Nephritogenicity of the lprcg gene on the MRL background.

The novel lymphoproliferative and autoimmune lprcg gene, originally discovered in the CBA/K1Jms (CBA) strain of mice, was transferred onto the MRL/MpJ (MRL) strain background, and the resultant partially congenic MRL-lprcg/lprcg carrying 93% or more MRL genomes on average were examined for immune-complex glomerulonephritis and serological aberrations. Ordinary histological studies revealed that MRL-lprcg/lprcg mice developed glomerulonephritis histologically indistinguishable from that in MRL-lpr/lpr but at a lower frequency than in MRL-lpr/lpr mice. Glomerular immune complex deposition was almost the same in MRL-lprcg/lprcg and MRL-lpr/lpr mice. The levels of serum Ig, circulating immune complexes and autoantibodies in MRL-lprcg/lprcg were comparable to or even higher than those in MRL-lpr/lpr mice. Comparison of the serological abnormalities between MRL-lprcg/lprcg with glomerulonephritis and CBA-lprcg/lprcg without it evidenced the enhanced class switch from IgM to IgG responses in both class-specific autoantibody responses and serum Ig levels in MRL-lprcg/lprcg as in MRL-lpr/lpr mice. These results taken together indicate that the lprcg gene functions in much the same manner as lpr in induction of glomerulonephritis and serological abnormalities on the MRL background as expected from the allelism between the two mutant genes.     

Distribution of cocaine recognition sites in rat brain: In vitro and ex vivo autoradiography with [I]RTI-55

The distribution of binding sites of [¹²⁵I]RTI-55 (3β-(4-iodophenyl)tropan-2β-carboxylic acid methyl ester), a phenyl tropane analog of cocaine, and the selective labelling of the dopamine transporter (DAT) were studied by in vitro and ex vivo autoradiography in the rat whole brain. Recent evidence has shown that RTI-55 binds to not only DAT but also serotonin transporter (5HTT). In the present study, in vitro autoradiography revealed that [¹²⁵I]RTI-55 bound to the olfactory tubercle, the caudate putamen, the accumbens nucleus, the midline and lateral geniculate nuclei of the thalamus, the hypothalamic nuclei, the substantia nigra compact part, the subthalamic nucleus, the ventral tegmental area, the superior colliculus, the dorsal raphe nucleus, and the facial nucleus. Further, in the presence of clomipramine, a selective ligand for 5HTT, [¹²⁵I]RTI-55 binding was remarkably inhibited in the midline and lateral geniculate nuclei of the thalamus, the hypothalamic nuclei, the superior colliculus, the dorsal raphe nucleus, and the facial nucleus, while [¹²⁵I]RTI-55 binding remained in the olfactory tubercle, the caudate putamen, the accumbens nucleus, the substantia nigra compact part, the subthalamic nucleus, and the ventral tegmental area. These findings suggest that [¹²⁵I]RTI-55 binds to 5HTT in the former areas and to DAT in the latter areas. It is therefore concluded that RTI-55 is a suitable ligand for studying the action of cocaine in whole brain regions, including the thalamus, the hypothalamus and the dorsal raphe nucleus, regions in which cocaine is thought to act evoking several neurological effects, e.g., analgesia and elevation of adrenocorticotropic hormone. DAT was also labelled selectively both in vitro and in vivo using [¹²⁵I]RTI-55 combined with clomipramine. Therefore, radiolabelled RTI-55, combined with unlabelled clomipramine, which displaces its binding to 5HTT, also appears to be suitable for the selective imaging of DAT in vivo.     

Management of prenatal ovarian cysts

OBJECTIVES: The aim of the present study was to analyze the antenatal and postnatal outcome of fetal ovarian cysts in relation to their ultrasonographic pattern and size. METHODS: Sixteen fetal ovarian cysts were diagnosed in 16 fetuses and followed with serial ultrasonograms in utero and after birth until spontaneous or surgical resolution. RESULTS: Eleven fetal ovarian cysts were simple cysts at first prenatal scan but 3 of the 11 became complex cysts at last prenatal scan and required postnatal laparoscopic surgery. Seven of the 11 simple cysts (63%) disappeared on follow-up imaging by ultrasonograms or MRI during pregnancy or within 2 months after birth. The rate of spontaneous resolution of simple cysts was higher than that of complex cysts (40.0%). The mean maximum diameter of the ovarian cysts before delivery that were subsequently excised surgically at postnatal period (50+/-13.4 mm) was not different from that of ovarian cysts that resolved spontaneously (42.8+/-12.8 mm, P=0.2918). CONCLUSION: In our study, cyst size did not predict the risk of ovarian loss. The opportunity of laparoscopic exploration versus conservative management needs to be investigated because some complex cysts resolved spontaneously in the postnatal period.     

