Neuroprotective effect of L-carnitine in the 3-nitropropionic acid (3-NPA)-evoked neurotoxicity in rats

A plant and fungal toxin, 3-NPA, acts as an inhibitor of mitochondrial function via irreversible inactivation of the mitochondrial inner membrane enzyme, succinate dehydrogenase (SDH). Inhibition of SDH disturbs electron transport and leads to cellular energy deficits and neuronal injury. We have shown that pretreatment with l-carnitine, while not significantly attenuating SDH inhibition, prevented hypothermia and oxidative stress-associated increased activity of free radical-scavenging enzymes. Here, a neurohistological method was applied to examine the effect of carnitine pretreatment against 3-NPA-induced neurotoxicity. Twenty adult male Sprague-Dawley rats were randomly divided into two groups (n = 10/group). Rats in the first group were injected twice with 3-NPA at 30 mg/kg s.c., 2 days apart, and the second group of animals received l-carnitine pretreatment at 100 mg/kg 30-40 min before 3-NPA administration. Rats in both groups were perfused 7 days later and their brains harvested. Degenerating neurons were identified and localized via the fluorescent marker Fluoro-Jade B. In the three animals that survived 3-NPA dosing, one exhibited no pathology, one exhibited moderate unilateral damage to the striatum, and the third exhibited extensive bilateral neuronal degeneration in multiple forebrain regions. In the seven surviving animals that received l-carnitine prior to 3-NPA insult, six exhibited no lesions, while one exhibited a modest unilateral lesion in the striatum. It appears that l-carnitine is protective against 3-NPA-induced toxicity, as reflected by both reduced mortality and significantly reduced neuronal degeneration.     

Diagnostic role of fine-needle aspiration of bone lesions in patients with a previous history of malignancy

At the present time fine-needle aspiration (FNA) is considered a routine diagnostic procedure in evaluating neoplastic vs. nonneoplastic lesions in many organs, with high sensitivity and specificity. The purpose of this study was to assess the utility of FNA in areas of diagnostic difficulty and its limitations in evaluating bone lesions in patients with a previous history of malignancy. From 1989 to 2000, 249 CT-guided FNAs of bone lesion were performed at our institutions; 187/249 (75.1%) patients had a previous history of malignancy. Aspirated material was air-dried for Diff-Quik stain or fixed in ethanol for Papanicolaou staining. Subsequent surgical tissue was available in 69/187 (36.9%) of the cases. There were 114 males and 73 females, ages 14-86 yr (mean, 64 yr). The primary tumor site was lung 49, genitourinary 46, breast 31, gastrointestinal 28, hematopoietic 26, soft tissue/skin 5, and thyroid 2. There were 125 FNAs of the vertebral spine, 19 from the pelvis, 11 from the ribs, 9 from the sternum, 5 from the femur, and 18 from miscellaneous bone sites. Out of 187, 166 (88.7%) were malignant aspirates confirming the patients' primary malignancies. The most common malignancy encountered was adenocarcinoma, 126/187 (67.4%). Surgical tissue was available for review in 69 patients and the results were in agreement with the FNAs diagnosis in all cases. Nine out of 187 (4.8%) cases were diagnosed as marrow elements on cytological material. These patients have been followed for 1-9 yr and have failed to reveal signs or symptoms of clinical recurrence. Three out of 187 (1.6%) cases showed osteomyelitis. Nine out of 187 (4.8%) were unsatisfactory specimens, with biopsy follow-up available in four cases, showing three metastatic tumors and one case of osteomyelitis. FNA of metastatic bone lesions is a major step in pretreatment diagnosis. On satisfactory specimens, the cytological diagnosis viewed in the clinical-radiological context proves to be similar to surgical diagnosis. FNA is an excellent technique with a high accuracy rate in assessing metastatic bone lesions.     

Application of adjunct techniques in cytologic material in the diagnosis of rhabdomyosarcoma: case report and review of the literature

A 4(1/2)-yr-old female presented with right-sided pleural effusion and a retroperitoneal mass. Cytologic analysis of the pleural fluid yielded malignant small round blue cells, which were noncohesive, 3-4 times the size of lymphocytes. The malignant cells had hyperchromatic, pleomorphic nuclei with moderate amounts of vacuolated cytoplasm. A few fiber-shaped cells were also seen. Immunostains for desmin, muscle-specific actin were positive; ultrastructural findings of thick and thin actin-myosin filaments confirmed the diagnosis of embryonal rhabdomyosarcoma. This case illustrates the importance of performing appropriate immunohistochemical stains and ultrastructural studies on cytological material to arrive at a definitive diagnosis.     

Neuropathogenesis of Chimeric Simian/Human Immunodeficiency Virus infection In Pig-tailed and Rhesus Macaques

We recently reported that a chimeric simian/human immunodeficiency virus (SHIV_KU-1) developed in our laboratory caused progressive depletion of CD4⁺T lymphocytes and AIDS within 6 months of inoculation into pig-tailed macaques (M.nemestrina). None of the pig-tailed macaques showed productive SHIV infection in the central nervous system (CNS). In this report, we show that by further passage of the pathogenic virus in rhesus macaques [M. mulatta], we have derived a new strain of SHIV (SHIV_KU-2) that has caused AIDS and productive CNS infection in 3 of 5 rhesus macaques infected with the virus. Productive replication of SHIV in the CNS was clearly shown by high infectivity titers and p27 protein levels in brain homogenates, and in 2 of the 3 rhesus macaques this was associated with disseminated, nodular, demyelinating lesions, including focal multinucleated giant cell reaction, largely confined to the white matter. These findings were reminiscent of HIV-1 associated neurological disease, and our immunohistochemical and in situ hybridization data indicated that the neuropathological lesions were associated with the presence of SHIV-specific viral antigens and nucleic acid respectively. However, the concomitant reactivation of opportunistic infections in these macaques suggested that such pathogens may have influenced the replication of SHIV in the CNS, or modified the neuropathological sequelae of SHIV infection in the rhesus species, but not in pig-tailed macaques. Our findings in the two species of macaques highlight the complexities of lentiviral neuropathogenesis, the precise mechanisms of which are still elusive.     

