Late ascended testes: is non-orthotopic gubernacular insertion a confirmation of an alternative embryological etiology?

INTRODUCTION: Re-ascended testes account for a proportion of all undescended testes (UDTs); one main hypothesis relating to their etiology relates to a patent processus vaginalis peritonei. The aim was to investigate gubernacular insertion points in boys with late ascended testis as a possible guide to an alternative embryological etiology. PATIENTS AND METHODS: Patients with proven ascended testes were recruited from four different pediatric urology centers between May 2016 and September 2017. All patients were evaluated regarding their gubernacular insertion during orchidopexy. The presence of accompanying patent processus vaginalis and the association between the epididymis and testis were also documented. RESULTS: Seventy-seven children (mean age = 73.1 ± 41.2 months [range 18-176]) were enrolled into the study. A non-orthotopic gubernacular insertion point was found in 96.1% (n = 74); 34.2% (n = 26) of these were located in the groin and 63.2% (n = 48), high within the scrotum. Figure A. An open processus vaginalis peritonei was found in 35.1%. Twelve patients (15.6%) had small, dysplastic appearing testis with testis-epididymis dissociation. Boys with a higher insertion of the non-orthotopic gubernaculum (n = 48, groin) were operated earlier (mean age at surgery, 62.3 months) compared with those with a gubernacular insertion at a high scrotal site (mean age at surgery, 90.5 months; p = 0.004). Figure B. DISCUSSION: This study revealed that non-orthotopic gubernacular insertion is found in the vast majority of the ascending testis cases. Patent processus vaginalis was accompanying only 35.1% of all children and might be the cause of the ascending testis in this small subgroup of patients in line with the earlier reports [1]. In boys with ascending testes, in this population, the gubernaculum was very likely to insert non-orthotopically. In concordance with previous reports [2] and regarding the finding of a an earlier age at surgery in boys with higher inserting gubernacula, this could provide a logical explanation as to how these testes are initially palpable in the scrotum and then, during body growth are retracted to the groin. CONCLUSION: In 96.1% of the patients, a non-orthotopic gubernacular insertion was found. This points to embryologic etiology, complying well with earlier reports and further underlining the critical importance of timely diagnosis and treatment for this group of patients.

Plasma deoxysphingolipids: a novel class of biomarkers for the metabolic syndrome?

AIMS/HYPOTHESIS: Sphingolipid synthesis is typically initiated by the conjugation of L-serine and palmitoyl-CoA, a reaction catalysed by serine palmitoyltransferase (SPT). SPT can also metabolise other acyl-CoAs (C(12) to C(18)) and other amino acids such as L-alanine and glycine, giving rise to a spectrum of atypical sphingolipids. Here, we aimed to identify changes in plasma levels of these atypical sphingolipids to explore their potential as biomarkers in the metabolic syndrome and diabetes. METHODS: We compared the plasma profiles of ten sphingoid bases in healthy individuals with those of patients with the metabolic syndrome but not diabetes, and diabetic patients (n = 25 per group). The results were verified in a streptozotocin (STZ) rat model. Univariate and multivariate statistical analyses were used. RESULTS: Deoxysphingolipids (dSLs) were significantly elevated (p = 5 × 10⁻6) in patients with the metabolic syndrome (0.11 ± 0.04 µmol/l) compared with controls (0.06 ± 0.02 µmol/l) but did not differ between the metabolic syndrome and diabetes groups. Levels of C(16)-sphingosine-based sphingolipids were significantly lowered in diabetic patients but not in patients with the metabolic syndrome but without diabetes (p = 0.008). Significantly elevated dSL levels were also found in the plasma and liver of STZ rats. A principal component analysis revealed a similar or even closer association of dSLs with diabetes and the metabolic syndrome in comparison with the established biomarkers. CONCLUSIONS/INTERPRETATION: We showed that dSLs are significantly elevated in patients with type 2 diabetes mellitus and non-diabetic metabolic syndrome compared with healthy controls. They may, therefore, be useful novel biomarkers to improve risk prediction and therapy monitoring in these patients.