Paradoxical Relationship Between B-type Natriuretic Peptide and Pulmonary Vascular Resistance in Patients with Ventricular Septal Defect and Concomitant Severe Pulmonary Hypertension

B-type natriuretic peptide (BNP) reflects volume overload on left ventricle and pulmonary hypertension (PH) in patients with ventricular septal defect (VSD). Pulmonary vascular resistance (PVR) has been reported to correlate positively with BNP in VSD patients with various degrees of PH. We aimed to investigate the relationship between PVR and BNP in VSD patients with severe PH. We examined 24 subjects with VSD concomitant severe PH aged from 2 months to 17 years (median: 4 months). The ratio of pulmonary to systemic pressure (Pp/Ps), the ratio of pulmonary to systemic flow (Qp/Qs), the ratio of pulmonary to systemic resistance (Rp/Rs), and PVR were determined by cardiac catheterization. PVR and Rp/Rs ranged from 1.6 to 15.5 (mean: 5.7 ± 3.9) Wood unit · m² and 0.1 to 0.8 (mean: 0.4 ± 0.2), respectively. BNP ranged from 5.5 to 69 (mean: 31 ± 19) pg/ml. Negative correlations were observed between BNP and PVR (r = -0.56, p = 0.004) and BNP and Rp/Rs (r = -0.51, p = 0.01). BNP was significantly lower (<10 pg/ml) in VSD patients with Eisenmenger physiology as compared with the others (p = 0.003). We should draw attention to evaluate BNP values in VSD patients with severe PH.     

A paradoxical thrombogenic mutation in factor II at the target site of arthropod bleeding toxin

Loss-of-function mutations in coagulation cascade proteins lead to bleeding diasthesis. In contrast, gain-of-function mutations in these proteins, which are exceptionally rare, lead to hereditary thrombosis. This is best exemplified by Factor V (i.e., Factor V Leiden) and Factor II (i.e., p.Arg596Leu). Here, we report a family with hereditary thrombosis. The proposita presented with cerebral venous thrombosis accompanied by infarction at the age of 12 years. Despite anticoagulation therapy with oral warfarin, she later developed deep venous thrombosis in her hepatic portal veins at the age of 27 years. A medical exome analysis identified a de novo heterozygous mutation p.Tyr434His in Factor II, which was segregated within the family. A retrospective molecular diagnosis was made using a preserved surgical specimen from the proposita's mother, who had died 10 years earlier. The p.Tyr434 residue, which was substituted in the presently reported family, was located in “exosite I” of thrombin, a critical recognition site for fibrinogen, protein C, and thrombin aptamer. Therefore, the mutant thrombin likely exerted its thrombophilic effect by altering the affinity of thrombin to downstream substrates. Furthermore, the “exosite I” domain of thrombin was inhibited by the arthropod bleeding toxin Triabin (a protein discovered from the saliva of the blood-sucking triatomine bug Triatoma pallidipennis). Our observation that patients with a p.Tyr434His mutation exhibited recurrent thrombosis provides the first proof-of-concept in humans that a pharmacologic agent targeting “exosite I” could be an effective means of specifically modulating the thrombogenic-side of the coagulation system via the inhibition of factor II.     

