Tissue Doppler gated (TDOG) dynamic three-dimensional ultrasound imaging of the fetal heart.

Dynamic three-dimensional (3D) ultrasound imaging of the fetal heart is difficult due to the absence of an electrocardiogram (ECG) signal for synchronization between loops. In this study we introduce tissue Doppler gating (TDOG), a technique in which tissue Doppler data are used to calculate a gating signal. We have applied this cardiac gating method to dynamic 3D reconstructions of the heart of eight fetuses aged 20-24 weeks.The gating signal was derived from the amplitude and frequency contents of the tissue Doppler signal. We used this signal as a replacement for ECG in a 3D-volume reconstruction and visualization, utilizing techniques established in ECG-gated 3D echocardiography.The reliability of the TDOG signal for fetal cardiac cycle detection was experimentally investigated. Simultaneous recordings of tissue Doppler of the heart and continuous wave (CW) spectral Doppler of the umbilical artery (UA) were performed using two independent ultrasound systems, and the TDOG signal from one system was compared to the Doppler spectrum data from the other system. Each recording consisted of a two-dimensional (2D) sector scan, transabdominally and slowly tilted by the operator, covering the fetal heart over approximately 40 cardiac cycles. The total angle of the sweep was estimated by recording a separate loop through the center of the heart, in the elevation direction of the sweep.3D reconstruction and visualization were performed with the EchoPAC-3D software (GE Medical Systems). The 3D data were visualized by showing simultaneous cineloops of three 2D slices, as well as by volume projections running in cineloop.Synchronization of B-mode cineloops with the TDOG signal proved to be sufficiently accurate for reconstruction of high-quality dynamic 3D data. We show one example of a B-mode recording with a frame rate of 96 frames/s over 20 seconds. The reconstruction consists of 31 volumes, each with 49 tilted frames. With the fetal heart positioned 5-8 cm from the transducer, the sampling distances were approximately 0.15 mm in the beam direction, 0.33 degrees approximately 0.37 mm azimuth and 0.45 degrees approximately 0.51 mm elevation. From this single dataset we were able to generate a complete set of classical 2D views (such as four-chamber, three-vessel and short-axis views as well as those of the ascending aorta, aortic and ductal arches and inferior and superior venae cavae) with high image quality adequate for clinical use.     

An examination of the relationships among three outcome scales in schizophrenia.

The functioning of 94 schizophrenic subjects was rated using the Global Assessment Scale, the Strauss and Carpenter Outcome Scale, and the Role Functioning Scale. The convergent validity among the scales was quite modest and highly variable. Solid empirical convergence only occurred when two of the scales each measured social and vocational dimensions of functioning. It is argued that these findings strongly illustrate the need for conceptual and operational consensus in this area. The findings also support the notion of outcome in schizophrenia as a set of distinct, yet linked, dimensions. Other implications of the findings for the definition and measurement of outcome in schizophrenia when using global and multidimensional scales are discussed.     

Lysine 322 in the human IgG3 C(H)2 domain is crucial for antibody dependent complement activation

The classical complement activation cascade of the immune system is initiated by multivalent binding of its first component, C1q, to the Fc region of immunoglobulins in immune complexes. The C1q binding site on mouse IgG2b has been shown to contain the amino acids Glu 318, Lys 320 and Lys 322 in the C(H)2 domain (Duncan, A.R., Winter, G.,1988. The binding site for C1q on IgG. Nature 322 738-740). Identical or closely related motifs are found on all IgGs in all species, and the binding site has therefore been thought to be universal. However, the results from another study indicate that the site is different in human IgG1 molecules (Morgan, A., Jones, N.D., Nesbitt, A.M., et al., 1995. The N-terminal end of the C(H)2 domain of chimeric human IgG1 anti-HLA-DR is necessary for C1q, Fc gamma RI and Fc gamma RIII binding. Immunology 86 319-324). To determine the site(s) responsible for complement activation in anti-NIP-mouse/human IgG3 antibodies, we have mutated amino acids Lys 276, Tyr 278, Asp 280, Glu 318, Lys 320 and Lys 322 in two beta-strands in the C(H)2 domains of human IgG3. In addition, we mutated the Glu 333, which resides in close proximity to the postulated C1q-binding site of mouse IgG2b, as well as Leu 235 in the lower hinge region. All mutants were tested in Antibody Dependent Complement Mediated Lysis (ADCML)(4) assays, where the antigen concentration on target cells was varied and human serum was complement source. Only the mutants that lacked the positively charged side chain of lysine in position 322 showed strong reduction in ADCML, particularly at low antigen density on target cells. Alanine scanning of positions 318 and 320 did not affect ADCML, contrary to what was observed for mouse IgG2b. Neither did a leucine to glutamic acid mutation in position 235 have the effect that has been reported for human IgG1. These results suggest that the complement binding site on human IgG3 molecules is different from that found on mouse IgG2b, and possibly on human IgG1 as well. Thus the contact site may not be conserved.     