A novel pathogenic MLH1 missense mutation, c.112A > C, p.Asn38His, in six families with Lynch syndrome.

BACKGROUND: An unclassified variant (UV) in exon 1 of the MLH1 gene, c.112A > C, p.Asn38His, was found in six families who meet diagnostic criteria for Lynch syndrome. The pathogenicity of this variant was unknown. We aim to elucidate the pathogenicity of this MLH1 variant in order to counsel these families adequately and to enable predictive testing in healthy at-risk relatives. METHODS: We studied clinical data, microsatellite instability and immunohistochemical staining of MMR proteins, and performed genealogy, haplotype analysis and DNA testing of control samples. RESULTS: The UV showed co-segregation with the disease in all families. All investigated tumors showed a microsatellite instable pattern. Immunohistochemical data were variable among tested tumors. Three families had a common ancestor and all families originated from the same geographical area in The Netherlands. Haplotype analysis showed a common haplotype in all six families. CONCLUSIONS: We conclude that the MLH1 variant is a pathogenic mutation and genealogy and haplotype analysis results strongly suggest that it is a Dutch founder mutation. Our findings imply that predictive testing can be offered to healthy family members. The immunohistochemical data of MMR protein expression show that interpreting these results in case of a missense mutation should be done with caution.

Low bone mineral density is not associated with angiographically determined coronary atherosclerosis in men.

UNLABELLED: This study for the first time investigates the association of bone mineral density (BMD) with angiographically determined coronary atherosclerosis in men. Our data show that the prevalence of low BMD is very high in men undergoing coronary angiography. However, neither osteopenia nor osteoporosis is associated with an increased prevalence of angiographically determined coronary atherosclerosis. INTRODUCTION: The association of low BMD with angiographically determined coronary atherosclerosis in men is unknown. METHODS: We enrolled 623 consecutive men undergoing coronary angiography for the evaluation of established or suspected coronary artery disease (CAD). BMD was assessed by dual X-ray absorptiometry. CAD was diagnosed in the presence of any coronary artery lumen narrowing at angiography; coronary stenoses with lumen narrowing > or =50% were considered significant. RESULTS: From the total study cohort (mean age of 64 +/- 11 years), 207 patients (33.2%) had osteopenia and 65 (10.4%) had osteoporosis; at angiography, CAD was diagnosed in 558 patients (89.6%) and 403 (64.7%) had significant coronary stenoses. In multivariate logistic regression analysis neither osteopenia nor osteoporosis was associated with an increased prevalence of CAD (adjusted odds ratios (ORs) = 0.71 [95% confidence interval 0.40-1.23]; p = 0.222 and 1.03 [0.38-2.80]; p = 0.955, respectively) or with significant coronary stenoses (OR 0.74 [0.52-1.07], p = 0.112 and 0.72 [0.41-1.26]; p = 0.251, respectively). Also, as a continuous variable, BMD was not associated with angiographically diagnosed CAD. CONCLUSIONS: The prevalence of low BMD is very high in men undergoing coronary angiography. However, low BMD is not associated with angiographically determined coronary atherosclerosis in men.

The float model: visualizing personal reflection in healthcare.

