Clinical outcome of subchromosomal events detected by whole-genome noninvasive prenatal testing.

OBJECTIVE: A novel algorithm to identify fetal microdeletion events in maternal plasma has been developed and used in clinical laboratory-based noninvasive prenatal testing. We used this approach to identify the subchromosomal events 5pdel, 22q11del, 15qdel, 1p36del, 4pdel, 11qdel, and 8qdel in routine testing. We describe the clinical outcomes of those samples identified with these subchromosomal events. METHODS: Blood samples from high-risk pregnant women submitted for noninvasive prenatal testing were analyzed using low coverage whole genome massively parallel sequencing. Sequencing data were analyzed using a novel algorithm to detect trisomies and microdeletions. RESULTS: In testing 175,393 samples, 55 subchromosomal deletions were reported. The overall positive predictive value for each subchromosomal aberration ranged from 60% to 100% for cases with diagnostic and clinical follow-up information. The total false positive rate was 0.0017% for confirmed false positives results; false negative rate and sensitivity were not conclusively determined. CONCLUSION: Noninvasive testing can be expanded into the detection of subchromosomal copy number variations, while maintaining overall high test specificity. In the current setting, our results demonstrate high positive predictive values for testing of rare subchromosomal deletions.

Current hematological findings in cobalamin deficiency. A study of 201 consecutive patients with documented cobalamin deficiency.

With the introduction of automated assays for measuring serum cobalamin levels over the last decades, the hematological manifestations related to cobalamin deficiency have been changed from the description reported in 'old' studies or textbooks. We studied the hematological manifestations or abnormalities in 201 patients (median age: 67 +/- 6 years) with well-documented cobalamin deficiency (mean serum vitamin B12 levels 125 +/- 47 pg/ml) extracted from an observational cohort study (1995-2003). Assessment included clinical features, blood count and morphological review. Hematological abnormalities were reported in at least two-third of the patients: anemia (37%), leukopenia (13.9%), thrombopenia (9.9%), macrocytosis (54%) and hypegmented neutrophils (32%). The mean hemoglobin level was 10.3 +/- 0.4 g/dl and the mean erythrocyte cell volume 98.9 +/- 25.6 fl. Approximately 10% of the patients have life-threatening hematological manifestations with documented symptomatic pancytopenia (5%), 'pseudo' thrombotic microangiopathy (Moschkowitz; 2.5%), severe anemia (defined as Hb levels <6 g/dl; 2.5%) and hemolytic anemia (1.5%). Correction of the hematological abnormalities was achieved in at least two-thirds of the patients, equally well in patients treated with either intramuscular or oral crystalline cyanocobalamin. This study, based on real data from a single institution with a large number of consecutive patients with well-documented cobalamin deficiency, confirms several 'older' findings that were previously reported before the 1990s in several studies and in textbooks.

[3 Tesla MRI: successful results with higher field strengths]. / 3 Tesla-MRT: Der Erfolg höherer Feldstärken.

The recent development of 3 Tesla MRI (3T MRI) has been fueled by promise of increased signal-to-noise ratio(SNR). Many are excited about the opportunity to not only use the increased SNR for clearer images, but also the chance to exchange it for better resolution or faster scans. These possibilities have caused a rapid increase in the market for 3T MRI, where the faster scanning tips an already advantageous economic outlook in favor of the user. As a result, the global market for 3T has grown from a research only market just a few years ago to an ever-increasing clinically oriented customer base. There are, however, significant obstacles to 3T MRI presented by the physics at higher field strengths. For example, the T1 relaxation times are prolonged with increasing magnet field strength. Further, the increased RF-energy deposition (SAR), the larger the chemical shift and the stronger susceptibility effect have to be considered as challenges. It is critical that one looks at both the advantages and disadvantages of using 3T. While there are many issues to address aand a number of different methods for doing so, to properly tackle each of these concerns will take time and effort on the part od researchers and clinicians. The optimization of 3T MRI scanning will have to be a combined effort, though much of the work to date has been in neuroimaging. Multiple applications have been explored in addition to clinical anatomical imaging, where resolution is improved showing structure in the brain never seen before in human MRI. Body and cardiac imaging provide a great challenge but are also achievable at 3T. As an example, the full range of clinical applications currently achieved on today's state-of-the-art 1.5T cardiac MR scanners has also been demonstrated at 3T. In the body, the full range of contrast is available over large fields of view allowing whole liver studies in the clinic or, as needed, one may choose a smaller field of view for high-resolution imaging of the pancreas. The ability to increase resolution for musculoskeletal imaging has provided previously unseen detail. Bone structure, cartilage, and tendons and ligaments can be clearly visualized and pathology more easily detected due to an increased image quality. As the increase in field strength continues, a push to look at 7T has begun. The design philosophy is to keep the system as similar as possible, while changing only the frequency-dependent components. To date, both animal and human imaging have been performed on a whole body 7T scanner. Results show promise for both detailed imaging and functional MRI, but the road ahead is too long to be able to predict where it will end. The move toward higher field strengths is an exciting adventure in which 3T plays the role of trailblazer.

Distinct and interactive effects of d-amphetamine and haloperidol on levels of neurotensin and its mRNA in subterritories in the dorsal and ventral striatum of the rat.

Striatal tissue concentrations of neurotensin, expression of neurotensin/neuromedin N (NT/N) mRNA, and numbers of neurotensin-immunoreactive neurons are increased by d-amphetamine (amph), which stimulates dopamine release in the striatum, and haloperidol (hal), a dopamine receptor antagonist with high affinity for D2-like receptors. The possibility that the effects of these drugs involve distinct subpopulations of striatal neurons was addressed in this study, in which the relative numbers and distributions of striatal neuron profiles containing neurotensin immunoreactivity and/or NT/N mRNA were compared following administrations of hal, amph, hal and amph co-administered, and vehicle. Fourteen striatal subterritories in caudate-putamen, nucleus accumbens, and olfactory tubercle were evaluated. Amph produced increases in the expression of neurotensin preferentially in the ventromedial and caudodorsal subterritories of the caudate-putamen, the rostrobasal cell cluster and lateral shell of the nucleus accumbens, and the olfactory tubercle. Haloperidol produced increased neurotensin expression in much of dorsal and ventral striatum, most prominently in the rostral, dorsomedial and ventrolateral quadrants of the caudate-putamen, and in the rostrobasal cell cluster, rostral pole, medial and lateral shell of the nucleus accumbens and the olfactory tubercle. The numbers of neurons responding to amph and hal in all subterritories following co-administration of the two drugs were significantly less than the summed numbers responding individually to amph and hal. Furthermore, in the subterritories where immunohistochemically detectable responses elicited by amph exceeded those produced by hal, co-administration of the two drugs resulted in responses comparable to those elicited by hal given alone. It is suggested that some of the reported anti-dopaminergic behavioral effects of basal ganglia neurotensin may be attenuated in conditions of reduced dopamine neurotransmission.