Sleep condition and cognitive decline in Japanese community‐dwelling older people: Data from a 4‐year longitudinal study

This study examined whether sleep duration and excessive daytime sleepiness (EDS) are related to cognitive decline among community‐dwelling older adults with intact cognition at baseline, using 4‐year longitudinal data. A total of 3,151 community‐dwelling older individuals aged ≥65 years were studied. They were assessed for cognitive function, including memory, attention, executive function and processing speed. Cognitive impairment was defined based on a score >1.5 standard deviations below the age‐ and education‐specific mean. Cognitive decline was defined in one or more cognitive tests at follow‐up. Self‐reported sleep duration (short, ≤6.0 hr; medium, 6.1–8.9 hr; long, ≥9.0 hr) and EDS at first‐wave examination were assessed and logistic regression analyses were used to examine the associations of sleep duration and EDS with cognitive status at second‐wave examination. The incidence of cognitive decline differed significantly among the sleep‐duration groups (short, 15.9%; medium, 11.9%; long, 20.1%; p = 0.001). The prevalence of having EDS was 13.1%, which was associated with a higher rate of cognitive decline than having no EDS (18.9% vs. 12.5%, p = 0.004). Long sleep duration compared with medium sleep duration (OR, 1.50; 95% CI, 1.05–2.13) and EDS (1.43; 1.01–2.03) independently impacted the incidence of cognitive decline. The results were similar after multiple imputations (long, 1.68, 1.12–2.52; EDS, 1.55, 1.05–2.29). In conclusion, our study revealed that both long sleep duration and EDS were independent risk factors associated with cognitive decline after 4 years among older adults.     

A rare case of pulmonary typical carcinoid with prominent acinic cell differentiation,resembling acinic cell carcinoma

We herein describe a rare case of low‐grade endobronchial tumor that exhibited two distinct features of typical carcinoid and acinic cell carcinoma (ACC) by immunohistochemical and ultrastructure study. ACC was suspected on transbronchial biopsy. The resected specimen showed that the tumor surface comprised an acinic cell component (40% of the tumor), and the central area comprised typical carcinoid (60% of the tumor). The acinic cell component was positive for chromogranin A, synaptophysin and alpha‐1‐antichymotrypsin. Additionally, this component showed focal apical membranous staining for DOG1 and weak positivity for BCL10 and SOX10. Conversely, the carcinoid component was negative for all proteins except for chromogranin A and synaptophysin. Electron microscopy indicated zymogen‐type granules (600–800 nm in diameter) in the acinic cell component, whereas neuroendocrine‐type granules (200–300 nm in diameter) were observed in the carcinoid component. Nuclear NR4A3 immunostaining, which is highly specific for ACC of the salivary gland, was negative in this case. We conclude that the pulmonary carcinoid tumor with true zymogen‐type granules could be seen but showed superficial similarities to ACC based on negative nuclear staining for NR4A3. Pulmonary carcinoids encompass a wide morphological spectrum and may exhibit prominent acinic cell differentiation.     

Localization of human phosphoribosylpyrophosphate synthetase subunit I and II genes (PRPS1 and PRPS2) to different regions of the X chromosome and assignment of two PRPS1-related genes to autosomes

Complementary DNA clones for phosphoribosylpyrophosphate synthetase subunits I and II (PRS I and PRS II) were used to determine the chromosomal localization of the corresponding human genes. Southern blot analysis of genomic DNAs isolated from human placenta and a panel of humanmouse somatic cell hybrids revealed that the rat PRS I cDNA probe detected at least five human specific DNA segments (23, 20, 14.5, 6.7, and 4.3 kb) in BamHI digests. The 23-, 14.5-, and 6.7-kb DNA segments were detected only if the hybrids contained human chromosome X or translocation chromosome 7p ⁺ (7qter>7p22::Xq21>Xqter), indicating the location of these segments to Xq21-qter (PRPS1). The 20- and 4.3-kb DNA segments did not cosegregate with the other three segments, and spot blot hybridization analysis using flow-sorted human chromosomes indicated that these are the PRPS1-related genes (PRPS1L1 and PRPS1L2) and could be assigned to chromosomes 7 and 9, respectively. The human-specific PRS II cDNA probe revealed a BamHI DNA segment (17 kb), which segregated condordantly with the X chromosome but not with the PRPS1 gene. We surmise that the gene for PRS II (PRPS2) is located at a different region of the X chromosome, namely Xpter-q21.Preliminary report of this research was presented at Ninth International Workshop on Human Gene Mapping, Abstract supplement p. 5 (1987).