Noninvasive detection of graft rejection by in vivo (19) F MRI in the early stage.

Diagnosis of transplant rejection requires tissue biopsy and entails risks. Here, we describe a new (19) F MRI approach for noninvasive visualization of organ rejection via the macrophage host response. For this, we employed biochemically inert emulsified perfluorocarbons (PFCs), known to be preferentially phagocytized by monocytes and macrophages. Isografts from C57BL/6 or allografts from C57B10.A mice were heterotopically transplanted into C57BL/6 recipients. PFCs were applied intravenously followed by (1) H/(19) F MRI at 9.4 T 24 h after injection. (1) H images showed a similar position and anatomy of the graft in the abdomen for both cases. However, corresponding (19) F signals were only observed in allogenic tissue. (1) H/(19) F MRI enabled us to detect the initial immune response not later than 3 days after surgery, when conventional parameters did not reveal any signs of rejection. In allografts, the observed (19) F signal strongly increased with time and correlated with the extent of rejection. In separate experiments, rapamycin was used to demonstrate the ability of (19) F MRI to monitor immunosuppressive therapy. Thus, PFCs can serve as positive contrast agent for the early detection of transplant rejection by (19) F MRI with high spatial resolution and an excellent degree of specificity due to lack of any (19) F background.

Biglycan is required for adaptive remodeling after myocardial infarction.

BACKGROUND: After myocardial infarction (MI), extensive remodeling of extracellular matrix contributes to scar formation and preservation of hemodynamic function. On the other hand, adverse and excessive extracellular matrix remodeling leads to fibrosis and impaired function. The present study investigates the role of the small leucine-rich proteoglycan biglycan during cardiac extracellular matrix remodeling and cardiac hemodynamics after MI. METHODS AND RESULTS: Experimental MI was induced in wild-type (WT) and bgn(-/0) mice by permanent ligation of the left anterior descending coronary artery. Biglycan expression was strongly increased at 3, 7, and 14 days after MI in WT mice. bgn(-/0) mice showed increased mortality rates after MI as a result of frequent left ventricular (LV) ruptures. Furthermore, tensile strength of the LV derived from bgn(-/0) mice 21 days after MI was reduced as measured ex vivo. Collagen matrix organization was severely impaired in bgn(-/0) mice, as shown by birefringence analysis of Sirius red staining and electron microscopy of collagen fibrils. At 21 days after MI, LV hemodynamic parameters were assessed by pressure-volume measurements in vivo to obtain LV end-diastolic pressure, end-diastolic volume, and end-systolic volume. bgn(-/0) mice were characterized by aggravated LV dilation evidenced by increased LV end-diastolic volume (bgn(-/0), 111+/-4.2 microL versus WT, 96+/-4.4 microL; P<0.05) and LV end-diastolic pressure (bgn(-/0), 24+/-2.7 versus WT, 18+/-1.8 mm Hg; P<0.05) and severely impaired LV function (EF, bgn(-/0), 12+/-2% versus WT, 21+/-4%; P<0.05) 21 days after MI. CONCLUSIONS: Biglycan is required for stable collagen matrix formation of infarct scars and for preservation of cardiac hemodynamic function.

Targeting murine heart and brain: visualisation conditions for multi-pinhole SPECT with (99m)Tc- and (123)I-labelled probes.

