Comparative studies on clinical features and CSF proteins of motor neuron disease patients

Clinical features such as types of diseases, sex ratio, age of onset, sites of initial involvement, the appearance of bulbar signs, and duration of illness were studied in 52 patients with motor neuron disease (MND) with a special reference to immunoglobulin in cerebrospinal fluid (CSF) and serum. Although MND has been thought to be a degenerative disease of unknown cause, our data suggested there are some immunological abnormalities in this disease. The duration of illness and the abnormalities of CSF immunoglobulins appeared to be correlated with the type of disease and the site of initial involvement. However, whether or not these abnormalities in CSF immunoglobulins are directly related to the pathogenesis of MND remains unclear.     

Pharmacokinetic and clinical studies with imipenem/cilastatin sodium in the pediatric field. Pediatric Study Group for Imipenem/Cilastatin Sodium

Pharmacokinetic and clinical studies of imipenem/cilastatin sodium (MK-0787/MK-0791), a new carbapenem antibiotic and a dehydropeptidase-I inhibitor, respectively, were carried out in a joint study in the pediatric field by a study group consisting of investigators at 16 institutions. The results were summarized below. Pharmacokinetic studies Peak plasma concentrations of MK-0787/MK-0791 were 27.7-190.0/28.3-216.4 micrograms/ml at doses of 10/10-50/50 mg/kg administered by a 30 or 60-minute drip infusion. The above findings proved that dose response was clearly observed. Over a period of 6 or 7 hours, the urinary excretion of MK-0787 and MK-0791 totaled 54.2-88.0% and 53.6-89.0% of the dose administered, respectively. Plasma half-lives of MK-0787 and MK-0791 in the beta-phase were 0.87-1.05 hours and 0.59-0.95 hour, respectively. The cerebrospinal fluid (CSF) levels of MK-0787 in patients with purulent meningitis were 2.0-14.4 micrograms/ml; however, the penetration rate of the drug into the CSF was relatively poor in patients with normal meninges. Clinical study Clinical efficacy was evaluated in 283 patients. In 112 patients the daily dosage ranged from 30/30 mg/kg to 59/59 mg/kg, and in 138 patients it ranged from 60/60 mg/kg to 99/99 mg/kg. The maximum dose administered was 222/222 mg/kg. The drug was administered either 3 or 4 times per day. The clinical efficacy rate was 92.5% among 187 patients with identified etiologic pathogens. The drug was effective in 3 out of 4 patients with purulent meningitis and in 7 out of 10 patients with septicemia. The clinical efficacy rate was 96.7% in 90 patients with respiratory tract infection (pneumonia, lung abscess, etc.), 96.5% in 57 patients with urinary tract infection, 90.9% in 11 patients with SSTI. The clinical efficacy rate in those with no identified etiologic pathogen was 97.0% among 101 patients. Bacteriologically, the eradication rate for S. aureus was 87.9% of 33 isolates. Comprehensively, the eradication rate for Gram-positive bacteria was 94.7% of 75 isolates. The eradication rate for P. aeruginosa was 87.5% of 8 isolates. Including these strains, the eradication rate for Gram-negative bacteria was 90.3% of 134 isolates. The MK-0787/MK-0791 exhibited an eradication rate of 91.9% among a total of 211 Gram-positive and Gram-negative bacteria including anaerobes.(ABSTRACT TRUNCATED AT 400 WORDS)     

A common FGFR3 mutation functions as a diagnostic marker for achondroplasia-group disorders in the Japanese population

Recent DNA studies performed by several groups have detected mutations of the gene encoding fibroblast growth factor receptor 3 (FGFR3) in patients with achondroplasia-group disorders, including achondroplasia (ACH), hypochondroplasia (HCH), and thanatophoric dysplasia (TD). For this study, we analyzed theFGFR3 gene in 31 Japanese patients with typical ACH, four with HCH, three with a condition intermediate between ACH and HCH (ACH/HCH-intermediate), and one with TD. Of the 31 typical ACH patients, 29 showed a G1138 to A transition and the other two a G1138 to C transversion, both resulting in a common Gly380Arg substitution in the transmembrane domain of FGFR3. The one TD and the four HCH patients did not display any mutations in the transmembrane domain of FGFR3. Of the three ACH/HCH-intermediate cases, one patient showed the Gly380Arg substitution and one did not, and further analysis of the second patient revealed the presence of Asn540Lys substitution. The first patient was, therefore, genotypically diagnosed as ACH and the second as HCH. Peripheral blood leukocyte DNA analysis in the remaining ACH/HCH-intermediate patient indicated an unequal ratio of mutant to normal PCR products, possibly representing a somatic mosaic for the Gly380Arg mutation. Analysis of the common FGFR3 mutation thus appears to help in the molecular diagnosis of patients with achondroplasia-group disorders.     

Hepatocellular carcinoma: Efficacy of transcatheter oily chemoembolization in relation to macroscopic and microscopic patterns of tumor growth among 100 patients with partial hepatectomy

Purpose: To evaluate the efficacy of transcatheter oily chemoembolization (TOCE) for hepatoceliular carcinoma (HCC) on the basis of microscopic and macroscopic findings postembolization. Methods: HCCs ranging in size from 0.5 to 13 cm (mean 3.6 cm) were obtained from partial hepatectomies of 100 consecutive patients who had undergone TOCE between 20 and 246 days (mean 59.5 days) prior to surgery. The efficacy of TOCE was assessed on the basis of the necrotic to live cell ratio of the tumors. The microscopic pattern of tumor growth was grouped into expanding type (complete capsule formation) and replacing type (incomplete or no capsule). There were five types of macroscopic groupings: single nodule, single nodule with extranodular growth (SNE), contiguous and noncontiguous multinodular, and massive growth type. Results: Among 79 cases with the expanding type, 29 (37%) had 100% HCC necrosis, but none with 100% necrosis were in the replacing type. By macroscopic grouping, the efficacy of TOCE decreased from the single nodule type (50% of patients had 100% necrosis) to the SNE type (21%), and the other types (9%).     