CHALLENGE: Healthcare students and practitioners need to be able to critically assess themselves and their actions in order to learn from their experiences and improve their care of patients. Students' behaviours can be directly observed and faculty can provide direct feedback on it, when necessary. But 'reflection', a mechanism for assessing one's self, is less visible and often remains an abstract notion that is difficult to understand, use, and assess. EDUCATIONAL MODEL: We designed an educational model to help healthcare educators and learners visualize reflection. We posit that it can provide a greater understanding of what reflection is, how it works and how to facilitate its development and use by individuals. As a metaphor we used the angler's (fisherman's) float, which to function properly must stand balanced and steady in the water. Likewise, healthcare practitioners try to maintain an upright balance to be able to learn and work effectively. The visible component of the float, the portion above the water, is the 'behaviour'. The hidden, "mental" components of the float are under water: expert thinking (a combination of 'clinical reasoning' and 'scientific thinking'), 'personal reflection', and 'unconscious thoughts'. Each of these mental components plays a role in maintaining balance in learning and working, varying with the circumstances and context. And of course, without water a float has no meaning. In the float model, the water symbolizes the organisational and cultural context in which each practitioner must learn to function. APPLICATIONS: We propose that the float model can be used to reveal the interplay among clinicians' mental processes, which occur unseen "underneath the water" but subtly influence the appropriateness of the behaviour witnessed at the surface. We believe the model can help prevent errors in understanding practitioners' behaviours and their causes, such as when they blur scientific thinking and personal reflection, take reflection as a goal in and of itself, and deny the value of the intuitive and unconscious aspects influencing their behaviours.

Synergistic effects of the apolipoprotein E epsilon3/epsilon2/epsilon4, the cholesteryl ester transfer protein TaqIB, and the apolipoprotein C3 -482 C>T polymorphisms on their association with coronary artery disease.

The single nucleotide polymorphisms (SNPs) apolipoprotein E (APOE) epsilon3/epsilon2/epsilon4, cholesteryl ester transfer protein (CETP) TaqIB, and apolipoprotein C3 (APOC3) -482 C>T have been associated with an atherogenic lipid profile and, in some studies, with increased cardiovascular risk. However, no data exist on their combined impact on atherosclerotic disease. We therefore aimed at investigating the combined impact of these SNPs on the presence of angiographically determined coronary artery disease (CAD). Genotyping was performed in 557 consecutive Caucasian patients undergoing coronary angiography for the evaluation of CAD. From the individual SNPs, only the APOE epsilon3epsilon4/epsilon4epsilon4 genotype was significantly associated with an increased risk of significant coronary stenoses with lumen narrowing >or=50% (odds ratio (OR)=1.77 [1.16-2.71]; p=0.008). However, the risk of CAD strongly increased when more than one of the analysed genetic variants was present: ORs were 2.74 [1.29-5.83]; p=0.009 for patients with both the APOE epsilon3epsilon4/epsilon4epsilon4 and the CETP B1B1 genotype, 1.97 [1.06-3.66]; p=0.031 for patients with both the APOE epsilon3epsilon4/epsilon4epsilon4 genotype and the APOC3 -482T allele, 2.12 [1.31-3.44]; p=0.002 for patients with both the CETP B1B1 genotype and the APOC3 -482T allele, and 3.99 [1.57-13.79]; p=0.029 for patients with all three variants. Multivariate analyses confirmed these results. We conclude that there are strong synergistic effects of the APOE epsilon3/epsilon2/epsilon4, the CETP TaqIB, and the APOC3 -482 C>T polymorphisms on their association with CAD.

Thyroid cancer in a patient with a germline MSH2 mutation. Case report and review of the Lynch syndrome expanding tumour spectrum.

Lynch syndrome (HNPCC) is a dominantly inherited disorder characterized by germline defects in DNA mismatch repair (MMR) genes and the development of a variety of cancers, predominantly colorectal and endometrial. We present a 44-year-old woman who was shown to carry the truncating MSH2 gene mutation that had previously been identified in her family. Recently, she had been diagnosed with an undifferentiated carcinoma of the thyroid and an adenoma of her coecum. Although the thyroid carcinoma was not MSI-high (1 out of 5 microsatellites instable), it did show complete loss of immunohistochemical expression for the MSH2 protein, suggesting that this tumour was not coincidental. Although the risks for some tumour types, including breast cancer, soft tissue sarcoma and prostate cancer, are not significantly increased in Lynch syndrome, MMR deficiency in the presence of a corresponding germline defect has been demonstrated in incidental cases of a growing range of tumour types, which is reviewed in this paper. Interestingly, the MSH2-associated tumour spectrum appears to be wider than that of MLH1 and generally the risk for most extra-colonic cancers appears to be higher for MSH2 than for MLH1 mutation carriers. Together with a previously reported case, our findings show that anaplastic thyroid carcinoma can develop in the setting of Lynch syndrome. Uncommon Lynch syndrome-associated tumour types might be useful in the genetic analysis of a Lynch syndrome suspected family if samples from typical Lynch syndrome tumours are unavailable.