PURPOSE: The study serves to optimise conditions for multi-pinhole SPECT small animal imaging of (123)I- and (99m)Tc-labelled radiopharmaceuticals with different distributions in murine heart and brain and to investigate detection and dose range thresholds for verification of differences in tracer uptake. METHODS: A Triad 88/Trionix system with three 6-pinhole collimators was used for investigation of dose requirements for imaging of the dopamine D(2) receptor ligand [(123)I]IBZM and the cerebral perfusion tracer [(99m)Tc]HMPAO (1.2-0.4 MBq/g body weight) in healthy mice. The fatty acid [(123)I]IPPA (0.94 +/- 0.05 MBq/g body weight) and the perfusion tracer [(99m)Tc]sestamibi (3.8 +/- 0.45 MBq/g body weight) were applied to cardiomyopathic mice overexpressing the prostaglandin EP(3) receptor. RESULTS: In vivo imaging and in vitro data revealed 45 kBq total cerebral uptake and 201 kBq cardiac uptake as thresholds for visualisation of striatal [(123)I]IBZM and of cardiac [(99m)Tc]sestamibi using 100 and 150 s acquisition time, respectively. Alterations of maximal cerebral uptake of [(123)I]IBZM by >20% (116 kBq) were verified with the prerequisite of 50% striatal of total uptake. The labelling with [(99m)Tc]sestamibi revealed a 30% lower uptake in cardiomyopathic hearts compared to wild types. [(123)I]IPPA uptake could be visualised at activity doses of 0.8 MBq/g body weight. CONCLUSION: Multi-pinhole SPECT enables detection of alterations of the cerebral uptake of (123)I- and (99m)Tc-labelled tracers in an appropriate dose range in murine models targeting physiological processes in brain and heart. The thresholds of detection for differences in the tracer uptake determined under the conditions of our experiments well reflect distinctions in molar activity and uptake characteristics of the tracers.

T2 mapping cardiovascular magnetic resonance identifies the presence of myocardial inflammation in patients with dilated cardiomyopathy as compared to endomyocardial biopsy.

Aims: The aim of this study was to determine the value of T2 mapping for the non-invasive assessment of myocardial inflammation in different stages of systolic left ventricular dysfunction in dilated cardiomyopathy (DCM) in comparison with endomyocardial biopsy (EMB). Methods and results: A total of 132 subjects were enrolled between 2013 and 2016 (62 controls and 70 patients with DCM). All patients underwent CMR at 1.5 T and received coronary angiogram and EMB. CMR applied standard protocols including T2 mapping with Gradient And SpinEcho sequence (GRASE). Global T2 relaxation time was significantly increased in patients with DCM compared to the healthy controls (T2 time DCM vs. controls: 65.9 ± 6.2 vs. 60.0 ± 4.2 ms; P < 0.001). Of note, patients with the presence of inflammatory cells in EMB exhibited further elevation of T2 values (T2 time in patients with the presence of inflammatory cells vs. T2 time in patients without: 68.8 ± 5.8 vs. 64.7 ± 5.9 ms; P = 0.02). Receiver operating characteristic analysis of our data deciphered a global myocardial T2 time >65.3 ms as the best cut-off for distinction between the healthy controls and patients with myocardial inflammation [sensitivity 93%, specificity 90%, P < 0.01, area under the curve (AUC) 0.95]. In patients with DCM, this threshold identified patients with biopsy-proven inflammation with a sensitivity of 79% and specificity 58% (AUC 0.72). Conclusion: In patients with DCM and presence of inflammatory cells in the myocardium, myocardial T2 relaxation times may help to non-invasively detect myocardial inflammation. Although there is an overlap of T2 values between patients and healthy controls, T2 mapping may facilitate the identification of patients who may benefit from EMB for therapeutic decision-making.

Role of T2 mapping in left ventricular reverse remodeling after TAVR.

