De novo interstitial deletion of 4q[46,XX,del(4)(q27q28.2)] with intact blood group-MN locus,confining its locus to 4q28.2–4q31.1

We report a malformed female infant withde novo interstitial deletion of 4q[46,XX,del(4)(q27q28.2)]. The MN blood type analysis of the family members showed that the patient had an intact blood group-MN locus. The locus of the gene responsible for the MN antigen activity is confined to a 4q28.2–4q31.1 segment on the basis of the result of this patient and the previous mapping data.     

In vitro and in vivo antifungal activities of FX0685, a novel triazole antifungal agent with potent activity against fluconazole-resistant Candida albicans.

To evaluate the therapeutic potential of FX0685, a new triazole antifungal agent, for the treatment of opportunistic fungal infections, particularly systemic candidiasis and aspergillosis, in vitro and in vivo studies were performed using fluconazole (FLC), itraconazole (ITC) and/or amphotericin B (AMB) as reference drugs. A preliminary in vitro study showed that the antifungal activity of FX0685 against FLC-susceptible Candida albicans, several non-C. albicans Candida species and Cryptococcus neoformans was superior to that of FLC and comparable or superior to those of ITC and AMB, while the anti-Aspergillus fumigatus activity of FX0685 was to varying degrees lower than that of ITC. FX0685 appeared to be comparable to FLC and ITC in the treatment of murine systemic C. albicans and pulmonary A. fumigatus infection, respectively. The biological property of FX0685 was characterized by its potent in vitro and in vivo activity against FLC-resistant C. albicans. Part of this unique property was explained by the finding that it retained potent inhibitory activity against those CYP51 molecules in which amino acid substitutions confer a phenotype of resistance to FLC and some other azole derivatives. All of these results lead to the possibility that FX0685 may be a potential antifungal drug candidate for the treatment of various clinical forms of systemic candidiasis, including those caused by FLC-resistant C. albicans, as well as for the treatment of pulmonary aspergillosis.     

Analysis of the dilution deviation in CA19-9 measurement

CA19-9 widely used as a tumor marker of the pancreas and a bile duct. There are a number of reports which describes the measured value discrepancies between RIA and non-RIA kits. RIA results also have shown lack of the linearity over 70 U/ml when the samples are diluted. The pH condition at assay reaction for RIA had been suggested as the major reason, it has been denied by the results from the same pH condition at assay reaction used by COBAS CORE CA19-9 EIA II. On the other hand, the lack of RIA antibody titer is indicated for the discordant results by changing the sample volume to reagent volume ratio in the reaction. Our further investigation also indicates that the specific Lewis blood type, i.e. Le (a-b+), shows the linearity issues by RIA. The discrepancies are not caused by the reaction pH, but the amount of the antibody used in the RIA kit is closely associated. Considering the CA19-9 antibody nature used in RIA kit, which covers broad molecular range, users need to pay more attention to setting up each laboratory's measuring range.     

Heparin-induced thrombocytopenia (HIT): pathogenesis, laboratory test, and treatment

Heparin-induced thrombocytopenia(HIT) due to immunological mechanisms is known as an important adverse reaction to heparin treatment, and heparin treatment should be applied while keeping in mind the risk of onset of HIT 5-14 days after the initiation of heparin. The presence of HIT had not been fully recognized in clinical practice in Japan despite the management of HIT being well confirmed in Western countries. Recognition of HIT has increased since argatroban, a direct thrombin inhibitor, obtained the approval of the FDA for prevention and treatment of HIT. Although the incidence of HIT in Japan has not yet been clarified, there is some evidence that HIT is encountered in critically ill patients undergoing heparin anticoagulation. Clinical diagnosis of HIT is performed by means of thrombocytopenia of a drop of 50% or 100 x 10(30/microl for 5 -14 days after starting heparin treatment. Confirmatory laboratory tests examine whether the patients have antibodies against heparin/PF4 complexes or not. Two assay tests for detecting heparin/PF4 complex antibodies are available in Japan. As a functional test, the heparin-induced platelet aggregation method is easily performed and the result is obtained in a short time. The result of the test has, however, been misleading due to the selection of donors. Low platelet activity of the donors on the addition of heparin induces a negative response in spite of positive antibodies in the sample. Before testing samples, it is important to check heparin reactivity of the donor's platelets. Enzyme immunoassay detecting the antibodies is available as a commercial kit. Sensitivity obtained by enzyme immunoassay is very high and often introduces false-positives. Careful attention to interpretation of the result is required. Treatment of HIT should be started at the time of recognition of thrombocytopenia while antibody testing for HIT is performed. As an alternative anticoagulant to heparin, argatroban should immediately be applied to avoid complication of thrombosis. Thrombocytopenia and hypercoagulability quickly recover to the preheparin level by the appropriate use of argatroban.     

