Is bipolar I disorder heterogeneous?

Abstract.Objectives: The question whether bipolar I disorder should be subdivided into a preponderantly manic group (M) with no depression or only mild depression (Md) and a nuclear manic-depressive group (MD) has been rarely studied although the problem was raised more than 50 years ago. This paper seeks to elucidate this question by contributing further data.Methods: 406 patients with mood disorders hospitalised at some time during the period 1959–1963 were followed-up every five years until 1985; mortality data were collected up to 1997. Data on episodes, outcome, suicides and attempted suicides, alcohol and substance abuse/dependence and long-term medication, as well as on personality (melancholic and manic type) were collected. Major mood disorders were subclassified according to their hospitalisation for depression (D) and/or mania (M).Results: 30 manic patients (M/Md), 130 bipolar I (MD), 60 bipolar II patients (Dm) and 186 major depressive patients (D) were compared. The manic group differed from the bipolar I group in several variables: better school achievement, milder course of the illness (fewer recurrences), significantly less suicidality and a trend to less chronicity and more recovery. Manic patients required less long-term medication than bipolars and they differed in personality types from bipolars, the personality of manic patients being more often of the manic rather than the melancholic type, they were also more aggressive than bipolars. The family history data showed that the overall morbidity risk of first degree relatives of manic patients was significantly lower than that of bipolar patients.Conclusions: In accord with several other studies our data point to the existence of a more manic (M/Md) group of bipolar subjects. The diagnosis predicts a better course, lower suicidality and fewer and different treatment needs than does nuclear bipolar I (MD) disorder. The M/Md groups, as clinically interesting subgroups of the mood spectrum, should become a target of further research.     

Single-cell analysis of mtDNA deletion levels in sporadic amyotrophic lateral sclerosis

One possible cause for the neuronal loss in sporadic amyotrophic lateral sclerosis (S-ALS) is an increase of free radicals, which may produce oxidative damage to susceptible biomolecules, which, in turn, can damage the mitochondrial DNA (mtDNA). Following laser microdissection of single motor neurons from paraffin-embedded autopsy tissue, we analyzed the presence of a common mtDNA deletion, the 5 kb common deletion (CD). Spinal cord neurons showed slightly higher CD detection rate in patients than controls (94% vs 75%). No significant differences were found between patients and controls for neurons derived from other motor or non-motor regions. A PCR assay of serial DNA dilutions (10-fold) showed no CD level differences between motor neurons in S-ALS and controls. These data suggest that neuronal death in S-ALS is not associated with significant accumulation of mtDNA deletions.     

Contrast-enhanced three-dimensional pulmonary perfusion magnetic resonance imaging: intraindividual comparison of 1.0 M gadobutrol and 0.5 M Gd-DTPA at three dose levels

RATIONALE AND OBJECTIVES: To compare 1.0 M gadobutrol and 0.5 M Gd-DTPA for contrast-enhanced three-dimensional pulmonary perfusion magnetic resonance imaging (3D MRI). MATERIALS AND METHODS: Ten healthy volunteers (3 females; 7 males; median age, 27 years; age range, 18-31 years) were examined with contrast-enhanced dynamic 3D MRI with parallel acquisition technique (FLASH 3D; reconstruction algorithm: generalized autocalibrating partially parallel acquisitions; acceleration factor: 2; TE/TR/alpha: 0.8/1.9 milliseconds/40 degrees; FOV: 500 x 375 mm; matrix: 256 x 86; slab thickness: 180 mm; 36 partitions; voxel size: 4.4 x 2 x 5 mm; TA: 1.48 seconds). Twenty-five consecutive data sets were acquired after intravenous injection of 0.025, 0.05, and 0.1 mmol/kg body weight of gadobutrol and Gd-DTPA. Quantitative measurements of peak signal-to-noise ratios (SNR) of both lungs were performed independently by 3 readers. Bolus transit times through the lungs were assessed from signal intensity time curves. RESULTS: The peak SNR in the lungs was comparable between gadobutrol and Gd-DTPA at all dose levels (15.7 vs. 15.5 at 0.1 mmol/kg bw; 12.9 vs. 12.5 at 0.05 mmol/kg bw; 7.6 vs. 8.9 at 0.025 mmol/kg bw). A dose of 0.1 mmol/kg achieved the highest peak SNR compared with all other dose levels (P < 0.05). A higher peak SNR was observed in gravity dependent lung (P < 0.05). Despite different injection volumes, transit times of the contrast bolus did not differ between both agents. CONCLUSION: Higher concentrated gadolinium chelates offer no advantage over standard 0.5 M Gd-DTPA for contrast-enhanced 3D MRI of lung perfusion.     

