Exome sequencing in 32 patients with anophthalmia/microphthalmia and developmental eye defects.

Anophthalmia/microphthalmia (A/M) is a genetically heterogeneous birth defect for which the etiology is unknown in more than 50% of patients. We used exome sequencing with the ACE Exome(TM) (Personalis, Inc; 18 cases) and UCSF Genomics Core (21 cases) to sequence 28 patients with A/M and four patients with varied developmental eye defects. In the 28 patients with A/M, we identified de novo mutations in three patients (OTX2, p.(Gln91His), RARB, p.Arg387Cys and GDF6, p.Ala249Glu) and inherited mutations in STRA6 in two patients. In patients with developmental eye defects, a female with cataracts and cardiomyopathy had a de novo COL4A1 mutation, p.(Gly773Arg), expanding the phenotype associated with COL4A1 to include cardiomyopathy. A male with a chorioretinal defect, microcephaly, seizures and sensorineural deafness had two PNPT1 mutations, p.(Ala507Ser) and c.401-1G>A, and we describe eye defects associated with this gene for the first time. Exome sequencing was efficient for identifying mutations in pathogenic genes for which there is no clinical testing available and for identifying cases that expand phenotypic spectra, such as the PNPT1 and COL4A1-associated disorders described here.

Sequence analysis of the mismatch repair gene hMSH6 in the germline of patients with familial and sporadic colorectal cancer.

To evaluate the involvement of hMSH6 in colorectal cancer, the complete coding sequence and flanking intron regions of the gene were analyzed by DNA sequencing in 10 patients fulfilling Bethesda Guidelines for colorectal tumors and 10 patients with sporadic colorectal carcinoma. In addition, 10 mono- and 10 dinucleotide repeat markers were analyzed for microsatellite instability. A protein-truncating T insertion at codon 218 was identified in the index person of a hereditary non-polyposis colorectal cancer (HNPCC)-like kindred and was accompanied by a somatic T deletion in the tumor. The tumor of this patient was positive for mono- but negative for dinucleotide repeat instability and lacked allelic losses at loci frequently affected in colorectal carcinomas. A novel amino acid change, F340S, was found in a patient with sporadic colon and breast cancer and leukemia but was not detected in 246 chromosomes from healthy anonymous blood donors. In addition, we describe 2 silent and 15 intronic sequence variants not previously reported. Although the frequency is low, we present further evidence for hMSH6 germline mutations that predispose patients to HNPCC-like phenotypes and suggest that mono- and dinucleotide repeat instability testing may be useful for distinguishing between individuals harboring an hMSH2 or hMLH1 mutation and a mutation of the hMSH6 gene.

[Can vasomotion be modified by vasoactive substances or hemodilution?]. / Kann die Vasomotion durch vasoaktive Substanzen oder Hämodilution beeinflusst werden?

The maintenance of adequate local tissue perfusion is the result of control mechanisms which reside at the level of microscopic blood vessels: The constriction and relaxation of the vessels whose vascular walls are endowed with smooth muscle. This phenomenon of vasomotion guarantees homeostatic conditions in peripheral tissues. Superior disorders of homeostasis are primarily compensated by activating the vasomotion. The increase of vasomotion results in prostration of the vasomotoric activity and ends in the local biological disaster finally. Therefore an essential therapeutic strategy to avoid or remove peripheral arterial reduced or lacking perfusion is the reactivation of vasomotion. In this pilot study the effect of conservative therapeutic strategies to the vasomotion was investigated with dynamic capillaroscopy in normal perfused areas of the finger nailfold. A significant influence of buflomedil and alprostadil to the capillary blood cell velocity was found. Vasomotion was susceptible to hydroxyethylstarch and alprostadil but was influenced significantly only by buflomedil. Nevertheless we cannot conclude that the applicated substances will have a favourable effect in ischemic areas too, where maximum dilatation still exists.

Thrombolytic treatment and balloon angioplasty in chronic occlusion of the aortic bifurcation.

