exercise on Functional Recovery after Joint Replacement: A Systematic Review and Meta-Analysis

Background: Our aim was to develop a rating scale to assess the therapeutic validity of therapeutic exercise programmes. By use of this rating scale we investigated the therapeutic validity of therapeutic exercise in patients awaiting primary total joint replacement (TJR). Finally, we studied the association between therapeutic validity of preoperative therapeutic exercise and its effectiveness in terms of postoperative functional recovery. Methods: (Quasi) randomised clinical trials on preoperative therapeutic exercise in adults awaiting TJR on postoperative recovery of functioning within three months after surgery were identified through database and reference screening. Two reviewers extracted data and assessed the risk of bias and therapeutic validity. Therapeutic validity of the interventions was assessed with a nine-itemed, expert-based rating scale (scores range from 0 to 9; score ≥6 reflecting therapeutic validity), developed in a four-round Delphi study. Effects were pooled using a random-effects model and meta-regression was used to study the influence of therapeutic validity. Results: Of the 7,492 articles retrieved, 12 studies (737 patients) were included. None of the included studies demonstrated therapeutic validity and two demonstrated low risk of bias. Therapeutic exercise was not associated with 1) observed functional recovery during the hospital stay (Standardised Mean Difference [SMD]: −1.19; 95%-confidence interval [CI], −2.46 to 0.08); 2) observed recovery within three months of surgery (SMD: −0.15; 95%-CI, −0.42 to 0.12); and 3) self-reported recovery within three months of surgery (SMD −0.07; 95%-CI, −0.35 to 0.21) compared with control participants. Meta-regression showed no statistically significant relationship between therapeutic validity and pooled-effects. Conclusion: Preoperative therapeutic exercise for TJR did not demonstrate beneficial effects on postoperative functional recovery. However, poor therapeutic validity of the therapeutic exercise programmes may have hampered potentially beneficial effects, since none of the studies met the predetermined quality criteria. Future review studies on therapeutic exercise should address therapeutic validity. (aut.ref.

Anorectal surgery in human immunodeficiency virus-infected patients - clinical outcome in relation to immune status

PURPOSE: Anorectal disease is commonly found in human immunodeficiency virus (HIV)-infected patients. The aim of this study was to determine the spectrum of anorectal disease, its surgical treatment, clinical outcome, and its relation to immune status. METHODS: Medical records of all HIV-infected patients with anorectal pathology that required surgical treatment from January 1984 to January 1994 were retrospectively reviewed. Patients were divided into five different groups: common anorectal pathology (hemorrhoids, polyps, Group A); condylomata acuminata (Group B); perianal sepsis (abscesses, fistulas, Group C); anorectal ulcers (Group D); malignancies (Group E). RESULTS: Eighty-three patients needed 204 surgical consultations (13 percent conservative, 87 percent operative) for 170 anorectal diseases. Fifty-one patients had multiple anorectal pathology. Operative intervention resulted in adequate wound healing and symptom relief in 59 percent of patients, adequate wound healing without relief of symptoms in 24 percent of patients, and disturbed wound healing in 17 percent of patients. Disturbed wound healing was related to type of anorectal disease (P <0.001) and to preoperative CD4(+)-lymphocyte counts (P <0.01). Disturbed wound healing and most insufficient immune status were encountered in Groups C, D, and E. Within these groups low CD4(+)-lymphocyte counts were a risk factor for disturbed wound healing (P = 0.004). Median postoperative survival was highest (4.7 years) in Group A, lowest (0.6 years) in Groups D and E, and related to type of anorectal disease (P = 0.0001). CONCLUSIONS: The spectrum of anorectal disease is complex. Type of anorectal disease is strongly related to immune status, mound healing, and postoperative survival

Anorectal surgery in human immunodeficiency virus-infected patients - clinical outcome in relation to immune status

PURPOSE: Anorectal disease is commonly found in human immunodeficiency virus (HIV)-infected patients. The aim of this study was to determine the spectrum of anorectal disease, its surgical treatment, clinical outcome, and its relation to immune status. METHODS: Medical records of all HIV-infected patients with anorectal pathology that required surgical treatment from January 1984 to January 1994 were retrospectively reviewed. Patients were divided into five different groups: common anorectal pathology (hemorrhoids, polyps, Group A); condylomata acuminata (Group B); perianal sepsis (abscesses, fistulas, Group C); anorectal ulcers (Group D); malignancies (Group E). RESULTS: Eighty-three patients needed 204 surgical consultations (13 percent conservative, 87 percent operative) for 170 anorectal diseases. Fifty-one patients had multiple anorectal pathology. Operative intervention resulted in adequate wound healing and symptom relief in 59 percent of patients, adequate wound healing without relief of symptoms in 24 percent of patients, and disturbed wound healing in 17 percent of patients. Disturbed wound healing was related to type of anorectal disease (P <0.001) and to preoperative CD4(+)-lymphocyte counts (P <0.01). Disturbed wound healing and most insufficient immune status were encountered in Groups C, D, and E. Within these groups low CD4(+)-lymphocyte counts were a risk factor for disturbed wound healing (P = 0.004). Median postoperative survival was highest (4.7 years) in Group A, lowest (0.6 years) in Groups D and E, and related to type of anorectal disease (P = 0.0001). CONCLUSIONS: The spectrum of anorectal disease is complex. Type of anorectal disease is strongly related to immune status, mound healing, and postoperative survival

MONOSACCHARIDES IN POST-WEANING DIET OF YOUNG MICE PROGRAM BODY COMPOSITION AND FEEDING BEHAVIOUR IN ADULTHOOD

Nutrition in early life has permanent consequences affecting development and later-life health. In this study we investigated the potential of monosaccharides in the post-weaning diet to program adult metabolic health. Female and male C57BL/6JRccHsd mice were time-mated and fed a low-fat diet ad libitum. Litters were culled to six pups per nest and randomly assigned to foster dams. Mice were weaned onto one of three experimental diets containing 32 energy% as glucose (GLU), fructose (FRU) or an equimolar mixture of glucose and galactose (GAL). At six weeks of age, all mice received the same high-fat diet (HFD). Food intake, body weight, and body composition were measured biweekly. Whole-body metabolism was analysed towards the end of the post-weaning diet and during the last stretch of the high-fat feeding period in GLU and FRU mice. Additionally, an oral glucose tolerance test and a fasting-refeeding challenge as an indicator of metabolic flexibility were performed. At the end of the post-weaning intervention period, no significant differences were found in body weight or lean mass across all dietary groups, and in 24-hour energy expenditure and substrate oxidation between GLU and FRU. At week 15, cumulative food intake, body weight, and fat mass were significantly lower in GAL females compared to GLU females. Glucose tolerance in all groups, and energy expenditure, fuel utilization, and metabolic flexibility between GLU and FRU did not reveal programmed differences in metabolic phenotype. None of the parameters studied indicated long-lasting effects in males. This study provides evidence of the potential of galactose in the post-weaning diet to program a reduction in food intake resulting in lower fat mass during adulthood. Our findings highlight the relevance of carbohydrates as a dietary intervention target for future clinical studies in the field of metabolic programming.Acknowledgements: Financially supported by NWO-Applied and Technical Sciences grant 1350