BACKGROUND: Patients with severe aortic stenosis (AS) are subjected to left ventricular hypertrophy (LVH) with increasing morbidity and mortality. Transcatheter aortic valve replacement (TAVR) induces reverse left ventricular remodeling which can be monitored by cardiovascular magnetic resonance (CMR). CMR is able to analyze myocardial tissue properties by magnetic relaxation times (parametric CMR). The objective of this study was to study myocardial T2 relaxation in reverse ventricular remodeling after TAVR. METHODS: Forty-three patients with severe AS (19 males, 81.9 ±â€¯4.9 years) underwent CMR with T2 mapping before and 6 months after TAVR. A cohort of age- and gender-matched volunteers served as controls. Analyzed parameters included left ventricular ejection fraction (LV-EF), mass indexed to body surface area (LVMi), interventricular septum thickness (IVS), end-diastolic volume (LVEDV), global longitudinal strain (GLS), peak diastolic strain rate (SRe) and myocardial T2 values. RESULTS: CMR characteristics for patients with AS displayed LVH concomitant to elevated myocardial T2 values, reduced GLS and SRe. Patients with T2 values above 70.2 ms at baseline were characterized by eccentric hypertrophy with reduced LV-EF. T2 values decreased after TAVR (67.4 ±â€¯3.4 to 63.3 ±â€¯4.2 ms, p < 0.01) during left ventricular remodeling. Patients with T2 values above 70.2 ms at baseline exhibited pronounced reverse remodeling which proved to be a significant predictor of LV-EF improvement and LVEDV reduction in uni- and multivariate analyses. CONCLUSIONS: Multiparametric CMR can be used to characterize myocardial hypertrophy due to severe AS and to monitor myocardial adaptations after TAVR. It may provide additional information in the prediction of left ventricular remodeling after TAVR.

Hemispheric asymmetries on computed tomographic scans in schizophrenia and mania. A controlled study and a critical review.

A major reason for reassessing hemispheric asymmetries in schizophrenics by computed tomography is the methodologic shortcomings of previously published measurement techniques. We used completely blind measurements, multiple measurements performed by two independent examiners of each region of the brain, and an SE of measurement with a confidence level of P less than .01 to define significant asymmetry. The frequency of reversed occipital asymmetry was significantly higher in the 36 schizophrenic than in the 18 manic right-handed male patients. Furthermore, when all of the previously published techniques were applied to these patients, the frequency of such a reversal was consistently higher in the schizophrenic than in the manic group. Further investigation of hemispheric asymmetries in schizophrenics is warranted.

Cerebral ventricular enlargement in subtypes of chronic schizophrenia.

A computed tomographic study of the brain in 55 young men with chronic schizophrenia and 27 age- and sex-matched control subjects showed a significantly higher ventricle-brain ratio (VBR) in the patients with chronic schizophrenia. Using the Tsuang-Winokur criteria, the sample was classified into paranoid and nonparanoid-hebephrenic subtypes. Nonparanoid patients who did not fulfill the criteria for hebephrenia were grouped as a nonparanoid-undifferentiated subtype. All three groups of subtypes had a significantly higher mean VBR than control subjects. Among the schizophrenia subtypes, the paranoid and nonparanoid-hebephrenic groups were not different, and both had a significantly larger mean VBR than the nonparanoid-undifferentiated group. The results suggest that although the extent of ventricular enlargement varies among schizophrenia subtypes, they all show a significant enlargement compared with the control group. Also, in contrast with previous reports linking a high VBR with negative symptoms, poor prognosis, and impaired cognition, the data in this study show the largest mean VBR in the paranoid patients who generally have a good premorbid history, positive symptoms, less impaired cognition, and relatively better prognosis.

Cerebral ventricular enlargement in schizophrenia. A preliminary follow-up study.

Lateral cerebral ventricular enlargement is now known to occur in some schizophrenic patients. To determine whether ventriculomegaly in schizophrenia is a static vs progressive process, we conducted a follow-up computed tomographic brain scan study on 11 young male patients, three years after initial scans were obtained. No significant change was found in the mean ventricles-brain ratio of this small schizophrenic sample after three years. Four of 11 patients showed noticeable increases (greater than 50%) in individual ratio. Methodologic problems are discussed and the need for follow-up studies as a research strategy is emphasized.

Monocyte imaging after myocardial infarction with 19F MRI at 3 T: a pilot study in explanted porcine hearts.

