Image guided aneurysm surgery in a Brainsuite® ioMRI Miyabi 1.5 T environment.

OBJECTIVE: Current literature only gives sparse account of aneurysm surgery in an intraoperative MRI environment. After installation of a BrainSuite(®) ioMRI Miyabi 1.5 T at our institution the aim of the present preliminary study was to evaluate feasibility, pros and cons of aneurysm surgery in this special setting. MATERIAL AND METHODS: Since February 2009, during a 3 months period we performed elective image guided aneurysm surgery in 4 ACM and 1 ACOM aneurysm (four patients) in this ioMRI setting. The patients' heads were rigidly fixed in the Noras 8-Channel OR Head Coil. Our imaging protocol included MP-RAGE, T2-TSE axial, TOF-MRA and diffusion-/perfusion-imaging immediately before surgery and after clip application. Presurgical 3D-planning was performed using the iPlan®-Software. RESULTS: All five aneurysms were operated without temporary clipping. There were no intra- or postoperative complications. Patient positioning and head fixation with the integrated Noras Head Clamp was feasible, but there were significant limitations particularly with regard to more complex approaches and patient physiognomy. Image quality especially TOF-MRA was good in 4, insufficient in 1 aneurysm. Presurgical planning especially vessel extraction from TOF-MRA was possible but certainly needs significant future improvement. Diffusion- and perfusion weighted examinations yielded good image quality. CONCLUSION: Our limited experience is encouraging so far. Further improvement particularly concerning flexibility of patient positioning and presurgical 3D-planning for vascular procedures is most necessary. As a future perspective image guided aneurysm surgery in an ioMRI-environment may be helpful especially in complex aneurysms and provide neurosurgeons and neuroanaesthesiologists with additional information about cerebral haemodynamics and perfusion pattern in the vascular territory distal to the target vessel.

Microsatellite instability in colorectal adenocarcinoma cell lines that have full-length adenomatous polyposis coli protein.

Almost 20% of colon cancers are characterized by genomic instability at simple repeated sequences. This instability is the result of a deficient DNA mismatch repair system. Sporadic, as well as hereditary carcinomas of the proximal colon display this effect. In this study, we examined colorectal adenocarcinoma cell lines, with or without wild-type adenomatous polyposis coli (APC) protein, for the presence of microsatellite instability. The three cell lines that maintained full-length APC protein also displayed the highest level of instability, suggesting a negative correlation between APC mutations and microsatellite instability. This data, in addition to other studies that show a negative correlation between microsatellite instability and mutations in p53 and K-ras, support the idea of a second pathway for colorectal cancer development.

Microsatellite instability in aberrant crypt foci from human colons.

Aberrant crypt foci (ACF) are distinct microscopic lesions of the colon thought to be the earliest identifiable precursors of colon cancer. As precursors of colon cancer, ACF may contain mutations in genes that are altered early in colorectal tumorigenesis. Candidates for these genes include APC, K-Ras, and those of the DNA mismatch repair system. Some colon cancers with mutations in DNA mismatch repair genes are characterized by genomic instability at simple repeated sequences, also known as microsatellite instability. In this study, we analyzed 19 ACF (> or = 20 crypts/focus) and adjoining, microscopically normal colonic mucosa from 10 colon cancer patients for the presence of microsatellite instability. DNA from two ACF from two different patients displayed microsatellite instability. None of the DNA samples from normal mucosa displayed microsatellite instability. These observations support the role of ACF as a precursor to colon cancer and provide some evidence that mutations in DNA mismatch repair genes are early somatic events in colon cancer.

IGSF1 Deficiency: Lessons From an Extensive Case Series and Recommendations for Clinical Management.

