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.     

Comparative study on deletions of the dystrophin gene in three Asian populations

The frequency and distribution of deletions of 19 deletion-prone exons clustered in two hot spots in the proximal and central regions of the dystrophin gene were compared in three populations from Singaporean, Japan, and Vietnam. DNA samples obtained from 105 Singaporean, 86 Japanese, and 34 Vietnamese Duchenne muscular dystrophy patients were examined by polymerase chain reaction amplification. Deletions of the examined exons were found in 51.2% of Japanese patients but in 40.0% or less of the Singaporeans and Vietnamese. About two thirds of the deletions were localized in the central region and the remaining deletions were clustered at the proximal region. The most commonly deleted exons at the central deletion hot spot were exon 50 in the Singaporean, exons 49 and 50 in the Japanese, and exon 51 in the Vietnamese population. At the proximal deletion hot spot, the most commonly deleted exons were exons 6 and 8 in the Singaporeans, exons 12 and 17 in the Japanese, and exons 8 and 12 in the Vietnamese. Two cases each from Singapore and Japan had large-scale gross mutations spanning both deletion hot spots. Our results suggest that, although the presence and frequency of the two deletion hot spots may be similar in the three Asian populations analyzed, the distribution and frequency of deletions among the different exons can vary as a result of population-specific intronic sequences that predispose individuals to preferential deletion breakpoints. Received: May 20, 2002 / Accepted: July 1, 2002     

Sensory inputs from the oral region to the cerebral cortex in behaving rats: an analysis of unit responses in cortical somatosensory and taste areas during ingestive behavior

1. The responses of 90 cortical neurons in the somatosensory and gustatory areas were recorded with chronically implanted fine wires in freely moving Wistar rats. The responses were analyzed mainly while the animals were freely licking solutions and eating dry pellets. Cortical neurons were classified into several groups according to their response properties. 2. "Mechanosensitive" neurons (n = 20) showed rhythmic phasic activity in different phases of the licking cycle, depending on the location of their receptive field in the peripheral orofacial region. 3. "Movement-related" neurons (n = 27) changed their activities tonically during licking, chewing, or grooming behavior. The responses were either excitatory or inhibitory. Receptive fields and adequate stimuli could not be identified. These neurons might receive somatosensory (except light tactile) inputs from wide or deep areas of intra- or perioral regions, or might be related to orofacial active movement. 4. "Taste" neurons (n = 35) increased or decreased their discharge rates during licking of particular taste solutions. Some taste neurons received convergence from somatosensory inputs. 5. "Temperature" neurons (n = 2) responded exclusively to water of temperatures lower or higher than room temperature. The responses were opposite in direction between cold and warm stimuli. 6. "Anticipation" neurons (n = 4) increased their impulse discharges before the start of licking in the situation in which the animal expected access to the drinking tube. 7. "Attention" neurons (n = 2) responded to arousal stimulation such as sound, a flash of light, and body touch. These neurons showed only a slightly increasing response during ingestive behavior. 8. The locations of 56 of 90 units were histologically identified. Mechanosensitive neurons were located in the appropriate parts of the somatotopic pattern within the primary somatic sensory area in the granular cortex. Taste neurons were found evenly in the dysgranular cortex and the agranular insular cortex. Other types of neurons were located mainly in the dysgranular cortex between the granular cortex and agranular insular cortex, and some were intermingled with taste neurons in the agranular insular cortex. 9. The present study has shown that cortical neurons in the orolingual somatosensory and taste areas have different response characteristics related to each aspect of ingestive behavior.(ABSTRACT TRUNCATED AT 400 WORDS)     