Intracerebral abscess caused by Nocardia otitidiscaviarum in a renal transplant patient--cured by evacuation plus antibiotic therapy

We present a 50-year-old female who experienced generalized convulsion 3 months after a successful cadaveric renal transplantation. The first cerebral CT scan indicated cerebral frontal infarction. Repeat CT some days later revealed progressive lesions, and a highly malignant tumor or abscess was suspected. Antifungal and broad-spectrum antibacterial therapy was initiated. Cerebral MRI could not differentiate between these conditions, but a neutrophil granulocyte scan strongly suggested an infectious process. A stereotactic puncture of the frontal lobe was followed by temporary improvement. A severe progressive left-sided hemiparalysis gave indication for a craniotomy with evacuation of the abscess 9 days later. Culture of aspirated pus yielded growth of a gram-positive, rod-shaped bacterium, later identified as Nocardia otitidiscaviarum by sequencing the 16S rRNA. The patient was treated with meropenem plus rifampicin intravenously for 6 weeks followed by oral ciprofloxacin and rifampicin for 2 months. Due to pharmacokinetic interaction with rifampicin, the prednisolone dose was doubled, and the dose of tacrolimus had to be tripled for maintenance of adequate trough concentrations. Five months following cessation of antibiotic treatment, the patient has regained normal strength and function in her left-sided extremities and has a serum creatinine level of about 160 micromol/l (1.8 mg/dl).     

Angiogenesis is an early event in the development of chemically induced skin tumors

In this study we have analyzed the vascular response induced in the two- stage carcinogenesis model in SENCAR mice. The role of angiogenesis has not been explored in this model, which is the paradigm of multistage carcinogenesis and a model for neoplastic lesions derived from exophytic premalignant lesions (e.g. colon carcinoma, bladder papilloma). We investigated if angiogenesis is involved in the formation of papillomas and in the progression from papilloma to carcinoma. To this end we analyzed the vasculature of normal and hyperplastic skin, focal epidermal hyperplasias that are precursors of papillomas, papillomas at different stages and squamous cell carcinomas. We also analyzed the vascularization of papillomas induced in two strains of mice that differ in their susceptibility to malignant progression. We show here that angiogenesis is turned on in the earliest stages of papilloma formation. In late stages, regardless of state of progression, the predominant response is an increase in the size of blood vessels. Thus, in the SENCAR mouse model, representative of exophytic tumors, the angiogenesis switch is a very early event, probably mechanistically related to the development of the primarily exophytic lesions. Therefore, the density of blood vessels cannot be used as a predictor of malignant progression in this model.      

The pentose phosphate pathway and pyruvate carboxylation after neonatal hypoxic-ischemic brain injury

The neonatal brain is vulnerable to oxidative stress, and the pentose phosphate pathway (PPP) may be of particular importance to limit the injury. Furthermore, in the neonatal brain, neurons depend on de novo synthesis of neurotransmitters via pyruvate carboxylase (PC) in astrocytes to increase neurotransmitter pools. In the adult brain, PPP activity increases in response to various injuries while pyruvate carboxylation is reduced after ischemia. However, little is known about the response of these pathways after neonatal hypoxia-ischemia (HI). To this end, 7-day-old rats were subjected to unilateral carotid artery ligation followed by hypoxia. Animals were injected with [1,2-¹³C]glucose during the recovery phase and extracts of cerebral hemispheres ipsi- and contralateral to the operation were analyzed using ¹H- and ¹³C-NMR (nuclear magnetic resonance) spectroscopy and high-performance liquid chromatography (HPLC). After HI, glucose levels were increased and there was evidence of mitochondrial hypometabolism in both hemispheres. Moreover, metabolism via PPP was reduced bilaterally. Ipsilateral glucose metabolism via PC was reduced, but PC activity was relatively preserved compared with glucose metabolism via pyruvate dehydrogenase. The observed reduction in PPP activity after HI may contribute to the increased susceptibility of the neonatal brain to oxidative stress.