CONTEXT: Mutations in the immunoglobulin superfamily, member 1 (IGSF1) gene cause the X-linked IGSF1 deficiency syndrome consisting of central hypothyroidism, delayed pubertal testosterone rise, adult macroorchidism, variable prolactin deficiency, and occasionally transient partial GH deficiency. Since our first reports, we discovered 20 new families with 18 new pathogenic IGSF1 mutations. OBJECTIVE: We aimed to share data on the largest cohort of patients with IGSF1 deficiency to date and formulate recommendations for clinical management. METHODS: We collected clinical and biochemical characteristics of 69 male patients (35 children, 34 adults) and 56 female IGSF1 mutation carriers (three children, 53 adults) from 30 unrelated families according to a standardized clinical protocol. At evaluation, boys were treated with levothyroxine in 89%, adult males in 44%, and females in 5% of cases. RESULTS: Additional symptoms in male patients included small thyroid gland volume (74%), high birth weight (25%), and large head circumference (20%). In general, the timing of pubertal testicular growth was normal or even premature, in contrast to a late rise in T levels. Late adrenarche was observed in patients with prolactin deficiency, and adult dehydroepiandrosterone concentrations were decreased in 40%. Hypocortisolism was observed in 6 of 28 evaluated newborns, although cortisol concentrations were normal later. Waist circumference of male patients was increased in 60%, but blood lipids were normal. Female carriers showed low free T4 (FT4) and low-normal FT4 in 18% and 60%, respectively, delayed age at menarche in 31%, mild prolactin deficiency in 22%, increased waist circumference in 57%, and a negative correlation between FT4 concentrations and metabolic parameters. CONCLUSION: IGSF1 deficiency represents the most common genetic cause of central hypothyroidism and is associated with multiple other characteristics. Based on these results, we provide recommendations for mutational analysis, endocrine work-up, and long-term care.

Exploring Innovative Solutions for Quality of Life and Care of Bed-Ridden Nursing Home Residents through Codesign Sessions.

Bed-ridden nursing home residents are in need of environments which are homelike and facilitate the provision of care. Design guidance for this group of older people is limited. This study concerned the exploration and generation of innovative environmental enrichment scenarios for bed-ridden residents. This exploration was conducted through a combination of participatory action research with user-centred design involving 56 professional stakeholders in interactive work sessions. This study identified numerous design solutions, both concepts and products that are available on the marketplace and that on a higher level relate to improvements in resident autonomy and the supply of technological items and architectural features. The methodology chosen can be used to explore the creative potential of stakeholders from the domain of healthcare in product innovation.

Mechanistic basis for unexpected bioavailability enhancement of polyelectrolyte complexes incorporating BCS class III drugs and carrageenans.

The objective of this study was to investigate the potential of λ-carrageenan to work as an absorption modifying excipient in combination with formulations of BCS class 3 substances. Trospium chloride was used as a model BCS class 3 substance. Polyelectrolyte complexes of trospium and λ-carrageenan were produced by layer-by-layer complexation. A λ-carrageenan-containing formulation was administered either in capsules size 9 to rats by gavage or directly into ligated intestinal loops of rats. Exceptionally strong variations were observed in the plasma concentrations of the rats that received λ-carrageenan compared to the control group, but enhanced plasma concentrations were observed only in some of the rats. In vitro permeability studies were performed across Caco2-monolayers and across excised segments of rat jejunum in a modified Ussing chamber to learn more about the mechanism of absorption enhancement. The complex did not show any effect in Caco2-cells, but led to a major enhancement of permeability across excised segments in modified Ussing chambers. Carrageenan did not lead to alterations of tight junctions. The bioavailability enhancing effect thus was most likely due to an interaction of the polyelectrolyte-drug complex with the mucus, which provided an intimate contact between the drug and the absorbing surface. A similar effect was also achievable with other types of carrageenan and was also transferable to other compounds. In conclusion, λ-carrageenan-drug complexes show interesting excipient-drug-epithelium interactions - however, for full utilization of the permeation enhancing potential, an intimate and reproducible contact between absorbing epithelia and the complex is needed.

The IGSF1 deficiency syndrome: characteristics of male and female patients.

