Haematological improvement by long-term administration of recombinant human granulocyte-colony stimulating factor and recombinant human erythropoietin in a patient with severe aplastic anaemia

A 6-year-old girl with post-hepatitic severe aplastic anaemia was referred to our hospital. Haematological examination showed a haemoglobin level of 5.2 g/dl, platelet count of 8,000/l, and white blood cell count of 130/l with 17% neutrophils. She was treated with recombinant human granulocytecolony stimulating factor (15 g/kg/day i.v.) and cyclosporin A (6 mg/kg/day p.o.). The absolute neutrophil count gradually increased, but Hb and platelets were not improved. The intravenous administration of recombinant human erythropoietin (100 U/kg three times a week) was started, and the reticulocyte count reached 20000/l on day 12. The platelets increased to 81000/l after 16 months of combined administration of recombinant human granulocyte-colony stimulating factor, recombinant human erythropoietin and cyclosporin A. After 20 months of combined administration, the haematological results were: Hb, 13.1 g/dl; platelets 80000/l: WBC, 9500/l with 40% neutrophils. After recombinant human granulocyte-colony stimulating factor treatment, the myeloid elements of the bone marrow and the number of granulocyte-macrophage colony forming units increased. Bone marrow erythropoiesis and erythroid colonies also increased after recombinant human erythropoietin administration. The clinical course suggested a beneficial effect of haemopoietic growth factors and cyclosporin A in post-hepatitic aplastic anaemia.     

Correlation between the blood supply and grade of malignancy of hepatocellular nodules associated with liver cirrhosis: evaluation by CT during intraarterial injection of contrast medium

OBJECTIVE: The purpose of this study is to evaluate the correlation between the intranodular blood supply revealed by CT during intraarterial injection of contrast medium, mainly using helical CT, and the grade of malignancy of hepatocellular nodules associated with liver cirrhosis as classified by the International Working Party of the World Congress of Gastroenterology. SUBJECTS AND METHODS: We studied 201 histologically proven nodules (101 resected and 100 biopsied nodules), including 47 low-grade dysplastic nodules (low-DNs), 56 high-grade dysplastic nodules (high-DNs), 24 well-differentiated hepatocellular carcinomas (wd-HCCs), and 74 moderately or poorly differentiated HCCs (mp-HCCs), in 139 cirrhotic patients. Findings on CT during arterial portography (n = 201) and CT during hepatic arteriography (n = 74) were reviewed and compared with the histologic diagnosis. RESULTS: CT findings were classified into four types relative to the surrounding liver: type A (isodense), type B (slightly hypodense), type C (partially hypodense), and type D (markedly hypodense) on CT during arterial portography and type I (isodense), type II (hypodense), type III (partially hyperdense), and type IV (hyperdense) on CT during hepatic arteriography. On CT during arterial portography, the distributions of each type were low-DN (n = 47 [A, n = 36; B, n = 8; C, n = 3]), high-DN (n = 56 [A, n = 18; B, n = 20; C, n = 10; D, n = 8]), wd-HCC (n = 24; [B, n = 4; C, n = 13; D, n = 7]), and mp-HCC (n = 74 [D, n = 74]). On CT during hepatic arteriography, the distributions were low-DN (n = 26 [I, n = 18; II, n = 7; III, n = 1]), high-DN (n = 19 [I, n = 6; II, n = 7; III, n = 4; IV, n = 2]), wd-HCC (n = 15 [I, n = 1; III, n = 8; IV, n = 6]), and mp-HCC (n = 14 [IV, n = 14]). We found a statistically significant correlation between the four types and the grade of malignancy of these nodules. CONCLUSION: Findings on CT during arterial portography and CT during hepatic arteriography correlated positively with histologic grading when overlap in appearance between dysplastic nodules and HCCs occurred. The concept revealed in this study can apply to diagnoses made on the basis of Doppler sonography, dynamic CT, and MR imaging.     

