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.     

Effect of distance and population size on patient trips in a prefecture of Japan: Application of a transportation distribution model to the demand for and supply of health services

The gravity model, a method for analyzing transportation distribution in transportation engineering, was used to explain patient trips between ten health service regions in a Japanese prefecture. The OD (Origin-Destination) tables were constructed with zoning by regions, distinguishing between out- and inpatients. The observed trips were determined from the data of a survey conducted in 1992 that reported the locations of patient residences and chosen medical facilities. The base values used in the model calculations were the population size of each region and the road distance between the centers of regions. Problems of intrazonal trip were avoided by setting a mean intrazonal movement distance. This model was calibrated by the linear regression method with simultaneous validation by the index of correlation coefficients. The model was found to accurately simulate the effect of distance on the choice of medical facilities and the differences between the characteristics of in- and out-patients. The population value in use showed the relation not only with demand but also the supply of clinical services. It was suggested that the model presented here was useful in the allocation of medical resources and would help explain the relationship between suppliers and consumers of medical services.     

Aprindine blocks the sodium current in guinea-pig ventricular myocytes

Summary Aprindine is a class Ib antiarrhythmic agent. We studied effects of aprindine (3 µmol/l) on the Na⁺ current using whole cell voltage clamp (tip resistance = 0.5 , [Na]_i and_o = 10 mmol/l at 18°C). Aprindine revealed tonic block (Kd_rest = 37.7 µmol/l, Kd_i = 0.74 µmol/l; n = 4). Aprindine, shifted inactivation curve to hyperpolarizing direction by 11.4 ± 3.5 mV (n = 4) without changes in slope factor. In the presence of 3 µmol/l aprindine, aprindine showed phasic block, i.e., duration-dependent block at 2 Hz (64% ±3070 at 1.5 ms, 82%±6% at 20 ms, 93%±7% at 200 ms; n = 4). Short single prepulse also produced aprindine-induced phasic block (12% at 1.5 ms, 22% at 100 ms; n = 2). After removal of fast inactivation of Na⁺ current by 3 mmol/l tosylchloramide sodium, aprindine revealed phasic block, independent of holding potential. The recovery time constant from aprindine-induced phasic block was 4.8 s at holding potential = –100 mV and 5.0 s at holding potential = –140 mV. This use-dependent block of aprindine had pH dependency. Under acidic condition (pH 6.0), 3 µmol/l aprindine showed smaller use-dependent block (14% ± 7% at 2 Hz; n = 4) comparing with either at pH 7,4 (68% ± 13%; n = 4) or at pH 8.0 (90% ±12%; n = 4).The results suggest that aprindine could bind to the receptor via activation process through channel pore, resulting in decrease of Na⁺ current, and egress from the receptor through the lipid bilayer. These effects might be attenuated under acidic condition due to changes in intracellular ratio of charged to neutralized form of drug molecule. Send offprint requests to: R. Sato at the above address     

Effect of recombinant granulocyte colony-stimulating factor (rG-CSF) on chemotherapy-induced neutropenia in patients with urogenital cancer

Summary The effects of recombinant granulocyte colony-stimulating factor (rG-CSF) on the myelosuppression, especially neutropenia, induced by cancer chemotherapy in patients with urogenital cancer were investigated in a randomized, controlled clinical study. In this study, rG-CSF was given subcutaneously at a dose of 2 g/kg per day for 14 consecutive days. Changes in neutrophil counts were compared between the first (no rG-CSF) and second cycles (rG-CSF treatment period) of chemotherapy. rG-CSF administration was found to be effective in reducing the duration of neutropenia, in elevating the neutrophil nadir, and in reducing recovery time. Based on comparisons between the randomized rG-CSF treatment group (with rG-CSF) and the control group, treatment with rG-CSF resulted in the moderation or prevention of neutropenia and the acceleration of recovery. These results demonstrate that in chemotherapy of patients with urogenital cancer, in which neutropenia is a dose- or schedule-limiting factor, the concomitant use of rG-CSF may enable an increase in the dose (higher single dose or increased dose per unit of time) or shorten the chemotherapy period.     

Overexpression of the aldo-keto reductase family protein AKR1B10 is highly correlated with smokers' non-small cell lung carcinomas.