AIM: Inflammation is a hallmark of cardiac healing after myocardial infarction and it determines subsequent cardiovascular morbidity and mortality. The aim of the present study was to explore whether inflammation imaging with two perfluorocarbon (PFC) nanoemulsions and fluorine magnetic resonance imaging ((19)F MRI) is feasible at 3.0 T with sufficient signal-to-noise ratio (SNR) using explanted hearts, an (19)F surface coil and dedicated MR sequences. METHODS AND RESULTS: Acute myocardial infarction (AMI) was induced by balloon angioplasty (50 min) of the distal left anterior descending artery in 12 pigs. One day thereafter, PFCs were injected intravenously to label circulating monocytes. Either emulsified perfluoro-15-crown-5 ether or already clinically applied perfluorooctyl bromide (PFOB) was applied. Four days after AMI and immediately after gadolinium administration, hearts were explanted and imaged with a 3.0 T Achieva MRI scanner. (19)F MRI could be acquired with an SNR of >15 using an in-plane resolution of 2 × 2 mm(2) within <20 min for both agents. Combined late gadolinium enhancement (LGE) and (19)F MRI revealed that (19)F signal was inhomogenously distributed across LGE myocardium reflecting patchy macrophage infiltration as confirmed by histology. In whole hearts, we found an apico-basal (19)F gradient within LGE-positive myocardium. The (19)F-positive volume was always smaller than LGE volume. Ex vivo experiments on isolated monocytes revealed that pig and human cells phagocytize PFCs even more avidly than mouse monocytes. CONCLUSION: This pilot study demonstrates that (19)F MRI at 3.0 T with clinically applicable PFOB is feasible, thus highlighting the potential of (19)F MRI to monitor the inflammatory response after AMI.

Morphological cerebral asymmetries in autistic children.

A group of 36 children with infantile autism and various neurological disorders matched closely on age, sex, and handedness underwent computerized tomographic (CT) scanning of the brain. All CT scans were assessed blindly and independently by a neuroradiologist. Two techniques modified from two published CT studies concerning cerebral asymmetries were used for measuring frontal and parieto-occipital asymmetries. The present study found that the CT pattern of cerebral asymmetries in autistic children is the same as observed in the neurological patients. Contradictory results were noted when the distributions of such asymmetries between the present autistic group and normal adults included in two previous studies were compared. One of the striking findings in this study is that the brains of the present autistic patients seem to be more symmetric than those of the normals. This finding, however, is also noted in the present matched controls as well as in the dyslexic children previously studied by other investigators. Further sophisticated studies are needed to explain the difference in the brain morphology between normals and children with a developmental disorder or a neurological disorder.

Third ventricular enlargement on CT scans in schizophrenia: association with cerebellar atrophy.

The width, length, and ventricle-to-brain area ratio (VBR) of the third ventricle were measured in 55 consecutive young male schizophrenic patients and 27 matched control subjects. No differences in third ventricular dimensions were found between the two groups. However, schizophrenic patients with cerebellar atrophy had a significantly greater mean third ventricular length. Correlations of third ventricular VBR with lateral ventricular VBR, but not with sulcal widening, were found. The possible existence of a subset of schizophrenic patients defined by cerebellar atrophy and third ventricular enlargement is discussed.

Cerebellar atrophy in schizophrenia and affective disorder.

The authors evaluated 108 patients with schizophrenia, 50 patients with affective disorder, and 74 age- and sex-matched control subjects by CAT scan for evidence of global cerebellar atrophy. No difference was found between control subjects and schizophrenic patients or between control subjects and patients with affective disorder. This study does not confirm previous reports linking cerebellar atrophy to schizophrenia.

Ventricular enlargement in schizophrenia: definition and prevalence.

