INVESTIGATION OF A PRACTICAL PATIENT DOSE INDEX FOR ASSESSMENT OF PATIENT ORGAN DOSE FROM CONE-BEAM COMPUTED TOMOGRAPHY IN RADIATION THERAPY USING A MONTE CARLO SIMULATION.

The purpose of this study was to investigate a practical patient dose index for assessing the patient organ dose from a cone-beam computed tomography (CBCT) scan by comparing eight dose indices, i.e. CTDI100, CTDIIEC, CTDI∞, midpoint doses f(0)PMMA for a cylindrical polymethyl methacrylate (PMMA) phantom, f(0)Ap for an anthropomorphic phantom and f(0)Pat for a prostate cancer patient, as well as the conventional size specific dose estimations (SSDEconv) and modified SSDE (SSDEmod), with organ dose for the prostate (ODprost) obtained via Monte Carlo (MC) simulation. The ODprost was the reference dose used to find the practical dose index at the center of the pelvic region of a prostate cancer patient. The smallest error rate with respect to the ODprost of 19.3 mGy (reference) among eight dose indices was 5% for f(0)Pat. The practical patient dose index was the f(0)Pat, which showed the smallest error with respect to the reference dose.

Caffeine activates preferentially α1-isoform of 5'AMP-activated protein kinase in rat skeletal muscle.

AIM: Caffeine activates 5'AMP-activated protein kinase (AMPK), a signalling intermediary implicated in the regulation of glucose, lipid and energy metabolism in skeletal muscle. Skeletal muscle expresses two catalytic α subunits of AMPK, α1 and α2, but the isoform specificity of caffeine-induced AMPK activation is unclear. The aim of this study was to determine which α isoform is preferentially activated by caffeine in vitro and in vivo using rat skeletal muscle. METHODS: Rat epitrochlearis muscle was isolated and incubated in vitro in the absence or presence of caffeine. In another experiment, the muscle was dissected after intravenous injection of caffeine. Isoform-specific AMPK activity, the phosphorylation status of AMPKα Thr(172) and acetyl-CoA carboxylase (ACC) Ser(79) , the concentrations of ATP, phosphocreatine (PCr) and glycogen, and 3-O-methyl-d-glucose (3MG) transport activity were estimated. RESULTS: Incubation of isolated epitrochlearis muscle with 1 mm of caffeine for 15 min increased AMPKα1 activity, but not AMPKα2 activity; concentrations of ATP, PCr and glycogen were not affected. Incubation with 3 mm of caffeine activated AMPKα2 and reduced PCr and glycogen concentrations. Incubation with 1 mm of caffeine increased the phosphorylation of AMPK and ACC and enhanced 3MG transport. Intravenous injection of caffeine (5 mg kg(-1) ) predominantly activated AMPKα1 and increased 3MG transport without affecting energy status. CONCLUSION: Our results suggest that of the two α isoforms of AMPK, AMPKα1 is predominantly activated by caffeine via an energy-independent mechanism and that the activation of AMPKα1 increases glucose transport and ACC phosphorylation in skeletal muscle.

Pilocytic astrocytomas in elderly adults.

Pilocytic astrocytomas are classified as WHO grade I gliomas that occur predominantly in children and young adults. Reports of the tumors in elderly adults are extremely rare. We describe two cases of pilocytic astrocytoma in elderly adults, a 68-year-old man and a 71-year-old woman. Brain computed tomography (CT) and magnetic resonance imaging (MRI) revealed well-circumscribed lesions associated with contrast enhancement and minimal surrounding edema. Pathological studies revealed findings consistent with pilocytic astrocytomas. Although these tumors are rarely found in elderly adults, pilocytic astrocytomas should be considered in the differential diagnosis if the radiographic features of the tumors are characteristic of pilocytic astrocytomas.

[Effect of background factors concerning both elderly persons and their families with regard to the caregiver burnout in the home].