CONTEXT: Ig superfamily member 1 (IGSF1) deficiency was recently discovered as a novel X-linked cause of central hypothyroidism (CeH) and macro-orchidism. However, clinical and biochemical data regarding growth, puberty, and metabolic outcome, as well as features of female carriers, are scarce. OBJECTIVE: Our objective was to investigate clinical and biochemical characteristics associated with IGSF1 deficiency in both sexes. METHODS: All patients (n = 42, 24 males) from 10 families examined in the university clinics of Leiden, Amsterdam, Cambridge, and Milan were included in this case series. Detailed clinical data were collected with an identical protocol, and biochemical measurements were performed in a central laboratory. RESULTS: Male patients (age 0-87 years, 17 index cases and 7 from family studies) showed CeH (100%), hypoprolactinemia (n = 16, 67%), and transient partial GH deficiency (n = 3, 13%). Pubertal testosterone production was delayed, as were the growth spurt and pubic hair development. However, testicular growth started at a normal age and attained macro-orchid size in all evaluable adults. Body mass index, percent fat, and waist circumference tended to be elevated. The metabolic syndrome was present in 4 of 5 patients over 55 years of age. Heterozygous female carriers (age 32-80 years) showed CeH in 6 of 18 cases (33%), hypoprolactinemia in 2 (11%), and GH deficiency in none. As in men, body mass index, percent fat, and waist circumference were relatively high, and the metabolic syndrome was present in 3 cases. CONCLUSION: In male patients, the X-linked IGSF1 deficiency syndrome is characterized by CeH, hypoprolactinemia, delayed puberty, macro-orchidism, and increased body weight. A subset of female carriers also exhibits CeH.

[The endoscopic management of the cubital tunnel syndrome--an anatomical study and first clinical results]. / Die endoskopische Dekompression des Kubitaltunnelsyndroms--Anatomische Grundlagen und erste klinische Ergebnisse.

Besides the carpal tunnel syndrome, the cubital tunnel syndrome (CuTS) represents the second most frequent nerve entrapment syndrome. The current gold standard for surgical therapy consists of simple open decompression. Recently, an endoscopic procedure involving long-distance decompression of the ulnar nerve has been developed and this is the topic of the present study. The first part of this paper describes preliminary anatomic investigations on 22 cadaver arms. In every sample we observed a thickening of the submuscular membrane between the heads of the flexor carpi ulnaris (FCU) which surrounds the ulnar nerve. This was especially the case for the first 10 cm from the medial epicondyle In the second part we report our experiences with this endoscopic decompression procedure in 36 patients. With this endoscopic decompression we achieved good to very good results according to the Bishop classification in 28 patients (78%). On the basis of anatomic considerations and our current experience, the endoscopic procedure seems to represent a promising alternative to simple decompression.

"De novo" design of peptides with specific lipid-binding properties.

In this study, we describe an in silico method to design peptides that can be made of non-natural amino acids and elicit specific membrane-interacting properties. The originality of the method holds in the capacities developed to design peptides from any non-natural amino acids as easily as from natural ones, and to test the structure stability by an angular dynamics rather than the currently-used molecular dynamics. The goal of this study was to design a non-natural tilted peptide. Tilted peptides are short protein fragments able to destabilize lipid membranes and characterized by an asymmetric distribution of hydrophobic residues along their helix structure axis. The method is based on the random generation of peptides and their selection on three main criteria: mean hydrophobicity and the presence of at least one polar residue; tilted insertion at the level of the acyl chains of lipids of a membrane; and conformational stability in that hydrophobic phase. From 10,000,000 randomly-generated peptides, four met all the criteria. One was synthesized and tested for its lipid-destabilizing properties. Biophysical assays showed that the "de novo" peptide made of non-natural amino acids is helical either in solution or into lipids as tested by Fourier transform infrared spectroscopy and is able to induce liposome fusion. These results are in agreement with the calculations and validate the theoretical approach.

Regenerative lesions in ulcerative colitis are characterized by microsatellite mutation.

An increased risk of colon cancer has been observed in individuals with long-standing ulcerative colitis (UC). In order to identify molecular genetic markers for the development of neoplasia in UC individuals, we isolated DNA from normal, regenerative, and dysplastic mucosa, as well as from colon carcinomas from UC patients, and evaluated it for the presence of mutations in microsatellite DNA sequences. DNAs isolated from regenerative mucosa displayed microsatellite mutation. These observations suggest that DNA mutation is an early event in the UC disease process.