The Preclinical Safety Evaluation of Human Monoclonal Antibody against Cytomegalovirus

The human monoclonal antibody against cytomegalovinis (Mab C23)was examined pharmacokinetically and toxicologically as partof the preclinical studies prior to approval for human use.Rats given repeated intravenous administrations of Mab C23 producedno antibodies against Mab C23 and maintained a blood Mab C23level in a dose-dependent manner. However, pregnant rabbitsproduced antibodies against Mab C23. The half-life of Mab C23in plasma was 15.9 days in rats, which was similar to that ofnormal human serum -globulin (NHSG). Neither behavioral effectsnor circulatory disturbance was found in mice, rats, and dogseven after a single intravenous injection of 100 or 200 mg/kg,which corresponds to 50 or 100 times the intended clinical dosage.The repeated doses of 2, 10, or 20 mg/kg of Mab C23 on six occasionswith 1- or 2-week intervals elicited a transient decrease inleukocyte counts in rats given 10 or 20 mg/kg, but no adverseeffects in cynomolgus monkeys. Mab C23 did not cause any reproductiveor developmental toxicity when administered to rats and rabbitsat dose levels of 20 mg/kg or less. However, pregnant animalsshowed lower plasma levels of Mab C23 than non-pregnant animals.The chromosomal aberration test disclosed no clastogenicityin human lymphocytes. An immunostaining for Mab C23 revealedno localizations in several tissues of cynomolgus monkeys givenintravenous doses of Mab C23. The preclinical safety evaluationin animals other than rabbits, which produced no antibodiesagainst Mab C23, showed that the behavior of Mab C23 is pharmacokineticallysimilar to that of NHSG and is as safe as NHSG, which has longbeen used as a biological agent. However, because there wasa difference in blood levels of Mab C23 between pregnant andnonpregnant animals, its clinical administration to pregnantpatients should differ from that to non-pregnant patients.     

Metastasizing atrial myxoma: a case with multiple subcutaneous tumours

We report a case with rapidly growing subcutaneous and intra-muscular tumours that were identical histopathologically to a pre-existing left atrial myxoma. No invasion of visceral organs or skeleton was found. This is a very rare case of metastasizing myxoma with wide dissemination and rapid metastastic growth, despite the benign appearance of the original tumour.     

Incremental Value of Objective Frailty Assessment to Predict Mortality in Elderly Patients Hospitalized for Heart Failure

Background

The impact of frailty on long-term prognosis in patients with heart failure (HF) remains unclear, and there is no simple and objective assessment for it. This study was performed to examine the association between frailty score and clinical outcome in elderly patients hospitalized for HF.

Is postoperative radiotherapy or maintenance chemotherapy necessary for carcinoma of the uterine cervix?

Summary. The effectiveness of postoperative radiotherapy and adjuvant chemotherapy was examined for patients with uterine cervical squamous cell carcinoma. Whole pelvis irradiation is unnecessary for patients with less than 2/3 of depth of cervical local involvement without pelvic regional lymph node metastases. Adjuvant chemotherapy with tegafur [l-(2-tetrahydrofuryl)-5-fluorouracil] (600 mg/day) has failed to improve the survival of patients with positive lymph node metastases.     

DIRECTIONAL NEURITE OUTGROWTH AND AXONAL DIFFERENTIATION OF EMBRYONIC HIPPOCAMPAL NEURONS ARE PROMOTED BY A NEURITE OUTGROWTH DOMAIN OF THE B2-CHAIN OF LAMININ

Molecular cues involved in directional neurite outgrowth and axonal differentiation of embryonic hippocampal neurons were studied on substrates coated in a striped 5 μm pattern with synthetic peptides from a neurite outgrowth (RDIAEIIKDI, P1543) and cell attachment (CDPGYIGSR, P364) domain of the B2- and B1-chains of laminin, respectively. Both peptides supported neuronal attachment, but only the B2-chain-derived P1543 promoted expression of a mature neuronal phenotype. Directional neurite outgrowth and axonal differentiation of embryonic hippocampal neurons were selectively induced by striped substrates of the B2-chain-derived P1543. Axonal differentiation was determined by expression of a phosphorylated epitope of the 200 kDa neurofilament protein in the longer “axonal” neurite of the bipolar embryonic hippocampal neurons. Ethanol (100 mM), a neuroactive compound known to delay neuronal development, impaired both directional neurite outgrowth and expression of a phosphorylated epitope of the 200 kDa neurofilament protein on a patterned P1543 substratum. The present results provide direct evidence that a 10 amino acid peptide (P1543), derived from a neurite outgrowth domain of the B2-chain of laminin, may be an axonal guidance and differentiation factor for embryonic hippocampal neurons in vitro. Published by Elsevier Science Ltd.     