OBJECTIVE: To evaluate nonsurgical alternatives in reopening chronically occluded aortic bifurcation. DESIGN: Uncontrolled randomized study. SETTING: University-affiliated referral center for vascular diseases. PATIENTS: Twenty-five of 39 consecutive patients with chronic aortoiliac disease including a totally occluded aortic bifurcation were found to be acceptable candidates for an aortobifemoral prosthetic graft. INTERVENTION: Patients were randomly assigned to receive either streptokinase or urokinase or recombinant tissue-type plasminogen activator (rt-PA). In cases of successful thrombolysis and residual obstructions, subsequent balloon angioplasty was attempted. Prosthetic bypass grafting was done if thrombolytic treatment and balloon angioplasty failed. RESULTS: Complete lysis was achieved in 5 of 25 patients (20%). In 10 (40%) patients, lysis showed residual obstructions, which were reopened mechanically in 8 patients; 2 patients had extra-anatomical bypass grafts. Ten patients (40%) without thrombolysis had surgical aortobifemoral bypass grafts. Overall, recanalization and clinical improvement were achieved in 13 of 25 patients (52%) by thrombolytic therapy and subsequent balloon angioplasty. The recanalization rate did not differ among the different thrombolytic drugs. However, rt-PA therapy resulted in reopening after 4 days of treatment; streptokinase, after 6 days; and urokinase, after 9 days (P < 0.005). No major complications or deaths occurred. CONCLUSION: Thrombolytic treatment followed by balloon angioplasty may help avoid the need for aorto-bifemoral prosthetic bypass grafting in more than 50% of patients with chronic aortoiliac disease.

Outpatient percutaneous transluminal angioplasty: preconditions and results.

The present study considers whether percutaneous transluminal angioplasty (PTA) using a balloon catheter may also be performed on an outpatient basis. The prerequisites for the choice of an out-patient procedure were location of the flow obstruction above the knee joint, exclusive catheter recanalisation, absence of any complications during and after the intervention, radiological and vascular surgical standby, patient compliance and adequate social environment. In our 36 patients, 12 PTAs were performed in the pelvic region, 23 in the area of the femoral artery and one in the area of the popliteal artery. The primary success rate in the pelvic region was 100%, that in the femoropopliteal region 91.7%. The cumulative patency rate after an average follow-up period of 4 months was 89% (one early recurrence within 24 hours, 2 late recurrences after 3 and 5 months, respectively). In order to prevent early recurrence, thrombocyte aggregation inhibitors were given in combination with heparin at standard dosage. Two patients had to be hospitalized for monitoring after an aspiration embolectomy in the one case and a major haematoma in the other case. The advantages of a PTA intervention performed on an out-patient basis were the reduced time lag between diagnosis and therapy, full mobility of the patient and minimisation of hospitalization costs. Our results justify the choice of an outpatient schedule for the performance of balloon catheter recanalization in a carefully selected patient population.

Surface coil proton MR imaging at 2 T.

We describe the design and application of surface coils for magnetic resonance (MR) imaging at high resonance frequencies (85 MHz). Circular, rectangular-frame, and reflector-type surface coils were used in the transmit-and-receive mode. With these coils, the required radio frequency power is reduced by factors of two up to 100 with respect to head and body coils. With the small, circular coils, high-resolution images of a small region of interest can be obtained that are free of foldback and motion artifacts originating outside the field of interest. With the rectangular-frame and reflector coils, large fields of view are also accessible. As examples of applications, single- and multiple-section images of the eye, knee, head and shoulder, and spinal cord are provided.

MR imaging using stimulated echoes (STEAM).

The introduction of STEAM (stimulated echo acquisition mode) magnetic resonance (MR) sequences provides access to a variety of MR parameters. T1-weighted and calculated T1 proton MR images of the head of healthy volunteers and a patient with an astrocytoma are presented. MR examinations were performed with a 2.0-T whole-body system. The STEAM T1 method can be used to characterize multiexponential relaxation behavior, to evaluate T1 relaxation times, and to improve the T1 contrast within MR images. Both the measuring time and the spatial resolution are the same as for a conventional image.

Dual-energy Compton scatter tomography.

A dual-energy Compton scatter imaging technique, analogous to that used in computed tomography and conventional radiography, has been explored. It is shown that this technique allows the photoelectric component of the attenuation factors for the primary and scattered radiations to be derived. Compton scatter images of the ear, corrected for photo-attenuation using dual energy, have been obtained with a novel Compton scatter scanner (Comscan) and are presented here. In addition, dual-energy Compton scatter imaging allows photo-effect slice images to be obtained which are a useful extension to the customary Compton images. The application of dual-energy Compton scatter to imaging bony structures and densitometry is illustrated.