A cross sectional survey was performed to quantify factors that exhaust caregivers. We report that the degree of difficulty for caregivers correlated well with the burnout score (r = -0.517; p < 0.001), but the correlation between caregivers' burnout score and the level of their patient's basic ADL was lower (r = -0.317; p = 0.014). In this paper, we investigated other factors related to exhaustion. Caregivers' burnout score correlated with their age. The level of disease that caregivers complained increased burnout score. The need for nocturnal care and continuous observation, as well as rejection of aid burned out caregivers. Multiple regression analysis clarified that significant independent contributing factors for burnout score were help with toilet use, nocturnal aid and diseases suffered by caregivers.

[Quantitative evaluation of the burden of those giving home care for senile dementia of Alzheimer type subjects using the burnout scale of pines].

We quantitatively measured the physical and psychological burden of caregivers of 25 patients with senile dementia of Alzheimer type (SDAT). The Barthel Index (BADL, full score: 20 points) and the caregiver burden in terms of physical symptoms correlated well (r = -0.964, p < 0.001), as did the degree of abnormal behavior and caregiver burden in terms of psychological symptoms (r = 0.946, p < 0.001). The correlation with the burnout scale (BOS) of Pines was best when both factors of psychological and physical symptoms were included. The correlation between BOS and the caregiver burden in terms of both physical and psychological symptoms was r = 0.874, p < 0.001, and the correlation between BOS and "the degree of abnormal behavior" +(20- "BADL") was r = 0.853, p < 0.001. The burden in terms of physical symptoms increased as the BADL score decreased, but the burden in terms of psychological symptoms increased initially and decreased in the last phase of the disease. We conclude that the BOS score of SDAT caregivers was stable in the initial phase, then increased rapidly, thereafter preserved high, and dropped rapidly as the BADL score decreased.

Evidence for surface Andreev bound states in cuprate superconductors from penetration depth measurements.

Tunneling and theoretical studies have suggested that Andreev bound states form at certain surfaces of unconventional superconductors. Through studies of the temperature and field dependence of the in-plane magnetic penetration depth lambda(ab) at low temperature, we have found strong evidence for the presence of these states in clean single crystal YBCO and BSCCO. Crystals cut to expose (110) surfaces show a strong upturn in lambda(ab) at around 7 K, when the field is oriented along the c axis. In YBCO this upturn is completely suppressed by a field of approximately 0.1 T.

Chronic neutrophilic leukemia with acute myeloblastic transformation.

We report a rare case of chronic neutrophilic leukemia (CNL) which terminated in acute myeloblastic transformation 3 years after the onset of the disease. The increased leukocytes were mainly neutrophils at various maturational stages until 1 month before transformation without dysplastic hematopoietic cells or other myeloproliferative disorders. Repeated analyses for the Philadelphia chromosome (Ph1), rearrangement of the BCR gene or chimeric BCR/ABL mRNA, major, minor and mu, were negative. Genomic analysis of granulocyte colony-stimulating factor (G-CSF) receptor did not reveal any abnormality. The clinical manifestations were characterized by hyperleukocyte syndrome with respiratory distress and ischemic legs with gangrene.

Morphological and cytogenetic changes in therapy-related leukemia developed in a t(8;21)-acute myeloid leukemia (M2) patient: sequential cytogenetic and molecular analyses.

A patient with acute myeloid leukemia (AML)-M2 with t(8;21)(q22;q22) achieved complete remission with remission-induction chemotherapy followed by consolidation and intensification chemotherapies. T(8;21)(q22;q22) disappeared, but chimeric AML1/MTG8 was continuously detected in bone marrow cells. Following the development of therapy-related leukemia after 1 year, evolution of therapy-related AML-M4 with t(11;17)(q23;q25) and the rearrangement of the MLL gene were observed, while AML/MTG8 disappeared. After reinduction and following intermittent chemotherapies, a subsequent alternative transformation to AML-M2 occurred after detection of t(3;21)(q21;q22), with a break in the AML1 gene shown by interphase fluorescence in situ hybridization analysis. This leukemia transformed to AML-M4 after t(9;22)(q34;q11), with a minor BCR/ABL rearrangement, and then finally to AML-M2. This therapy-related leukemia was resistant to chemotherapy. These findings indicate that alterations in cytogenetic and molecular events caused by chemotherapeutic agents contribute to the sequential evolution of new leukemic clones with different morphology.