The effect of enhanced experiential learning on the personal reflection of undergraduate medical students.

OBJECTIVE: This study's aim was to test the expectation that enhanced experiential learning is an effective educational method that encourages personal reflection in medical students. METHODS: Using a pre post-test follow-up design, the level of the personal reflection ability of an exposure group of first-year medical students participating in a new enhanced experiential learning program was compared to that of a control group of second- and third-year medical students participating in a standard problem-based learning program. Personal reflection was assessed using the Groningen Reflection Ability Scale (GRAS). Students' growth in reflection was analyzed with multilevel analysis. RESULTS: After one year, first-year medical students in the exposure group achieved a level of personal reflection comparable to that reached by students of the control group in their third year. This difference in growth of reflection was statistically significant (p<.001), with a small effect size (effect size = 0.18). The reflection growth curve of the control group declined slightly in the third year as a function of study time. CONCLUSION: Enhanced experiential learning has a positive effect on the personal reflection ability of undergraduate medical students.

The metabolic syndrome and risk of cardiovascular disease and diabetes: experiences with the new diagnostic criteria from the International Diabetes Federation.

Since the publication of the International Diabetes Federation (IDF) consensus definition of the metabolic syndrome (MetS) in 2005, numerous studies have compared the new IDF MetS category with previous MetS definitions in its association with the prevalence of cardiovascular disease, and in its ability to predict vascular events and incident diabetes. The present review shows that the amount of cardiovascular risk conferred by the respective MetS definitions varies between populations; in most populations it is lower with the IDF MetS than with alternative MetS definitions. For incident diabetes, the number of existing studies appears too limited to draw definite conclusions. Like earlier definitions of the MetS, the IDF MetS is based on distinctive cutoff points for MetS stigmata, neglecting the fact that the risk factors are continuous and not categorical variables.

The development of a scale to measure personal reflection in medical practice and education.

AIM: Personal reflection is important for acquiring, maintaining and enhancing balanced medical professionalism. A new scale, the Groningen Reflection Ability Scale (GRAS), was developed to measure the personal reflection ability of medical students. METHOD: Explorative literature study was conducted to gather an initial pool of items. Item selection took place using qualitative and quantitative methods. Medical teachers screened the initial item-pool on relevance, expert-analysis was used for screening the fidelity to the criterion and large samples of medical students and medical teachers were used to investigate the psychometric characteristics of the items. Finally, explorative factor analysis was used to investigate the structure of the scale. RESULTS: The psychometric quality and content validity of the GRAS are satisfactory. The items cover three aspects of personal reflection: self-reflection, empathetic reflection and reflective communication. The 23-item scale proved to be easy to complete and to administer. CONCLUSION: The GRAS is a practical measurement instrument that yields reliable data that contribute to valid inferences about the personal reflection ability of medical students and doctors, both at individual and group level.

Leptin, leptin soluble receptor and coronary atherosclerosis.