Otx1 function overlaps with Otx2 in development of mouse forebrain and midbrain

Background: We previously reported that the homozygous mutation of Otx2 gene, a mouse cognate of the Drosophila head gap gene orthodenticle , causes failure in the development of the rostral head anterior to rhombomere 3, which may correspond to earlier Otx2 expression in cells destined for the anterior mesoendoderm. At the same time, the Otx2 heterozygous mutation displayed a phenotype characterized as otocephaly, probably related to expression in the anterior neuroectoderm at the subsequent pharyngula stage. Defects were characteristic in the most anterior and posterior regions of Otx2 expression where Otx1 , another mouse cognate of orthodenticle , is not or weakly expressed. They were not found in the region where Otx1 is expressed.
Results: In the present work, Otx1 null mutant mice were generated by gene targeting in embryonic stem cells. No defects were apparent in the regionalization of the early embryonic rostral brain. The newborn brain defects were subtle and most likely related to later Otx1 -unique expression. Otx1 and Otx2 double heterozygous mutant brains, however, exhibited marked defects throughout the fore- and midbrains, where defects were not apparent with a single mutation alone.
Conclusions: Otx1 and Otx2 play synergistic roles in the development of the forebrain and midbrain where both genes are expressed.     

Responsiveness of the ANP providing system to volume load in conscious dogs

We examined in detail changes in arterial plasma ANP concentration in response to volume load in conscious dogs. In a 5-min volume load experiment, 18 ml/kg of isosmotic and isooncotic 3% Dextran 40 in saline was infused over a period of 5 min. Mean left atrial pressure (MLAP) increased transiently by 7.6±0.9 mm Hg. Plasma ANP level (P-ANP) did not significantly increase. Assayed P-ANP levels were corrected for hemodilution. Corrected P-ANP (C-ANP) significantly increased from 206±17 to 348±34 pg/ml. However, the level of C-ANP did not reach a steady state. No significant linear correlation was found between increases in MLAP and normalized C-ANP. In a 45-min volume load experiment, the elevated level of MLAP caused by the 5-min volume load was maintained for 40 min by supplemental infusion. C-ANP significantly increased from 196±18 pg/ml to 435±73 ng/ml. The level of C-ANP reached a steady state. A close linear correlation was observed between increases in MLAP and normalized C-ANP. However, the peak time of C-ANP lagged 10 min behind MLAP. These results indicate that it takes 10 min for P-ANP to reach a steady state in fully responding to a volume load, and that the long-term volume load is a prerequisite to the response of the ANP providing system.     

Lack of association between DNA base excision repair gene XRCC1 Gln399Arg polymorphism and risk of malignant lymphoma in Japan

Growing evidence suggests that the polymorphism of DNA base excision repair gene XRCC1 Arg399Gln is associated with altered DNA repair proficiency and subsequent cancer susceptibility; however, no evidence is available for malignant lymphoma. We therefore conducted a case-control study (372 cases, 500 controls) to evaluate links with malignant lymphoma risk in Japan. The risk was evaluated in terms of odds ratio (OR) and 95% confidence interval (CI) adjusted for age and sex in an unconditional logistic regression model. There was no statistical risk change with the Arg/Gln (adjusted OR 0.89; 0.65-1.23, P = 0.492) or the Gln/Gln (0.57; 0.27-1.17, P = 0.127) compared with the Arg/Arg of the XRCC1 Arg399Gln polymorphism. The results were unchanged in analyses according to histological subtype (diffuse large lymphoma, follicular lymphoma, low-grade lymphoma of mucosa-associated lymphoid tissue, and others). These data suggest that XRCC1 Gln399Arg polymorphism plays a limited role in lymphomagenesis. Further study on the interaction between the polymorphism and environmental exposure is required.     

Sotos syndrome associated with a de novo balanced reciprocal translocation t(5;8)(q35;q24.1).

We describe a de novo balanced reciprocal translocation between the long arms of chromosomes 5 and 8 [46,XX,t(5;8)(q35;q24.1)] in a 15-month-old girl with a typical Sotos syndrome phenotype. Involvement of the 5q35 region was previously reported (Maroun et al. [1994: Am J Med Genet 50:291-293]) as one of translocation breakpoints in the present patient. We suggest that the gene responsible for Sotos syndrome is located to a distal long-arm region of chromosome 5.