[Rosiglitazone (BRL-49653)].

Rosiglitazone, a thiazolidinedion antidiabetic agent, improves insulin resistance in patients with type 2 diabetes mellitus. Rosiglitazone binds to PPAR-gamma with high affinity and the in vivo antidiabetic potency of rosiglitazone is correlated with its high biding affinity. In animal models of insulin resistence, rosiglitazone decreased plasma glucose, triglyceride and insulin levels and also prevented diabetic nephropathy and pancreatic islet cell degeneration. In clinical trials in patients with type 2 diabetes mellitus, rosiglitazone, 2 to 12 mg/day (as a single daily dose or 2 divided daily doses), improved glycemic control as demonstrated, by decreases in fasting plasma glucose and HbA1C levels. Rosiglitazone did not appear to increase the risk of hypoglycemia and there was no evidence of hepatotoxicity in pre-clinical trials.

Triad proteins and intracellular Ca2+ transients during development of human skeletal muscle cells in aneural and innervated cultures.

Dihydropyridine receptors (DHPRs), ryanodine receptors (RyRs), and triadin are major components of triads of mature skeletal muscle and play crucial roles in Ca2+ release in excitation-contraction (E-C) coupling. We investigated the expression and localization of these proteins as well as intracellular Ca2+ transients during development of human muscle cells cultured aneurally and innervated with rat spinal cord. mRNAs encoding skeletal muscle isoforms of the DHPR alpha1 subunit (alpha1S-DHPR), the RyR, and triadin were scarce in myoblasts and increased remarkably after myotube formation. Immunocytochemically, alpha1S-DHPR was expressed after myoblast fusion and localized mainly within the cytoplasmic area of aneural myotubes whereas the cardiac isoform (alpha1C-DHPR) was abundant along the plasma membrane. RyRs and triadin were both detected after myotube formation and colocalized in the cytoplasm of aneural myotubes and innervated muscle fibers. Along the plasma membrane of aneural myotubes, colocalization of alpha1C-DHPR with the RyR was more frequently observed than that of alpha1S-DHPR. In innervated muscle fibers, alpha1S-DHPR and RyR were colocalized first along the plasma membrane and later in the cytoplasmic area and formed regular double rows of cross-striation. The alpha1C-DHPR diminished after innervation. In Ca2+ imaging, spontaneous irregular slow Ca2+ oscillations were observed in aneurally cultured myotubes whereas nerve-driven regular fast oscillations were observed in innervated muscle fibers. Both caffeine and depolarization induced Ca2+ transients in aneurally cultured myotubes and innervated muscle fibers. In aneurally cultured myotubes, depolarization-induced Ca2+ transients were highly dependent on extracellular Ca2+, suggesting immaturity of the Ca2+ release system. This dependence remarkably decreased after innervation. Our present results show that these proteins are expressed differently in aneurally cultured myotubes than in adult skeletal muscle, that Ca2+ release in aneurally cultured myotubes is different from in adult skeletal muscle, and that innervation induces formation of a mature skeletal muscle-like excitation-contraction coupling system in cultured human muscle cells.

[Effect of the level of basic activities of daily living on home caregiver burnout].

To relieve the stress of caregivers, it is critical to identify and classify the burden factors in the elderly patients. In order to determine the factors that exhaust caregivers, a cross sectional survey was done. The study employed a self-recording questionnaire form which included the Pines' burnout scale and the level of patient's basic activities of daily living (BADL). Seventy-three caregivers filled in the questionnaire. They reported the difficulty of care for an elderly patient in the home, and the degree of the difficulty correlated well with the burnout score (r = -0.517; p < 0.001). The caregivers' burnout score did not correlate so well with the level of their patient's BADL (r = -307; p = 0.014). Among the factors in BADL, aid for toilet use, feeding, sitting, and transferring raised the burnout scale. On the other hand, assistance for bathing and dressing did not correlate with the burnout score. On multiple regression analysis using the background factors for the burnout score as explanatory variables, aid for feeding and sitting were significant independent contributing factors. Since it became clear that the caregivers in the home were almost burnt out owing to the aid they need to give for the elderly person's BADL, attempts should be done to reduce their burden as soon as possible.

