From amaurotic idiocy to biochemically defined lipid storage diseases: the first identification of GM1-Gangliosidosis

On February 23rd 1936, a boy-child (“Kn”) died in an asylum near Munich after years of severe congenital dis-ease, which had profoundly impaired his development leading to inability to walk, talk and see as well as to severe epilepsy. While a diagnosis of “Little’s disease” was made during life, his postmortem brain investiga-tion at Munich neuropathology (“Deutsche Forschungsanstalt für Psychiatrie”) revealed the diagnosis of “amaurotic idiocy” (AI). AI, as exemplified by Tay-Sachs-Disease (TSD), back then was not yet understood as a specific inborn error of metabolism encompassing several disease entities. Many neuropathological studies were performed on AI, but the underlying processes could only be revealed by new scientific techniques such as biochemical analysis of nervous tissue, deciphering AI as nervous system lipid storage diseases, e.g. GM2-gangliosidosis. In 1963, Sandhoff & Jatzkewitz published an article on a “biochemically special form of AI” reporting striking differences when comparing their biochemical observations of hallmark features of TSD to tissue composition in a single case: the boy Kn. This was the first description of “GM1-Gangliosidosis”, later understood as resulting from genetically determined deficiency in beta-galactosidase. Here we present illus-trative materials from this historic patient, including selected diagnostic slides from the case “Kn” in virtual microscopy, original records and other illustrative material available. Finally, we present results from genetic analysis performed on archived tissue proving beta-galactosidase-gene mutation, verifying the 1963 interpre-tation as correct. This synopsis shall give a first-hand impression of this milestone finding in neuropathology

From amaurotic idiocy to biochemically defined lipid storage diseases: the first identification of GM1-Gangliosidosis

On February 23rd 1936, a boy-child (“Kn”) died in an asylum near Munich after years of severe congenital dis-ease, which had profoundly impaired his development leading to inability to walk, talk and see as well as to severe epilepsy. While a diagnosis of “Little’s disease” was made during life, his postmortem brain investiga-tion at Munich neuropathology (“Deutsche Forschungsanstalt für Psychiatrie”) revealed the diagnosis of “amaurotic idiocy” (AI). AI, as exemplified by Tay-Sachs-Disease (TSD), back then was not yet understood as a specific inborn error of metabolism encompassing several disease entities. Many neuropathological studies were performed on AI, but the underlying processes could only be revealed by new scientific techniques such as biochemical analysis of nervous tissue, deciphering AI as nervous system lipid storage diseases, e.g. GM2-gangliosidosis. In 1963, Sandhoff & Jatzkewitz published an article on a “biochemically special form of AI” reporting striking differences when comparing their biochemical observations of hallmark features of TSD to tissue composition in a single case: the boy Kn. This was the first description of “GM1-Gangliosidosis”, later understood as resulting from genetically determined deficiency in beta-galactosidase. Here we present illus-trative materials from this historic patient, including selected diagnostic slides from the case “Kn” in virtual microscopy, original records and other illustrative material available. Finally, we present results from genetic analysis performed on archived tissue proving beta-galactosidase-gene mutation, verifying the 1963 interpre-tation as correct. This synopsis shall give a first-hand impression of this milestone finding in neuropathology

Molecular dynamics derived life times of active substrate binding poses explain K_M of laccase mutants

Fungal laccases (EC 1.10.3.2) are important multi-copper oxidases with broad substrate specificity. Laccases from Trametes versicolor (TvL) are among the best-characterized of these enzymes. Mutations in the substrate-binding site of TvL substantially affect K(M), but a molecular understanding of this effect is missing. We explored the effect of TvL mutations on K(M) for the standard laccase substrate 2,6-dimethoxyphenol using 4500 ns of molecular dynamics, docking, and MMGBSA free energy computations. We show that changes in K(M) due to mutation consistently correlate with the dynamics of the substrates within the substrate-binding site. We find that K(M) depends on the lifetime (“dynamic stability”) of the enzyme-substrate complex as commonly assumed. We then further show that MMGBSA-derived free energies of substrate binding in the active pose consistently reproduce large vs. small experimental K(M) values. Our results indicate that hydrophobic packing of the substrate near the T1 binding site of the laccase is instrumental for high turnover via K(M). We also address the more general question of how enzymes such as laccases gain advantage of lower K(M) despite the Sabatier principle, which disfavors a stable enzyme–substrate complex. Our data suggest that the observed K(M) relates directly to the lifetime of the active substrate pose within a protein. In contrast, the thermochemical stability of the enzyme–substrate complex reflects an ensemble average of all enzyme–substrate binding poses. This distinction may explain how enzymes work by favoring longer residence time in the active pose without too favorable general enzyme–substrate interactions, a principle that may aid the rational design of enzymes

