The Use of Variant Maps to Explore Domain-Specific Mutations of FGFR1.

Here we describe the genotype-phenotype correlations of diseases caused by variants in Fibroblast Growth Factor Receptor 1 ( FGFR1) and report a novel, de novo variant in FGFR1 in an individual with multiple congenital anomalies. The proband presented with bilateral cleft lip and palate, malformed auricles, and bilateral ectrodactyly of his hands and feet at birth. He was later diagnosed with diabetes insipidus, spastic quadriplegia, developmental delay, agenesis of the corpus callosum, and enlargement of the third cerebral ventricle. We noted the substantial phenotypic overlap with individuals with Hartsfield syndrome, the rare combination of holoprosencephaly and ectrodactyly. Sequencing of FGFR1 identified a previously unreported de novo variant in exon 11 (p.Gly487Cys), which we modeled to determine its predicted effect on the protein structure. Although it was not predicted to significantly alter protein folding stability, it is possible this variant leads to the formation of nonnative intra- or intermolecular disulfide bonds. We then mapped this and other disease-associated variants to a 3-dimensional model of FGFR1 to assess which protein domains harbored the highest number of pathogenic changes. We observed the greatest number of variants within the domains involved in FGF binding and FGFR activation. To further explore the contribution of each variant to disease, we recorded the phenotype resulting from each FGFR1 variant to generate a series of phenotype-specific protein maps and compared our results to benign variants appearing in control databases. It is our hope that the use of phenotypic maps such as these will further the understanding of genetic disease in general and diseases caused by variation in FGFR1 specifically.

Polarizable atomic multipole X-ray refinement: weighting schemes for macromolecular diffraction.

In the past, weighting between the sum of chemical and data-based targets in macromolecular crystallographic refinement was based on comparing the gradients or Hessian diagonal terms of the two potential functions. Here, limitations of this scheme are demonstrated, especially in the context of a maximum-likelihood target that is inherently weighted by the model and data errors. In fact, the congruence between the maximum-likelihood target and a chemical potential based on polarizable atomic multipole electrostatics evaluated with Ewald summation has opened the door to a transferable static weight. An optimal static weight is derived from first principles and is demonstrated to be transferable across a broad range of data resolutions in the context of a recent implementation of X-ray crystallographic refinement using the polarizable AMOEBA force field and it is shown that the resulting models are balanced with respect to optimizing both R(free) and MolProbity scores. Conversely, the classical automatic weighting scheme is shown to lead to underfitting or overfitting of the data and poor model geometry. The benefits of this approach for low-resolution diffraction data, where the need for prior chemical information is of particular importance, are also highlighted. It is demonstrated that this method is transferable between low- and high-resolution maximum-likelihood-based crystallographic refinement, which proves for the first time that resolution-dependent parameterization of either the weight or the chemical potential is unnecessary.

A smooth and differentiable bulk-solvent model for macromolecular diffraction.

Inclusion of low-resolution data in macromolecular crystallography requires a model for the bulk solvent. Previous methods have used a binary mask to accomplish this, which has proven to be very effective, but the mask is discontinuous at the solute-solvent boundary (i.e. the mask value jumps from zero to one) and is not differentiable with respect to atomic parameters. Here, two algorithms are introduced for computing bulk-solvent models using either a polynomial switch or a smoothly thresholded product of Gaussians, and both models are shown to be efficient and differentiable with respect to atomic coordinates. These alternative bulk-solvent models offer algorithmic improvements, while showing similar agreement of the model with the observed amplitudes relative to the binary model as monitored using R, R(free) and differences between experimental and model phases. As with the standard solvent models, the alternative models improve the agreement primarily with lower resolution (>6 A) data versus no bulk solvent. The models are easily implemented into crystallographic software packages and can be used as a general method for bulk-solvent correction in macromolecular crystallography.

[Stress-associated hypertension in the work place: results of the STARLET project]. / Stressassoziierte Hypertonie am Arbeitsplatz--Ergebnisse des STARLET-Projekts.