Bone Metastases from Soft Tissue Sarcomas

The incidence, distribution, time of appearance, and radiologic findings of bone metastases from soft tissue sarcomas, exclusive of lymphomas, were evaluated in 320 patients with soft tissue sarcomas. Thirty patients (9.4%) had evidence of 58 bone metastases. Five of 30 patients presented with metastases, and 25 of 30 patients developed metastases up to 66 months after presentation with a mean time interval of 21.3 months. The incidence of skeletal metastases differed among histologic subtypes of sarcomas; alveolar soft part sarcoma (5 of 8), dedifferentiated liposarcoma (2 of 4), angiosarcoma (2 of 4), and rhabdomyosarcoma (5 of 16) tended to show a higher incidence of bone metastases. The sarcomas metastasized to the regional bones close to the primary tumor in 16 (53%) of 30 patients and to the axial bones in 18 (60%). On conventional radiographs, the osseous metastases demonstrated predominantly osteolytic changes, and evidence of pathological fracture was observed in 31% of 58 metastases.     

Relationship between HLA-DR Antigen and HLA-DRB1 Alleles and Prostate Cancer in Japanese Men

Purpose: Human leukocyte antigens (HLA) are cell surface glyco-proteins playing a key role in the immune system. In some cancers, changes in major histocompatibility complex (MHC) class I and II expression, usually a reduction or loss of these molecules, appear to provide a mechanism whereby tumour cells may escape host immunity. We investigated the relationship between HLA, especially class II, molecules and prostate cancer in Japanese men using molecular techniques. Materials and methods: HLA class II typing was performed by the polymerase chain reaction-sequence specific primer (PCR-SSP) method of analysis and/or a commercial rapid assay based on the PCR followed by reverse dot-blot hybridization of the PCR products (Inno-LiPA assay). Allele frequencies were calculated. HLA allele frequencies reported in 1216 healthy Japanese individuals were used as the control data. Differences in allele frequency between subjects and the control group were analyzed by the chi-square test. The relationship between HLA antigens/alleles and prostate cancer is expressed in terms of relative risk (RR). Results: The frequencies of HLA-DR4 were significantly higher in Japanese men with prostate cancer than in the healthy control group (gene frequency 36.2% vs. 26.3% in control, p<0.05), although the relative risk of prostate cancer was less than 2. Furthermore, the frequencies of HLA-DRB1-0406, 0410 and 1405 allele were significantly higher in the prostate cancer group than in the control group (allele frequency was 7.3%, 4.5% and 5.4% vs. 3.03%, 1.79% and 2.22%, p<0.05, respectively). RR of those HLA-DRB1 allele for prostate cancer was 2.6 in each allele. Conclusions: HLA molecules may be useful for the early detection of prostate cancer as a risk factor, and also for recognizing cancer activity by using them as a marker helpful in the choice of appropriate treatment by predicting prognosis.     

Molecular pharmacology and physiology of nociceptin

The family of the G protein-coupled opioid receptors was recently extended by a novel member that did not bind any of the typical opioid receptor ligands. Identification of the orphan receptor in this way led to the advent of "reverse pharmacology" to identify the corresponding physiological ligands. Nociceptin, a heptadecapeptide, which was discovered as an endogenous ligand, first, attracted us by its reported nociceptive or anti-opioid actions. However, following studies revealed that this peptide has both nociceptive and antinociceptive actions under different conditions; e.g., administration routes or doses affect its actions. In our recent studies using a unique peripheral peripheral nociception test, nociceptin given locally at lower doses was found to produce nociception through substance P release from nociceptor endings, while at higher doses, it produced antinociceptive actions through an inhibition of phospholipase C activity stimulated by nociceptive substances. Such hypothetical mechanisms can be applied to the mechanisms of nociceptin-induced paradoxical actions in the central nervous system. The physiological role of nociceptin has recently been reported using nociceptin receptor knock-out mice. Following the report of a hearing problem in such mice, the nociceptin receptor was found to be involved in the development of morphine analgesic tolerance. In this review, more findings on the physiological roles of nociceptin or its receptor, such as pain control and memory-learning, are discussed on the basis of reports using nociceptin receptor knock-out mice.     

