Anxiolytic-like profiles of histamine H3 receptor agonists in animal models of anxiety: a comparative study with antidepressants and benzodiazepine anxiolytic

Rationale  Histamine H3 receptor functions as a presynaptic auto- and hetero-receptor on histaminergic and non-histaminergic neurons in the brain regulating the synaptic release of numerous neurotransmitters. Therefore, the ligands for this receptor have been proposed to be of therapeutic interest for the treatment of various neuropsychiatric disorders. At present, however, the psychopharmacological profiles of H3 ligands, particularly H3 agonists, have not been extensively studied. Objective  The present study investigated the anxiolytic-like profiles of H3-selective agonists in a variety of classical (benzodiazepine-sensitive) and atypical (antidepressant-effective) animal models of anxiety. Comparator drugs used were diazepam and both fluvoxamine and desipramine in the former and latter models, respectively. Results  H3 agonist R-α-methylhistamine and immepip were inactive in rat elevated plus maze test and Vogel type conflict test where diazepam (5 mg/kg) produced significant anxiolytic-like effects. Meanwhile, these H3 agonists (10–30 mg/kg) significantly reduced isolation-induced vocalizations in guinea pig pups and isolation-induced aggressive behavior in mouse resident–intruder test. Moreover, in rat conditioned fear stress test, R-α-methylhistamine (30 mg/kg) and immepip (10 mg/kg) significantly decreased freezing time, which were completely reversed by concomitant treatment with H3 antagonist, thioperamide (10 mg/kg). In contrast to the limited efficacy obtained with desipramine (30 mg/kg), fluvoxamine (20–60 mg/kg) exhibited anxiolytic-like effects in all the latter three atypical models. Conclusions  These data suggest that the H3 agonists may have anxiolytic-like effects similar to those of selective serotonin reuptake inhibitors but not benzodiazepine anxiolytics and represent a novel strategy for the treatment of some anxiety disorders in which selective serotonin reuptake inhibitors are prescribed.     

De novo autoimmune hepatitis following living-donor liver transplantation for primary biliary cirrhosis

Abstract:  Since first being described in 1998, de novo autoimmune hepatitis (AIH) after liver transplantation has been reported in several cases suffering from non-autoimmune liver diseases and primary biliary cirrhosis (PBC). Glutathione S-transferase (GST) T1 genotype mismatches between donor and recipient have also been suggested to constitute a risk factor for de novo AIH. Here, we report a 33-yr-old woman who presented complaining of marked fatigue and jaundice four yr after living-donor liver transplantation for PBC. On examination, transaminase levels were highly elevated and ANA and antimitochondrial antibody M2 were positive. Histological findings showed zonal necrosis with lymphoplasmacytic infiltration closely resembling AIH. She had pretreatment AIH score of 16 and 19 points after relapse of de novo AIH. Two color fluorescence in situ hybridization with X and Y chromosome-specific probes clearly revealed that the hepatocytes were of donor origin and lymphocytes were of patient origin. The GSTT1 genotype of the patient and the donor were the same null type, suggesting that mechanisms other than GSTT1 mismatches may exist in de novo AIH development. In conclusion, recipient immune cells attacked the allogeneic transplanted liver of the patient via de novo AIH, although the exact participation of autoimmune mechanisms is unclear.     

The lacZ gene under the control of the 7 kb of human dystrophin muscle specific promoter is expressed in cardiac muscle but not in adult skeletal muscle in transgenic mice

In previous transgenic studies, we reported a 0.9 kb fragment from a mouse dystrophin muscle promoter that contains the regulatory elements required for expression of dystrophin only in the right heart. In this study, to further characterize the regulation of muscle type of promoter, we analyzed promoter activity and tissue specificity using a total 14 kb fragment around the human dystrophin muscular-specific exon 1 in vitro and in vivo. In vitro analysis showed that the lacZ construct of the 7 kb promoter and 7 kb intron 1 was expressed 2.5 times as strong as the lacZ construct of only the 7 kb promoter in C2/4 myotubes. In vivo analysis revealed expression of both constructs in the whole heart, skeletal muscle and vascular smooth muscle in embryos. However, in adults, the expression in skeletal muscle disappeared. We conclude that the 7 kb upstream region and the 7 kb intronic region included responsible elements for the expression in the heart, but not in skeletal muscle in vivo. It is possible that a strong enhancer element for skeletal muscle exists in some other region.     

Anti-carbonic anhydrase II antibody in autoimmune pancreatitis and tubulointerstitial nephritis

Nephrol Dial Transplant 2007; 22: 1273–1275;     

Quantitative phase analysis of myocardial wall thickening by technetium-99m 2-methoxy-isobutyl-isonitrile SPECT

Regional wall thickening was assessed by ECG-gated SPECT using technetium-99m 2-methoxy-isobutyl-isonitrile (99mTc-MIBI). For myocardial segments with an optimal short axis, regional count changes from end-diastole to end-systole were used to calculate the regional wall thickening. Functional images displaying amplitude, % wall thickening (% WT), and phase were generated by a fundamental Fourier analysis. In the control subjects, % WT analysis showed heterogeneous contraction among the left ventricular wall segments. The amplitude values showed a similar pattern to the %WT values. Phase images demonstrated that the timing of ventricular contraction was almost homogenous between the various wall segments. In the CAD patients, regional decreases in amplitude and %WT corresponding to zones of reduced perfusion were shown in the ischemic segments. Phase images also indicated asynchronous contraction in these segments. Phase analysis of regional wall thickening in 99mTc-MIBI scintigraphy seems to be useful for understanding regional myocardial function in combination with perfusion scanning.     

A clinicopathological study of pulmonary metastases in carcinoma of the uterine cervix

Carcinoma of the uterine cervix was evaluated in 1,121 patients at Kure National Hospital, Hiroshima, between 1969 and 1987. The patients were retrospectively evaluated for the presence of pulmonary metastases. On chest radiography, 35 patients were found to have metastases. Pulmonary metastases were seen in 3.1% of patients with carcinoma of the cervix. Thirty-two patients out of 35 could be evaluated about their clinical stage, histology, and disease course: 3 patients were classified into stage Ib, 10 were stage II, 15 were stage III, and 4 were stage IV. Histologically, 27 patients were squamous cell carcinoma, 2 were adenocarcinoma, and 3 were others. Mean interval from initial disease staging to detection of lung metastases was 17.1 months. Once pulmonary spread was discovered, half of them expired within 4 months. Twenty-two patients had other focus of metastasis besides lung.