Adult-onset type II citrullinemia and idiopathic neonatal hepatitis caused by citrin deficiency: involvement of the aspartate glutamate carrier for urea synthesis and maintenance of the urea cycle

Citrin is a mitochondrial aspartate glutamate carrier primarily expressed in the liver, heart, and kidney. We found that adult-onset type II citrullinemia is caused by mutations in the SLC25A13 gene that encodes for citrin. In this report, we describe the frequency of SLC25A13 mutations, the roles of citrin as a member of the urea cycle and as a member of the malate-aspartate shuttle, the relationship between its functions and symptoms of citrin deficiency, and therapeutic issues.     

Effects of body and head positions on bilateral difference in tympanic temperatures

Summary We have examined the nonparallel changes in tampanic membrane temperatures (T _ty) from the two ears in response to various changes in body and head positions. Upon assuming a lateral recumbent position, the T _ty on the lower side increased while that on the upper side decreased. Pressure application over a wide area of the lateral chest only caused inconsistent and obscure asymmetric changes in T _ty. A lateral flexion of the head with the subject sitting upright and a rotation of the head to the side in a supine position induced an increase in the T _ty on the lower side compared to that on the upper side. The temperature and blood flow of the forehead often decreased on the lower side and increased on the upper side, although such responses were not always concomitant with the asymmetric changes in T _ty. A dorsal flexion of the head with the subject in a reclining position caused a slight increase in the T _ty, whereas raising the head upright induced a slight decrease in them. Two additional experiments were carried out with single photon emission computed tomography using ^99mTc-hexamethylpropyleneamine oxime as tracer, and a slight, relative decrease in counts was noted in the right hemisphere during rotation of the head to the right. These results would strongly suggest that unilateral increases and decreases in T _ty could have been caused by one-sided decreases and increases, respectively, in blood flow to the brain and/or the tympanic membrane, induced by a vasomotor reflex involving vestibular stimulation.     

Neurological aspects of del(1q) syndrome

We have studied three children with de novo terminal deletion of the long arm of chromosome 1 (46,XX,del(1)(q43)). They all have minor anomalies and neurological signs (severe psychomotor developmental delay, generalized hypotonia, and seizures) that have been described previously. In addition, all of these three patients have autistic-like behavior. They avoid eye contact, show no interest in people, express little emotion, and repeat stereotypic movements such as head nodding and purposeless finger manipulation. They also spend excessive time in making unusual sounds consisting of a high-pitched shrill cry with little intonation in infancy and a harsh, strained, and glottal stridency in later life. They make no labial, lingual, or nasal sounds. We suggest that these observations may be unique clinical manifestations of certain terminal 1q deletions.     

ADRENAL PHEOCHROMOCYTOMA WITH BOTH BENIGN AND MALIGNANT COMPONENTS

A case of adrenal pheochromocytoma Is reported characterized by polygonal basophilic granular cells of benign type, plump eosinophilic granular cells of transitional type, and spindle-shaped cells of malignant type. In the primary tumor the neoplastic cells of each type revealed a distinctive topographical distribution. All gradations between the latter two varieties of cells were found, especially in the vicinity of the transitional cell area. Multiple metastases were present in the liver and lungs, where only anaplastic spindle-shaped cells could be found. Ultrastructurally, the benign cells contained predominantly large, rather light, secretory granules with a coarsely granulated core. In the malignant cells, the number, size, and intensity of granules varied considerably from cell to cell or even within a single cell. In general, the malignant cells had a higher frequency of smaller granules with electron-dense homogeneous cores. Moderate amounts of noradrenalin but not significant dopamine or adrenalin could be demonstrated from a metastatic nodule In liver. We postulate that this adrenal medullary pheochromocytoma was benign originally and underwent malignant transformation shortly before the patient's death. This is based upon the patient's clinical features and the peculiar structures of the primary tumor.