Ventricular enlargement in schizophrenia as measured by ventricular-brain ratio (VBR) has been described by three different research groups. Because of the possibility that the samples might not be representative of the broad population of schizophrenic patients, questions have been raised about generalizability. The authors report on ventricular enlargement in a rigorously defined but representative sample of schizophrenic patients intermittently hospitalized but living in the community. They provide additional evidence that ventricular enlargement does occur in schizophrenic patients, although not at rates as high as those previously reported. Issues related to the definition of ventricular enlargement, as well as the effects of sampling and choice of a control group, are discussed.

Cerebral hemiatrophy, hypoplasia of internal carotid artery, and intracranial aneurysm. A rare association occurring in an infant.

A 4-month-old child with a very rare association of primary (congenital) left cerebral hypoplasia, hypoplasia of the left internal carotid artery, and giant anterior communicating artery aneurysm was seen. The aneurysm was detected and treated before rupture. We briefly reviewed the literature on agenesis (hypoplasia) of the internal carotid artery, intracranial aneurysms in childhood, and primary cerebral hypoplasia. It is proposed that cerebral arteriography, cranial computed tomography, or magnetic resonance imaging be performed in all children with primary cerebral hemihypoplasia to establish an etiologic diagnosis and, more importantly, to detect and treat possible associated intracranial aneurysms before they become symptomatic.

The decompositions of N-(substituted benzalamino)phthalimide radical cations embody ion-neutral complexes and Stevenson's rule.

A previously unreported series of N-(substituted benzalamino)phthalimides was investigated by using the combined techniques of high resolution electron ionization mass spectrometry, metastable decomposition, and collisional activation mass spectrometry. The predominate fragmentation pathway is a McLafferty-type rearrangement. There also occurs, to a lesser extent, a transfer of hydrogen that originates from a substituent remote from the phthalimide moiety and terminates on the phthalimide, The process is interpreted as proceeding via an ion-neutral complex. The effects of substituents on both of the aforementioned fragmentation pathways provide a striking example that gives quantitative evidence for Stevenson's rule. The substituent effects are responsible for a trend in ion abundance that shows a sharp reversal at approximately the ionization energy of the iminium isomer of the phthalimide molecular ion.

Ion cloud manipulation using the radiofrequency-only-mode as an improvement for high mass detection in fourier transform mass spectrometry.

It has been difficult to achieve the expected high resolving power for high-mass biomolecule ions in Fourier transform mass spectrometry. Our hypothesis is that ion clouds produced by laser desorption or injection are diffuse and produce poor signals. To test the hypothesis, clouds of benzene molecular ions produced by electron ionization were purposefully expanded via magnetron mode excitation and characterized by a new experimental sequence for cloud sectional analysis. The expanded cloud was then successfully focused to the trap center by using a high-pressure dynamic event (radiofrequency-only mode). The expanded cloud in a conventional cubic trap produces no detectable signal, whereas the focused cloud in a compensated trap yields a high-resolution signal with good signal-to-noise ratio.

Inhibition of H2O2 production by iodoaldehydes in cultured dog thyroid cells.

2-Iodohexadecanal (IHDA) has been identified as a major thyroid iodolipid which can be formed upon addition of iodine to the vinyl ether group of plasmalogens (Pereira et al., 1990). In order to test whether IHDA plays a role in the thyroid autoregulation by iodide, we have investigated its effects on the production of H2O2 by cultured dog thyroid cells. IHDA inhibited the formation of H2O2 in dog thyroid cells stimulated by carbamylcholine (CCHOL). In the presence of BSA, which potentiated its action, the effect of IHDA was maximal after 2 h and had an IC50 around 5 microM. The effect of IHDA was not decreased by methimazole, which abolished the inhibition by iodide. IHDA also inhibited the stimulatory effect of bradykinin, but had only a marginal effect on the production of H2O2 induced by ionomycin or phorbol 12-myristate 13-acetate (PMA). The accumulation of inositol phosphates in CCHOL-stimulated thyroid cells was decreased by IHDA. As evaluated by measurements of 51Cr release and [3H]thymidine incorporation into DNA, IHDA had no adverse effect on thyroid cell viability. Several analogs of IHDA, of which the synthesis is described, have been tested for their inhibitory activity. This allowed the identification of two major structural features required for the biological activity: the carbonyl group at C1 and an halogen atom at C2, with iodine conferring a greater activity than bromine, while chlorine and fluorine were inactive. In conclusion, IHDA inhibits the production of H2O2 in CCHOL-stimulated dog thyroid cells by decreasing the phospholipase C cascade activity. This effect involves both the aldehyde function and the iodine atom. These results suggest that IHDA might be the mediator of some of the regulatory actions of iodide on the thyroid gland.