Mechanism of hepatorenal syndrome in rats of Long-Evans Cinnamon strain, an animal model of fulminant Wilson's disease.

Rats of Long-Evans Cinnamon (LEC) strain were used as a hepatorenal syndrome model of fulminant Wilson's disease. Copper levels in the kidneys increased markedly from 16 to 126 microg Cu/g from 12 to 16 weeks, and remained at the same level at 16 and 19 weeks when the rats suffered from severe renal dysfunction and also at 20 weeks in some other normal rats. The above findings imply that the renal dysfunction may have been induced independently of the copper level in the kidneys. The present study suggested the following mechanism: immediately after copper-induced hepatic dysfunction, plasma copper-metallothionein (CuMT), which was released from the liver, became elevated. The elevation was closely related to the increases in alkaline phosphatase, glucose and amino acids, all in the urine. The above findings suggest that plasma CuMT, which was released from the liver into the blood upon copper-induced hepatic dysfunction, was subsequently filtered at the glomeruli due to its smaller molecular weight, and then caused dysfunction of the brush border membrane of the renal proximal tubules probably after splitting into radical copper and amino acids in acidic vesicles close to the membrane. The critical concentration of plasma CuMT required to induce renal dysfunction was estimated as 1 microg Cu/l.

Second lung adenocarcinoma after combination chemotherapy in two patients with primary non-Hodgkin's lymphoma.

We report a rare complication of a secondary malignant solid tumor in two patients with non-Hodgkin's malignant lymphoma who developed lung adenocarcinoma after treatments with combination chemotherapies. The first was a case of primary malignant lymphoma of the cervical spinal cord which had been previously treated with radiation to the spinal lesion and combination chemotherapies and entered complete remission. The patient was further treated for relapse with autologous bone marrow transplantation preconditioned with high-dose chemotherapy. Lung adenocarcinoma developed 5.5 years after the initial diagnosis. The second case of malignant lymphoma of lymph nodes did not respond to conventional combination chemotherapies and did not enter remission. Lung adenocarcinoma developed 1 year after the initial diagnosis. The two patients died of lung carcinoma. The clinical profiles of these cases are presented and the causal relationship of primary malignant neoplasms to the second malignant neoplasms is discussed.

Decreased expression of myotonic dystrophy protein kinase and disorganization of sarcoplasmic reticulum in skeletal muscle of myotonic dystrophy.

Pathological expression of myotonic'dystrophy protein kinase (DMPK) in skeletal muscle of myotonic dystrophy (DM) was studied by Western blot analysis, immunohistochemistry, and immunoelectron microscopy of DMPK. Western blot analysis showed that DMPK protein in DM skeletal muscles dramatically decreased. DMPK-positive muscle fibers showed typical DM pathological changes such as type I atrophy, central nuclei, nuclear chains, and sarcoplasmic masses. In degenerated DMPK-positive muscle fibers, cross-striated bands disappeared, and irregular granular DMPK-positive materials appeared in sarcoplasm. By immunoelectron microscopy, DMPK was localized in the terminal cisternae of the sarcoplasmic reticulum (SR) in DM muscle. Swollen DMPK-positive SRs were detected between well preserved myofibrils in the early stage of DM muscle degeneration, and degenerated intramembranous structures with DMPK and an accumulation of mitochondria were observed between disorganized myofibrils in degenerated DM muscle. We concluded that SR is the primary site of the degeneration of DM skeletal muscle and that the decreased DMPK might cause dysregulation of intracellular calcium metabolism, which is followed by DM muscle degeneration.

TMC-171A,B,C and TMC-154, novel polyketide antibiotics produced by Gliocladium sp. TC 1304 and TC 1282.