PURPOSE: Squamous cell carcinoma (SCC) and adenocarcinoma of the lung are currently subject to similar treatment regimens despite distinct differences in histology and epidemiology. The aim of this study is to identify a molecular target with diagnostic and therapeutic values for SCC. EXPERIMENTAL DESIGN: Genes specifically up-regulated in SCC were explored through microarray analysis of 5 SCCs, 5 adenocarcinomas, 10 small cell lung carcinomas, 27 normal tissues, and 40 cancer cell lines. Clinical usefulness of these genes was subsequently examined mainly by immunohistochemical analysis. RESULTS: Seven genes, including aldo-keto reductase family 1, member B10 (AKR1B10), were identified as SCC-specific genes. AKR1B10 was further examined by immunohistochemical analysis of 101 non-small cell lung carcinomas (NSCLC) and its overexpression was observed in 27 of 32 (84.4%) SCCs and 19 of 65 (29.2%) adenocarcinomas. Multiple regression analysis showed that smoking was an independent variable responsible for AKR1B10 overexpression in NSCLCs (P < 0.01) and adenocarcinomas (P < 0.01). AKR1B10 staining was occasionally observed even in squamous metaplasia, a precancerous lesion of SCC. CONCLUSION: AKR1B10 was overexpressed in most cases with SCC, which is closely associated with smoking, and many adenocarcinoma cases of smokers. These results suggest that AKR1B10 is a potential diagnostic marker specific to smokers' NSCLCs and might be involved in tobacco-related carcinogenesis.     

Colokinetic effect of somatostatin in the spinal defecation center in rats

Somatostatin and its receptors are expressed in the spinal cord, but the functional roles of the peptide remain unknown. In this study, we examined the colokinetic effect of somatostatin in the spinal defecation center in anesthetized rats. Intrathecal application of somatostatin into the lumbo-sacral cord caused propulsive contractions of the colorectum. However, somatostatin administered intravenously or intrathecally to the thoracic cord failed to enhance colorectal motility. Transection of the thoracic cord had no significant impact on the colokinetic action of somatostatin. The enhancement of colorectal motility by intrathecal administration of somatostatin was abolished by severing the pelvic nerves. Our results demonstrate that somatostatin acting on the spinal defecation center causes propulsive motility of the colorectum in rats. Considering that somatostatin is involved in nociceptive signal transmission in the spinal cord, our results provide a rational explanation for the concurrent appearance of chronic abdominal pain and colonic motility disorders in IBS patients.     

Transposable elements shape the human proteome landscape via formation of cis‐acting upstream open reading frames

Transposons are major drivers of mammalian genome evolution. To obtain new insights into the contribution of transposons to the regulation of protein translation, we here examined how transposons affected the genesis and function of upstream open reading frames (uORFs), which serve as cis‐acting elements to regulate translation from annotated ORFs (anORFs) located downstream of the uORFs in eukaryotic mRNAs. Among 39,786 human uORFs, 3,992 had ATG trinucleotides of a transposon origin, termed “transposon‐derived upstream ATGs” or TuATGs. Luciferase reporter assays suggested that many TuATGs modulate translation from anORFs. Comparisons with transposon consensus sequences revealed that most TuATGs were generated by nucleotide substitutions in non‐ATG trinucleotides of integrated transposons. Among these non‐ATG trinucleotides, GTG and ACG were converted into TuATGs more frequently, indicating a CpG methylation‐mediated process of TuATG formation. Interestingly, it is likely that this process accelerated human‐specific upstream ATG formation within transposon sequences in 5′ untranslated regions after divergence between human and nonhuman primates. Methylation‐mediated TuATG formation seems to be ongoing in the modern human population and could alter the expression of disease‐related proteins. This study shows that transposons have potentially been shaping the human proteome landscape via cis‐acting uORF creation.     

Clinical application of stress-breaking ball attachment for implant overdenture

PatientThe patient was a 62-year-old partially edentulous woman with missing bilateral premolars and molars in the mandibular jaw. The patient selected implant supported-removable partial denture rehabilitation. Implants were placed bilaterally at the distal extension of the denture base in order to minimize denture displacement. The stress-breaking ball (SBB) attachment consists of a flat-top ball head male and O-ring rubber female. The female was covered by a silicone housing with three amounts of space to allow three kinds of settlement (0.3 mm, 0.5 mm, and 0.7 mm); they were selected by thickness or pressure displacement of the mucosa and occlusal force. After the healing period, the SBB attachments (0.3 mm) were placed on the implants, and the implant-supported removable partial denture was then conventionally fabricated. The delivered denture had sufficient retention and appropriate stress breaking.DiscussionThe advantages of SBB attachments over conventional attachments are as follows: (1) they prevent the implant from excessive occlusal force, (2) they are ready-made, (3) they show appropriate retention, and (4) they can be easily mounted on the denture base. The disadvantages of these attachments are as follows: (1) they are approximately 1 mm higher than conventional ball attachments and (2) the retentive force cannot be adjusted.ConclusionThe use of a stress-breaking attachment for implant overdenture rehabilitation should be considered so that the occlusal force is equally distributed between the alveolar ridge and the implants.