Reversal of multidrug resistance by new dihydropyridines with lower calcium antagonistic activity

Summary BS compounds, a series of new dihydropyridines, successfully overcame multidrug resistance in P388/ADR cells in vitro. These agents synergistically potentiated the cytotoxicity of Adriamycin to P388/ADR cells at a concentration of 1–2 M, whereas they showed hardly any synergistic effect in the parental cell line (P388/S) at the same concentration. They inhibited the active drug efflux in P388/ADR cells as well as the binding of [G-³H]-vinblastine to membrane vesicles from P388/ADR, which was increased in resistant P388 cells as compared with parental cells. Besides, unlike the activity of clinically used calcium antagonists, the calcium antagonistic activity associated with BS compounds was very weak: their arterial relaxation activity was <21% of that of verapamil. These data suggest that BS compounds specifically overcome multidrug resistance without the serious hypotensive side effects that accompany the use of verapamil orother calcium antagonists.     

MR imaging of renal cell carcinoma: associations among signal intensity, tumor enhancement, and pathologic findings

The purpose of this study was to compare the MR characteristics of renal cell carcinomas against histologic findings and to assess the correlations among signal intensity, tumor enhancement, and pathologic findings. Fifty-four patients (56 lesions) were examined by MR imaging and then underwent partial or radical nephrectomy. The pathologic diagnosis of all lesions was renal cell carcinoma. All MR examinations were performed as dynamic studies using the same 1.5-T scanner. MR characteristics were compared against pathologic findings after resection, and the correlations among signal intensity, tumor enhancement, and pathologic findings were then assessed. A significant correlation was observed between tumor grade and tumor enhancement, with G3 lesions tending to show little enhancement. Regardless of the histologic classification, G3 tumors were found to contain highly heterotypic cancer cells and very few vessels by histopathologic examination. No significant correlations were noted between the other MR characteristics and pathologic findings. Renal cell carcinomas showing little enhancement tend to be highly malignant lesions based on the pathologic findings. Special consideration is required for these tumors with regard to the selection of surgical intervention and follow-up observation.     

Toll-like receptor 9 is expressed on follicle-associated epithelia containing M cells in swine Peyer's patches

The precise distribution and expression of Toll-like receptor (TLR) 9 in gut-associated lymphoid tissues (GALTs) has not been elucidated. In this study, we investigated the expression pattern of TLR9 in adult and neonatal swine GALTs by real-time quantitative PCR, western blot, confocal laser microscopy and flow cytometric analysis. The swine TLR9 gene was preferentially expressed in adult Peyer's patches (Pps) and mesenteric lymph nodes (MLNs), which contained approximately three times higher TLR9 than the spleen. Other tissues exhibited only weak expression of TLR9. In neonatal swine, elevated expression of TLR9 was detected only in MLNs. We firstly showed that highly expressive (TLR9(+)) cells were formed in Pps and MLNs. In addition, TLR9(+) cells were present not only in immune cells such as dendritic cells and B cells but also in follicle-associated epithelia (FAE) including membranous cells (M cells) in Pps. These results suggest that Pps and MLNs provide the host defense with the ability to respond to a variety of bioactive oligonucleotides (ODNs) from bacteria at a conductive site of initial immune responses.     

Reduced-intensity unrelated cord blood transplantation for patients with advanced malignant lymphoma.

We report the results of reduced-intensity unrelated cord blood transplantation (RI-UCBT) in patients with advanced malignant lymphoma. Twenty patients (median age, 46.5 years; range, 27-66 years) underwent RI-UCBT with a preparative regimen consisting of fludarabine 125 mg/m2 , melphalan 80 mg/m 2 , and 4 Gy of total body irradiation. The median infused total cell dose was 2.75 x 10(7)/kg (range, 2.3-3.4 x 10(7)/kg). Graft-versus-host disease (GVHD) prophylaxis was composed of cyclosporine or tacrolimus alone. Fifteen patients achieved primary neutrophil engraftment after a median of 20 days. Eight patients developed grade II to IV acute GVHD, and 2 developed chronic GVHD. Of the 16 patients with evaluable disease, 10 achieved a complete response. Primary disease recurred in 1 patient, and transplant-related mortality within 100 days occurred in 8 of 20 patients. The estimated 1-year probability of progression-free survival was 50%. These data suggest that RI-UCBT is a feasible option for patients with refractory lymphoma who lack an HLA-matched donor.     

Vascularization in vivo caused by the controlled release of fibroblast growth factor-2 from an injectable chitosan/non-anticoagulant heparin hydrogel

Addition of various heparinoids to the lactose-introduced, water-soluble chitosan (CH-LA) aqueous solution produces an injectable chitosan/heparinoid hydrogel. In the present work, we examined the capability of the chitosan/non-anticoagulant heparin (periodate-oxidized (IO(4)-) heparin) hydrogel to immobilize fibroblast growth factor (FGF)-2, as well as the controlled release of FGF-2 molecules from the hydrogel in vitro and in vivo. The hydrogel was biodegraded in about 20 days after subcutaneous injection into the back of a mouse. When the FGF-2-incorporated hydrogel was subcutaneously injected into the back of both mice and rats, a significant neovascularization and fibrous tissue formation were induced near the injected site. These results indicate that the controlled release of biologically active FGF-2 molecules is caused by biodegradation of the hydrogel, and that subsequent induction of the vascularization occurs.