Four new antibiotics, TMC-171A (2), B (3), C (4) and TMC-154 (5) have been isolated from the fermentation of fungal strains Gliocladium sp. TC 1304 and TC 1282, respectively. Spectroscopic and degradation studies have shown that TMC-171s and TMC-154 were new members of the TMC-151 class of antibiotics, unique polyketides modified with a D-mannose and a D-mannitol or a D-arabitol. These compounds showed moderate cytotoxicity to various tumor cell lines.

Two cases of myelodysplastic syndrome with extramedullary polyclonal plasma cell proliferation and autoantibody production: possible role of soluble Fas antigen for production of excessive self-reactive B cells.

Two cases of myelodysplastic syndrome (MDS) with extramedullary polyclonal plasma cell proliferation and autoantibody production are reported. These cases, which showed leukemic change of refractory anemia with excess of blast (RAEB), developed lymph node swelling and muscle abscess; both were infiltrated mainly with plasma cells, without preceding infection. The proliferation of plasma cells was polyclonal and was proven by negative rearrangement of immunoglobulin heavy chain gene or polyclonal staining of immunoglobulin light chains. These patients showed polyclonal gammopathy and autoantibody production such as positive antinuclear factor and direct antiglobulin test. As was observed in one of the present cases, and as we reported previously, the elevated level of soluble Fas antigen in MDS patients, and its inhibition of apoptotic signaling may be responsible for the excessive accumulation of self-reactive B cells, resulting in these clinical manifestations.

Granulocyte colony-stimulating factor (G-CSF) dependent hematopoiesis with monosomy 7 in a patient with severe aplastic anemia after ATG/CsA/G-CSF combined therapy.

We report a case of secondary myelodysplastic syndrome (MDS) with monosomy 7, which evolved from severe aplastic anemia (SAA) after long-term use of granulocyte colony-stimulating factor (G-CSF). A 36 year old female was admitted for detailed examination and treatment of pancytopenia. SAA was diagnosed based on hypoplastic bone marrow and a normal chromosome study. She was treated with anti-thymocyte globulin (ATG), ciclosporin A (CsA) and G-CSF, which resulted in gradual improvement of not only the myeloid but also the erythroid-megakaryocyte series. However, bone marrow dysplasia with monosomy 7 was observed after 7 months of a combination therapy of immunosuppressant and G-CSF, which prompted the discontinuation of G-CSF administration. Thereafter, bone marrow hypoplasia gradually progressed, resulting in a second aplastic crisis. During this process, the proportion of marrow cells showing monosomy 7 decreased, and the proportion with normal karyotype increased. Re-administration of G-CSF induced a trilineage, though dysplastic, hematological response; but the monosomy 7 positive population increased again. These observations indicated the presence of G-CSF dependent hematopoiesis associated with monosomy 7 in this patient. Although many G-CSF related MDS/AML cases with this leukemia-specific abnormal karyotype have been reported with emphasis on the harmful effects of G-CSF, G-CSF was useful even after the appearance of monosomy 7 as a means of avoiding life-threatening infection in this patient.

Plasma cadmium-metallothionein, a biological exposure index for cadmium-induced renal dysfunction, based on the mechanism of its action.

Thirteen rabbits were given subcutaneous cadmium (0.3 mg Cd/kg) daily. The plasma cadmium-metallothionein (CdMT) and the Cd-induced hepatic and renal functions were determined at 0, 5, 8, 11, 12, 13 and 14 weeks. Hepatic dysfunction, an elevated plasma CdMT and renal dysfunction were detected mostly between 12 and 14 weeks. The hepatic dysfunction parameters were closely related with the plasma CdMT, which was then found to correlate with the renal dysfunction parameters. All the above findings suggest the following mechanism for the Cd-induced renal dysfunction: hepatic CdMT is released into the plasma upon the Cd-induced hepatic dysfunction, and then excess plasma CdMT, whose concentration is proportional to the CdMT in the renal proximal tubular lumen, induces renal dysfunction. The critical concentration of plasma CdMT to induce renal dysfunction was estimated as 80 microg Cd/l. The plasma CdMT is proposed therefore as a biological exposure index for the Cd-induced renal dysfunction, based on the mechanism of its action.