BACKGROUND AND OBJECTIVE: To assess the influence of work stress and initial blood pressure on the prognosis of hypertension. SUBJECTS AND METHODS: In a prospective, controlled, multicentre, observational study, ambulatory 24-hour blood pressure measurements (ABPM) of employees from different work places were recorded at the work place on working days. Recurrent ABPM were performed for up to 5 years on 3448 subjects (mean age 44.6 years) who gave consent for follow-up. Subjects with hypertension were told to consult their family doctor so that they could receive antihypertensive treatment (the angiotensin receptor blocker eprosartan, an ACE-inhibitor or a beta-blocker were recommended for initial treatment). Subjects were classified as being in mental strain (stress-positive [stress+]/ stress-negative [stress-]), using standardized questionnaires. RESULTS: Only 1242 (36.0%) of the 3448 employees (69.% males) were normotensives. Only 166 (7.5%) of the 2206 hypertensives had normal ABPMs (<135/85 mmHg) and received antihypertensive treatment at the time of inclusion into the trial. During follow-up 57.8% of patients were treated with eprosartan or ACE-inhibitors, 34.6% with beta-blockers. By the time of the final visit 80.5% of hypertensives had achieved improvement of systolic and/or diastolic blood pressures (29.1% normotensive). Patients with hypertensive ABPM at baseline had more cardiovascular events than normotensives (normotensives 3.0%; grade 1 7.8%, grade 2-3 9.8%). Hypertensive ABPMs at the last follow up or an increase in blood pressure grade were associated with higher event rates than normotensives (stable normotensives 1.8% events vs. stable hypertensives 7.9%, vs. worsening or grade 2-3: 9.1%) More hypertensives were classified as stress+ than normotensives. Persons classified as stress- (or changing to stress-) had fewer events (6.2%) than those regarded as stress+ or changing to stress+ (7.1%). Persons regarded as stable stress- had lower mean blood pressures than those who were stable stress+. Change to another stress group was associated with an increase or decrease of mean blood pressure. CONCLUSIONS: Many employed people are hypertensive at work and are not treated adequately. ABPM control and antihypertensive treatment based on eprosartan, ACE-inhibitors or beta-blockers resulted in a significant increase in the number of patients with lower blood-pressure levels and a reduction in cardiovascular events. Patients under mental strain were more likely to be hypertensive. Mental strain was associated with changes in blood pressure.

[Relevance of childhood trauma for later drug dependence]. / Der Einfluss kindlicher Traumatisierung auf eine spätere Drogenabhängigkeit.

UNLABELLED: There are various publications on the impact of the experience of violence and abuse during childhood as it relates to future substance abuse. This study aims to examine how childhood abuse differentiated by type and severity, impacts on future potential for substance abuse. Particular attention is paid to specific psychological symptoms and degree of addiction. METHODS: 100 patients being treated for substance abuse completed a questionnaire where they were questioned about a childhood history of sexual, physical and emotional abuse, neglect and family violence. Psychopathology and severity of addiction were assessed using the EuropASI and SCL-90. RESULTS: The results demonstrated that the respondents had been exposed to multiple risk factors in their childhood. The subjects were differentiated into groups according to type of abuse. The type and severity of psychological symptoms were measured by the SCL-90-R. The type and severity of psychosocial and environmental problems were measured by the EuropASI. It was shown that patients with a history of abuse had a significantly higher incidence of symptomatology, particularly of co-morbid psychological conditions. When differentiating victims of abuse by sex, women showed a significantly stronger impairment in 2 categories. These were insecurity in social contact and phobic fear. For all other variables of impairment, there were no differences between men and women. The severity of the various types of abuse was then correlated to the course of the disease. A strong correlation was found between severe forms of abuse where victims were involved in sexual abuse or family violence and future severe psychological symptoms.

Diagnosis of impaired glucose tolerance in hypertensive patients in daily clinical practice.

Many patients with hypertension suffer from impaired glucose tolerance or type 2 diabetes mellitus. Although these diagnoses are generally simple and reliable, it is more difficult to diagnose impaired glucose tolerance. As the gold standard (oral glucose tolerance test (OGTT)) is complicated to perform, a simpler alternative would be useful. The aims of the Pre-Diabetes Score study are to correlate demographic and/or laboratory parameters that are clinically simple to determine with the results of the OGTT and to determine the diagnostic significance of the combinations of parameters with regard to impaired glucose tolerance. A total of 260 patients were included in the evaluation; 39% had impaired glucose tolerance and 12% had diabetes mellitus. A combination of HbA1c of > or =6%, a venous fasting glucose of > or =110 mg/dl, an age of > or =55 years, a systolic blood pressure of > or =140 mmHg and an enlarged waist size is highly predictive of impaired glucose tolerance.

Assessing the accuracy of a prototype drill guide for fibular graft placement in femoral head necrosis.

A prototype drill guide was developed to improve the accuracy of surgical placement of fibular grafts for the treatment of femoral head necrosis. To document performance, two tantalum beads, one placed on the lateral femoral shaft and the other embedded in the superior portion of the head, were used to define the desired graft tract in a series of seven surrogate femurs. Two orthogonal x-rays of the drill guide mounted on each surrogate femur were taken both before and after drilling. After stylus digitization of each x-ray pair, a computer program calculated the achieved accuracy of the drill. The mean of the absolute error between the desired versus obtained position of the drill tip was 3.68 mm (s.d. 1.24 mm), and the random component of the error was 1.98 mm (s.d. 0.89 mm).