BACKGROUND: The adipose tissue-related hormone leptin plays an important role in the regulation of body weight. The associations of leptin and leptin soluble receptor (sOb-R) with coronary artery disease (CAD) are not clear. DESIGN: We measured leptin and sOb-R in 543 consecutive patients (379 men, 164 women) referred for coronary angiography for the evaluation of CAD. Coronary artery stenoses with lumen narrowing > or = 50% were considered significant. RESULTS: Serum leptin correlated significantly with body mass index (r(s) = 0.443), with insulin resistance as assessed by the homeostasis model for the assessment of insulin resistance (r(s) = 0.339), with serum triglycerides (r(s) = 0.181), with systolic as well as diastolic blood pressure (r(s) = 0.170 and r(s) = 0.133, respectively) and, inversely, with sOb-R (r(s) = -0.346; P < 0.01 for all correlations). Coronary angiography revealed significant coronary artery stenoses in 331 (61%) of our patients. Serum leptin was significantly lower in patients with significant coronary artery stenoses than in patients without such lesions (8.5 +/- 7.8 vs. 13.2 +/- 12.2 ng mL(-1); P < 0.001). Multivariate logistic regression analysis proved serum leptin inversely and independently associated with the presence of significant coronary artery stenoses (standardized adjusted odds ratio 0.746, 95% confidence interval 0.566-0.983, P = 0.038). In contrast to serum concentrations of leptin, serum concentrations of sOb-R did not significantly differ between patients with significant stenoses and those without such lesions (22.4 +/- 8.3 vs. 23.1 +/- 12.1 ng mL(-1); P = 0.655). CONCLUSIONS: Serum leptin but not sOb-R is significantly lower in patients with angiographically determined CAD. Despite its association with cardiovascular risk factors, leptin should not be simply regarded as a promoter of atherosclerosis.

First report of a de novo germline mutation in the MLH1 gene.

Hereditary non-polyposis colorectal carcinoma (HNPCC) is an autosomal dominant disorder associated with colorectal and endometrial cancer and a range of other tumor types. Germline mutations in the DNA mismatch repair (MMR) genes, particularly MLH1, MSH2, and MSH6, underlie this disorder. The vast majority of these HNPCC-associated mutations have been proven, or assumed, given the family history of cancer, to be transmitted through several generations. To the best of our knowledge, only a single case of a de novo germline MMR gene mutation (in MSH2) has been reported till now. Here, we report a patient with a de novo mutation in MLH1. We identified a MLH1 Q701X truncating mutation in the blood lymphocytes of a male who had been diagnosed with rectal cancer at the age of 35. His family history of cancer was negative for the first- and second-degree relatives. The mutation could not be detected in the patient' parents and sibling and paternity was confirmed with a set of highly polymorphic markers. Non-penetrance and small family size is the common explanation of verified negative family histories of cancer in patients with a germline MMR gene mutation. However, in addition to some cases explained by non-paternity, de novo germline mutations should be considered as a possible explanation as well. As guidelines that stress not to restrict MMR gene mutation testing to patients with a positive family history are more widely introduced, more cases of de novo MMR gene germline mutations may be revealed.

Core characteristics of the competent general practice trainer, a Delphi study.

INTRODUCTION: The specific skills, attitude, knowledge, and personality characteristics, which should define the competent GP-trainer have been subject of research for many years. What are the most important of these characteristics have yet to be delineated. AIM: The aim of this study is to identify which characteristics are prerequisite for a competent GP-trainer. METHOD: A modified Delphi procedure was used to answer the research question. Earlier qualitative research using focus groups identified 43 characteristics defining the competent GP-trainer. These characteristics were the subject of the Delphi procedure in which 48 experts chosen from the entire field of Dutch General Practice Training participated. RESULTS: After two rounds of the Delphi procedure, 37 characteristics were identified as being important for a competent GP-trainer. The characteristics which were ranked as the most important were 1. a competent GP-trainer is good at giving feedback, 2. dares to give feedback, 3. is critical of the GP-trainee and the learning process, 4. is good at communicating with the GP-trainee, and 5. has respect for the trainee. An important new characteristic has been identified: "being able to inspire reflection in the trainee". CONCLUSION: The core characteristics of the GP-trainer as identified in this research project, form a profile for the ideal GP-trainer to be used as a blueprint for objectives of schooling and for the assessment of GP-trainers.