Inhibition of human thyroid adenylyl cyclase by 2-iodoaldehydes.

2-Iodohexadecanal (IHDA), which can be formed upon addition of iodine to the vinyl ether group of plasmalogens, has been identified as a major thyroid iodolipid (Pereira et al. (1990) J. Biol. Chem. 265, 17018-17025). In this study, we have investigated the possibility that it would be a mediator of the inhibitory effect of iodide on thyroid adenylyl cyclase. In human thyroid membranes, IHDA inhibited the adenylyl cyclase activity stimulated by thyrotropin (TSH), GTP-gamma-S or forskolin (FSK), whereas it did not decrease the specific binding of TSH to its receptors. The inhibitory effect on the cyclase reached a maximum after a 1-h-pre-incubation of the membranes with IHDA at 30 degrees C and was poorly reversible. It was also observed following a 4-h incubation with IHDA at 4 degrees C, a condition in which adenylyl cyclase is protected against heat inactivation. IHDA decreased the Vmax of adenylyl cyclase, but had no effect on the Km for ATPMg2-.IHDA also inhibited the FSK-stimulated adenylyl cyclase activity in liver and kidney cortex membranes, but had no effect on the Mg(2+)-ATPase activity of thyroid membranes. The inhibitory effect of IHDA has also been demonstrated in intact cells. As in membranes, IHDA decreased the rise in cAMP induced by TSH in cultured dog thyroid cells and this inhibition was maintained following pretreatment of the cells with pertussis toxin. In order to evaluate the specificity of the IHDA action, various analogs have been synthesized. This study has permitted the identification of two major structural features required for the inhibition of human thyroid adenylyl cyclase; the terminal aldehyde function and an iodine atom at C2, other halogens being ineffective. In conclusion, we have shown that IHDA exerts a direct inhibitory effect at or near adenylyl cyclase; all the properties of this effect characterized so far are identical to those of the adenylyl cyclase inhibition obtained following the exposure of thyroid tissue to iodide.

Cerebral asymmetry in subtypes of schizophrenia.

CT scans of 26 nonparanoid and 10 paranoid right-handed male schizophrenics were examined. Multiple measurements were made of each region of the brain and a standard error of measurement with a confidence level of p less than .01 was used to define significant asymmetry. Three aspects of cerebral asymmetry, i.e., local hemispheric width, local hemispheric protrusion, and regional hemispheric size, were examined. Paranoid and nonparanoid patients were similar in their patterns of frontal asymmetries. However, a substantial proportion of nonparanoid schizophrenics had wider, longer, and larger right parieto-occipital lobes compared to paranoid patients.

Cortical atrophy in schizophrenia and mania: a comparative CT study.

Fifty-five schizophrenic, 24 manic and 27 control subjects, all males between 20-45 years of age, were examined for structural brain abnormalities with computerized tomography (CT) scans. Both manic and schizophrenic samples had significantly larger ventricles than the control group. Cerebral atrophy was more frequent in schizophrenia, while cerebellar atrophy was more frequent in mania. An association between increased ventricular size and cerebellar atrophy was found in mania but not in schizophrenia. Cerebral atrophy was not associated with ventricular enlargement in either disorder. Implications of these findings are discussed.