Evaluation of chest motion and volumetry during the breathing cycle by dynamic MRI in healthy subjects: comparison with pulmonary function tests

RATIONALE AND OBJECTIVES: To investigate diaphragm and chest wall motion during the whole breathing cycle using magnetic resonance imaging (MRI) and a volumetric model in correlation with spirometry. MATERIALS AND METHODS: Breathing cycles of 15 healthy volunteers were examined using a trueFISP sequence (5 slices in 3 planes, 3 images per second). Time-distance curves were calculated and correlated to spirometry. A model for vital capacity (VC), continuous time-dependent vital capacity (tVC), and investigating the influence of horizontal and vertical parameters on tVC was introduced. RESULTS: Time-distance curves of the breathing cycle using MRI correlated highly significant with spirometry (P < 0.0001). VC calculated by the model was similar to VC measured in spirometry (5.00 L vs. 5.15 L). tVC correlated highly significantly with spirometry (P < 0.0001). Vertical parameters had a more profound influence on tVC change than horizontal parameters. CONCLUSIONS: Dynamic MRI is a simple noninvasive method to evaluate local chest wall motion and respiratory mechanics. It widens the repertoire of tools for lung examination with a high temporal resolution.     

Low mechanical index contrast-enhanced ultrasound better reflects high arterial perfusion of liver metastases than arterial phase computed tomography

RATIONALE AND OBJECTIVES: We investigated whether observing the arterial vascularization of liver metastases by contrast-enhanced ultrasound with low mechanical index (low-MI) imaging offers additional diagnostic information for the characterization of the liver lesions. METHODS: Twenty nine patients with untreated liver metastases of different primaries were examined. Measurements were performed using a low frame rate, low-MI pulse inversion technique after injection of 2.4 mL SonoVue. The relative maximum signal intensity of the liver lesions related to the normal liver tissue was quantified. Ultrasound findings were compared with contrast-enhanced, dual-phase computed tomography (CT) using a pattern-based classification scheme. RESULTS: Compared with contrast-enhanced CT, this modality better detects arterial perfusion. Metastases, even those usually considered hypovascularized, often showed homogeneous enhancement (66%) and higher arterial vascularization than normal liver tissue. CT did not show a comparable vascularization pattern (P < 0.001) or any similarly early signal intensity (P < 0.001). CONCLUSIONS: Contrast-enhanced CT may not be able to visualize short-lasting but large differences of the arterial perfusion of liver metastases, as does contrast-enhanced low-MI ultrasound. This offers new methods for their characterization and for monitoring of therapeutic effects.     

EUS in the diagnosis of early chronic pancreatitis: a prospective follow-up study

BACKGROUND: The aim of this prospective, follow-up study was to investigate the value of EUS in the diagnosis of alcohol-induced chronic pancreatitis. METHODS: One hundred thirty patients with known (n = 51) or clinically suspected (n = 79) chronic pancreatitis were included. Patients with a history of chronic use of alcohol and recurrent abdominal pain underwent endoscopic retrograde pancreatography and EUS. The 38 patients with normal endoscopic retrograde pancreatography but signs of chronic pancreatitis on EUS were included in a follow-up program. RESULTS: All patients with chronic pancreatitis confirmed by retrograde pancreatography (n = 92; 70.8%) had ductal or parenchymal changes detectable with EUS. Among 38 patients (29.2%) with normal retrograde pancreatography, 32 (84.2%) presented with morphologic features consistent with chronic pancreatitis by EUS. During follow-up (median 18 months, range 6-25 months) chronic pancreatitis was confirmed by repeat endoscopic retrograde pancreatography in 22 of these 32 patients (68.8%). On the basis of these follow-up data, the sensitivities of EUS and endoscopic retrograde pancreatography at the time of the first examination were, respectively, 100% and 80.7% (p < 0.001). CONCLUSION: EUS detects chronic pancreatitis in all cases if endoscopic retrograde pancreatography was suggestive for chronic pancreatitis. However, EUS is more sensitive than endoscopic retrograde pancreatography in the detection of early morphologic changes of chronic pancreatitis in patients with abdominal pain and a history of chronic and continued ingestion of alcohol.     