MOLECULAR IDENTIFICATION AND ANTIMICROBIAL RESISTANCE PATTERN OF SEVEN CLINICAL ISOLATES OF Nocardia spp. IN BRAZIL

Nocardia is a ubiquitous microorganism related to pyogranulomatous infection, which is difficult to treat in humans and animals. The occurrence of the disease is on the rise in many countries due to an increase in immunosuppressive diseases and treatments. This report of cases from Brazil presents the genotypic characterization and the antimicrobial susceptibility pattern using the disk-diffusion method and inhibitory minimal concentration with E-test® strips. In summary, this report focuses on infections in young adult men, of which three cases were cutaneous, two pulmonary, one neurological and one systemic. The pulmonary, neurological and systemic cases were attributed to immunosuppressive diseases or treatments. Sequencing analysis of the 16S rRNA segments (1491 bp) identified four isolates of Nocardia farcinica, two isolates of Nocardia nova and one isolate of Nocardia asiatica. N. farcinica was involved in two cutaneous, one systemic and other pulmonary cases; N. nova was involved in one neurological and one pulmonary case; and Nocardia asiatica in one cutaneous case. The disk-diffusion antimicrobial susceptibility test showed that the most effective antimicrobials were amikacin (100%), amoxicillin/clavulanate (100%), cephalexin (100%) and ceftiofur (100%), while isolates had presented most resistance to gentamicin (43%), sulfamethoxazole/trimethoprim (43%) and ampicillin (29%). However, on the inhibitory minimal concentration test (MIC test), only one of the four isolates of Nocardia farcinica was resistant to sulfamethoxazole/trimethoprim.     

High-density lipoproteins from probucol-treated patients have increased capacity to promote cholesterol efflux from mouse peritoneal macrophages loaded with acetylated low-density lipoproteins

To elucidate the anti-atherogenic effect of probucol, high-density lipoprotein (HDL) was isolated from probucol-treated patients (n = 14) and compared with that from control subjects (n = 12). The HDL obtained from probucol-treated patients was low in cholesteryl ester (CE) in comparison with that from control subjects (21.3 ± 3.9 mol per cent vs. 27.6 ± 3.2 mol% of total lipids, P < 0.001), and the peak diameters of patients' HDL were significantly smaller than those of control subjects on 4–30% non-denaturing polyacrylamide gradient gel electrophoresis (10.6 ± 0.6 nm vs. 12.1 ± 0.4 nm, P < 0.001). These data may be explained by the increased cholesteryl ester transfer protein (CETP) activities of probucol-treated patients (129 ± 12% of control subjects, P < 0.001). The in vitro ability of HDL to remove CE from lipid-laden macrophages induced by incubation with acetylated low-density lipoprotein (Ac-LDL) was studied. The small and CE-poor HDL obtained from probucol-treated patients had a greater capacity to promote CE efflux from macrophages than did control HDL (59.8 ± 6.9% vs. 44.2 ± 5.4%, P < 0.01). Furthermore, the ability of HDL to promote cholesterol efflux correlated negatively with the CE content and particle diameter of HDL (r = ?0.561 and r = ?0.583 respectively; P < 0.01). When the inhibitory effect of HDL on the incorporation of [¹⁴C]-oleate into cellular cholesteryl ester was compared, the HDL from patients and control subjects inhibited CE formation to a similar extent. The enhanced ability of probucol-treated patients' HDL may, therefore, be involved in the acceleration of hydrolysis of the CE pool in macrophages. Taken together, we conclude that CETP plays a crucial role in making HDL more active in its anti-atherogenic function by reducing CE and making HDL smaller, and that probucol may enhance reverse cholesterol transport by activating CE transfer in vivo. The current study demonstrated, for the first time, that HDL modified by enhanced CETP activity in vivo is potentially anti-atherogenic.     

Detection of heterozygotes of X-linked ichthyosis by measuring steroid sulphatase activity of lymphocytes. Mode of inheritance in three families

Steroid sulphatase activity in peripheral blood lymphocytes was assayed in all available members of three families in which cases of X-linked ichthyosis were frequently seen. Lymphocytes from all the patients with this disease lacked steroid sulphatase activity and some female members who were probably heterozygotes, showed significantly lower enzyme activity compared with other healthy family members and normal controls. This suggest that females heterozygous for X-linked ichthyosis in these families could be traced enzymatically. Three childless females in these families were found to be possible heterozygotes in view of their lower enzyme levels. It was found that polyacrylamide gel electrophoretic mobility of serum low-density lipoproteins was increased in X-linked ichthyosis patients but was not changed in the probable heterozygotes. The detection of individuals heterozygous for X-linked ichthyosis, for the purpose of precise genetic counselling, may be possible by measuring steroid sulphatase activity of peripheral blood lymphocytes.