In vivo molecular signal transduction of peripheral mechanisms of pain

Although we have obtained a number of pharmacological tools and mutant mice lacking specific genes related to the pain, the distinct molecular basis of the pain-producing mechanism has remained to be fully clarified since we have been using conventional paradigms of the nociception test that may drive multiple endogenous molecules affecting nociception at the same time. Here, I will introduce a new paradigm of the nociception test. In this test, we focused on polymodal C-fibers by measuring nociceptive flexor responses induced by the peripheral application of a single species of nociceptive molecule. In addition, we identified the site of drug actions on nociceptor endings by the fact that the nociception was abolished by the intrathecal pretreatment with antisense oligodeoxynucleotide for receptors. Throughout experiments using this paradigm of the nociception test, it was firstly revealed that substance P, a major neurotransmitter of polymodal C-fibers, directly stimulates nociceptor endings through activation of Gq/11 and phospholipase C, followed by Ca2+ influx through plasma membrane-bound inositol trisphosphate receptors, and that bradykinin and histamine, both endogenous representative pain-producing substances, share this mechanism. Another unique mechanism is through Gi-coupled receptors such as receptors for nociceptin (orphanin FQ) or kyotorphin (tyrosine-arginine). The latter mechanism was found to be mediated through a substance P release from nociceptor endings. Future studies including some modifications of this paradigm should be also clinically useful for neuropathic pain research as well as understanding of pain physiology.     

Cuff bulk of tracheal tubes in adolescence

Purpose

To investigate cuff types for potential use in late childhood and early adolescence for appropriate fit.

Method

Formulae suggest the use of a tracheal tube having a 6.5 mm internal diameter at ages 8 to 10 years, so a model system was used to test the passage of cuffed and uncuffed tracheal tubes of 6.5 mm internal diameter through calibrated holes 8.1–16.6 mm diameter, in plastic plates.

Results

Uncuffed tracheal tubes passed through 9.0 mm diameter holes. “High pressure” cuffed tubes passed through 10.5 to 11.3 mm holes. “Low pressure” cuffed tubes passed through 12.3 to16.4 mm.

Conclusion

Patients aged 8 to 10 yr have a limiting internal diameter at the cricoid of 8 to 10 mm. Their unstretched tracheal diameter below the cricoid is only about 11 mm. The actual outside diameters of “low pressure” cuffs chosen by commonly used formulae considerably exceed the limiting diameters of eight to ten year old patients, even considering recommended compensation factors. Analysis of background data indicates that these problems are especially aggravated at this age by non-linear growth of the cricoid.     

An acute fatal occupational cadmium poisoning by inhalation

Summary A 43-year-old male smelter was admitted to a hospital on account of severe dyspnea about 2 days after exposure to brownish-yellow smoke produced by melting of copper scrap. On admission pronounced hypoxemia was revealed, and an oxygen-enriched gas was administered after intubation. Although inspired oxygen concentration was gradually increased, hypoxemia progressed and he died on day 11 in hospital.The principal autopsy finding was chiefly confined to the lungs. Both lungs were heavy (the left weighing 1,470 g; the right 1,710 g) and firm to the touch. Histologically, no normal alveoli were found throughout the entire lung. Some alveolar spaces were occupied by pneumocytes, others by organized exudate with fibrosis. Interstitial fibrosis was present. Patchy areas of inflammatory cell infiltrations as well as intra-alveolar hemorrhages were observed. On the basis of the above findings a diagnosis of diffuse alveolar damage was made.Based on the available evidence (presence of cadmium in the copper scrap, feature of the smoke, clinical signs with latent time, and high cadmium concentration of the lung), the diffuse alveolar damage was considered to have been caused by inhaled cadmium. The pulmonary change of the present case was more advanced in pathologic stage in comparison with those reported in the literature.