Drug interaction of spirapril hydrochloride monohydrate and hydrochlorothiazide. A clinical study to compare the pharmacokinetics after administration of spirapril hydrochloride monohydrate tablets,hydrochlorothiazide tablets and fixed combination bi-layer tablets

The potential influence of concomitantly administered hydrochlorothiazide (CAS 58-93-5) on the pharmacokinetics of spirapril (CAS 94841-17-5)/spiraprilat (CAS 83602-05-5) and of concomitantly administered spirapril on the pharmacokinetics of hydrochlorothiazide was investigated in an open, randomised, 3-way crossover study in 12 healthy male subjects. The test drug was a newly developed bi-layer tablet containing a fixed combination of spirapril hydrochloride monohydrate and hydrochlorothiazide (Quadroplus). The reference formulations were tablets containing solely spirapril hydrochloride monohydrate (Quadropril) or hydrochlorothiazide (produced exclusively for study medication). For spirapril, spiraprilat and hydrochlorothiazide the 90% confidence intervals of the AUC(0-infinity) as a measure for the extent of absorption were entirely included within the equivalence range of 0.8 to 1.25 and the 90% confidence intervals of the Cmax as a measure for the rate of absorption were entirely included within the extended equivalence range of 0.7 to 1.43. Therefore, bioequivalence was concluded for the test and reference formulations. The results suggest that hydrochlorothiazide does not interact in the fixed combination with the pharmacokinetics of spirapril and vice versa.     

The effects of nifedipine on ventricular fibrillation mean frequency in a porcine model of prolonged cardiopulmonary resuscitation

We assessed the effects of a calcium channel blocker versus saline placebo on ventricular fibrillation mean frequency and hemodynamic variables during prolonged cardiopulmonary resuscitation (CPR). Before cardiac arrest, 10 animals were randomly assigned to receive either nifedipine (0.64 mg/kg; n = 5) or saline placebo (n = 5) over 10 min. Immediately after drug administration, ventricular fibrillation was induced. After 4 min of cardiac arrest and 18 min of basic life support CPR, defibrillation was attempted. Ninety seconds after the induction of cardiac arrest, ventricular fibrillation mean frequency was significantly (P < 0.01) increased in nifedipine versus placebo pigs (mean +/- SD: 12.4 +/- 2.1 Hz versus 8 +/- 0.7 Hz). From 2 to 18.5 min after the induction of cardiac arrest, no differences in ventricular fibrillation mean frequency were detected between groups. Before defibrillation, ventricular fibrillation mean frequency was significantly (P < 0.05) increased in nifedipine versus placebo animals (9.7 +/- 1.2 Hz versus 7.1 +/- 1.3 Hz). Coronary perfusion pressure was significantly lower in the nifedipine than in the placebo group from the induction of ventricular fibrillation to 11.5 min of cardiac arrest; no animal had a return of spontaneous circulation after defibrillation. In conclusion, nifedipine, but not saline placebo, prevented a rapid decrease of ventricular fibrillation mean frequency after the induction of cardiac arrest and maintained ventricular fibrillation mean frequency at approximately 10 Hz during prolonged CPR; this was nevertheless associated with no defibrillation success. IMPLICATIONS: This study evaluates the effects of a calcium channel blocker on ventricular fibrillation mean frequency, hemodynamic variables, and resuscitability during prolonged cardiopulmonary resuscitation (CPR) in pigs. Nifedipine, but not saline placebo, prevented a rapid decrease of ventricular fibrillation mean frequency after the induction of cardiac arrest and maintained ventricular fibrillation mean frequency at approximately 10 Hz during prolonged CPR but did not improve resuscitability.     

Protein kinase C delta activation and translocation to the nucleus are required for fatty acid-induced apoptosis of insulin-secreting cells

Insulin resistance as well as pancreatic beta-cell failure can be induced by elevated free fatty acid (FFA) levels. We studied the mechanisms of FFA-induced apoptosis in rat and human beta-cells. Chronic treatment with high physiological levels of saturated fatty acids (palmitate and stearate), but not with monounsaturated (palmitoleate and oleate) or polyunsaturated fatty acids (linoleate), triggers apoptosis in approximately 20% of cultured RIN1046-38 cells. Apoptosis restricted to saturated FFAs was also observed in primary cultured human beta-cells, suggesting that this mechanism is potentially relevant in vivo in humans. To further analyze FFA-induced signaling pathways leading to apoptosis, we used RIN1046-38 cells. Apoptosis was accompanied by a rapid (within 15 min) nuclear translocation of protein kinase C (PKC)-delta and subsequent lamin B1 disassembly. This translocation was impaired by the phospholipase C inhibitor U-73122, which also substantially reduced apoptosis. Furthermore, lamin B1 disassembly and apoptosis were decreased by cell transfection with a dominant-negative mutant form of PKC-delta. These data suggest that nuclear translocation and kinase activity of PKC-delta are both necessary for saturated fatty acid-induced apoptosis.