Inside Out: Modern Imaging Techniques to Reveal Animal Anatomy

Animal anatomy has traditionally relied on detailed dissections to produce anatomical illustrations, but modern imaging modalities, such as MRI and CT, now represent an enormous resource that allows for fast non-invasive visualizations of animal anatomy in living animals. These modalities also allow for creation of three-dimensional representations that can be of considerable value in the dissemination of anatomical studies. In this methodological review, we present our experiences using MRI, CT and μCT to create advanced representation of animal anatomy, including bones, inner organs and blood vessels in a variety of animals, including fish, amphibians, reptiles, mammals, and spiders. The images have a similar quality to most traditional anatomical drawings and are presented together with interactive movies of the anatomical structures, where the object can be viewed from different angles. Given that clinical scanners found in the majority of larger hospitals are fully suitable for these purposes, we encourage biologists to take advantage of these imaging techniques in creation of three-dimensional graphical representations of internal structures

Low birthweight is associated with a higher incidence of type 2 diabetes over two decades independent of adult BMI and genetic predisposition

Aims/hypothesis: Low birthweight is a risk factor for type 2 diabetes. Most previous studies are based on cross-sectional prevalence data, not designed to study the timing of onset of type 2 diabetes in relation to birthweight. We aimed to examine associations of birthweight with age-specific incidence rate of type 2 diabetes in middle-aged to older adults over two decades. Methods: Adults aged 30–60 years enrolled in the Danish Inter99 cohort in 1999–2001 (baseline examination), with information on birthweight from original birth records from 1939–1971 and without diabetes at baseline, were eligible. Birth records were linked with individual-level data on age at diabetes diagnosis and key covariates. Incidence rates of type 2 diabetes as a function of age, sex and birthweight were modelled using Poisson regression, adjusting for prematurity status at birth, parity, polygenic scores for birthweight and type 2 diabetes, maternal and paternal diabetes history, socioeconomic status and adult BMI. Results: In 4590 participants there were 492 incident type 2 diabetes cases during a mean follow-up of 19 years. Type 2 diabetes incidence rate increased with age, was higher in male participants, and decreased with increasing birthweight (incidence rate ratio [95% CI per 1 kg increase in birthweight] 0.60 [0.48, 0.75]). The inverse association of birthweight with type 2 diabetes incidence was statistically significant across all models and in sensitivity analysis. Conclusions/interpretation: A lower birthweight was associated with increased risk of developing type 2 diabetes independent of adult BMI and genetic risk of type 2 diabetes and birthweight

Changing Preferences for Survival After Hospitalization With Advanced Heart Failure

ObjectivesThis study was designed to analyze how patient preferences for survival versus quality-of-life change after hospitalization with advanced heart failure (HF).BackgroundAlthough patient-centered care is a priority, little is known about preferences to trade length of life for quality among hospitalized patients with advanced HF, and it is not known how those preferences change after hospitalization.MethodsThe time trade-off utility, symptom scores, and 6-min walk distance were measured in 287 patients in the ESCAPE (Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheter Effectiveness) trial at hospitalization and again during 6 months after therapy to relieve congestion.ResultsWillingness to trade was bimodal. At baseline, the median trade for better quality was 3 months' survival time, with a modest relation to symptom severity. Preference for survival time was stable for most patients, but increase after discharge occurred in 98 of 145 (68%) patients initially willing to trade survival time, and was more common with symptom improvement and after therapy guided by pulmonary artery catheters (p = 0.034). Adjusting days alive after hospital discharge for patients' survival preference reduced overall days by 24%, with the largest reduction among patients dying early after discharge (p = 0.0015).ConclusionsPreferences remain in favor of survival for many patients despite advanced HF symptoms, but increase further after hospitalization. The bimodal distribution and the stability of patient preference limit utility as a trial end point, but support its relevance in design of care for an individual patient

Carbohydrate Intake in the Etiology of Crohn's Disease and Ulcerative Colitis

Background: Diet may have a role in the etiology of inflammatory bowel disease. In previous studies, the associations between increased intakes of carbohydrates, sugar, starch, and inflammatory bowel disease are inconsistent. However, few prospective studies have investigated the associations between these macronutrients and incident Crohn's disease (CD) or ulcerative colitis (UC). Methods: A total of 401,326 men and women were recruited between 1991 and 1998. At recruitment, dietary intakes of carbohydrate, sugar, and starch were measured using validated food frequency questionnaires. The cohort was monitored identifying participants who developed incident CD or UC. Cases were matched with 4 controls, and odds ratios were calculated for quintiles of total carbohydrate, sugar, and starch intakes adjusted for total energy intake, body mass index, and smoking. Results: One hundred ten participants developed CD, and 244 participants developed UC during follow-up. The adjusted odds ratio for the highest versus the lowest quintiles of total carbohydrate intake for CD was 0.87, 95% CI = 0.24 to 3.12 and for UC 1.46, 95% CI = 0.62 to 3.46, with no significant trends across quintiles for either (CD, Ptrend = 0.70; UC, Ptrend = 0.41). Similarly, no associations were observed with intakes of total sugar (CD, Ptrend = 0.50; UC, Ptrend = 0.71) or starch (CD, Ptrend = 0.69; UC, Ptrend = 0.17). Conclusions: The lack of associations with these nutrients is in agreement with many case–control studies that have not identified associations with CD or UC. As there is biological plausibility for how specific carbohydrates could have an etiological role in inflammatory bowel disease, future epidemiological work should assess individual carbohydrates, although there does not seem to be a macronutrient effect