Radioprotective potential of ginseng

A majority of potential radioprotective synthetic compounds have demonstrated limited clinical application owing to their inherent toxicity, and thus, the seeking of naturally occurring herbal products, such as ginseng, for their radioprotective capability has become an attractive alternative. In general, ginseng refers to the roots of the species of the genus Panax. As a medicinal herb, ginseng has been widely used in traditional Chinese medicine for its wide spectrum of medicinal effects, such as tonic, immunomodulatory, antimutagenic, adaptogenic and antiaging activities. Many of its medicinal effects are attributed to the triterpene glycosides known as ginsenosides (saponins). This review addresses the issue of the radioprotective effects of ginseng on mammalian cells both in vitro and in vivo. Results indicate that the water-soluble extract of whole ginseng appears to give a better protection against radiation-induced DNA damage than does the isolated ginsenoside fractions. Since free radicals play an important role in radiation-induced damage, the underlying radioprotective mechanism of ginseng could be linked, either directly or indirectly, to its antioxidative capability by the scavenging free radicals responsible for DNA damage. In addition, ginseng's radioprotective potential may also be related to its immunomodulating capabilities. Ginseng is a natural product with worldwide distribution, and in addition to its antitumor properties, ginseng appears to be a promising radioprotector for therapeutic or preventive protocols capable of attenuating the deleterious effects of radiation on human normal tissue, especially for cancer patients undergoing radiotherapy.     

Regulation of human basophil adhesion to endothelium under flow conditions: Different very late antigen 4 regulation on umbilical cord blood-derived and peripheral blood basophils

BACKGROUND: Although soluble mediators released by basophils in tissue sites contribute to the chronic injury that occurs in hypersensitivity diseases, only limited information is available about how circulating basophils are recruited to tissues. In particular, the interaction of basophils with endothelium under conditions that mimic physiologic flow has not been explored. OBJECTIVE: We sought to identify adhesion molecules regulating the attachment of human basophils to IL-4-activated human umbilical vein endothelial cells (HUVECs) under flow conditions. METHODS: A parallel-plate flow chamber and blocking mAbs were used to define the adhesion molecules involved in the interactions of peripheral blood basophils (PBBs) and cord blood-derived basophils (CBDBs) with IL-4-activated HUVECs and with Chinese hamster ovary (CHO) cell transfectants expressing specific adhesion molecules. A fluorescent ligand specific for very late antigen 4 (VLA-4) was used to directly examine the VLA-4 affinity state of basophils. RESULTS: Flowing PBBs and CBDBs attached to activated HUVECs and to CHO cells expressing P- or E-selectin. However, only CBDBs attached to vascular cell adhesion molecule 1 (VCAM-1)-transfected CHO cells under flow conditions. The attachment of CBDBs to CHO cells was blocked by mAbs directed against E-selectin, P-selectin, and VCAM-1, whereas attachment of PBBs was blocked by E-selectin and P-selectin mAbs. Activating VLA-4 with Mn(2+) on PBBs resulted in adhesion to the VCAM-1-transfected CHO cells, indicating that VLA-4 activity on PBBs can be regulated, at least in part, through affinity changes. The Mn(2+)-induced upregulation of basophil VLA-4 affinity was demonstrated directly by using a fluorescent ligand for VLA-4 and flow cytometry. CONCLUSIONS: The interaction of human CBDBs and PBBs with endothelium under flow conditions is mediated in part by both P- and E-selectin. VLA-4 additionally contributes to the adhesion of flowing CBDBs. However, the affinity of VLA-4 is too low to support the adhesion under flow conditions of unstimulated PBBs.     

Cytomegalovirus Isolation from a Chimpanzee with Acute Demyelinating Disease After Inoculation of Multiple Sclerosis Brain Cells

A strain of cytomegalovirus (CMV) was isolated during the third subcultivation of explants from the left frontal lobe of a chimpanzee that developed paralysis more than 3 years after intracerebral inoculation at birth with brain cell cultures derived from a patient with multiple sclerosis. Another strain of CMV was also isolated from a lymph node culture taken from the same chimp. The isolates, designated MZM-13 and MZM-14, produced a cytopathic effect characteristic for CMV when inoculated into brain, ganglion, or fibroblast cultures of human or simian origin. Infected cells contained characteristic Cowdry A intranuclear as well as intracytoplasmic inclusion bodies, and 100-nm spherical herpes-like virus particles were detected by electron microscopy in the nucleus and cytoplasm of infected cells. Virus was further identified as CMV with convalescent human anti-CMV serum. Complement-fixing antibody to CMV was present at a titer of 1:32 when the acutely ill chimpanzee was sacrificed. No antibody was detected at birth or at 1 or 2 years of age. A newborn chimpanzee inoculated intracerebrally with MZM-13 developed clinically asymptomatic lesions in the central nervous system characterized by acute and chronic inflammation and degeneration of myelin in cranial and spinal nerve roots. Restriction endonuclease analysis of viral deoxyribonucleic acid isolated from these two viruses indicated that MZM-13 and MZM-14 are identical and are closely related to chimpanzee CMV. No similarity in restriction endonuclease fragment patterns was found between MZM virus and the Towne and Clegg strains of human CMV.     

Studies on Acute Methionine Toxicity: I. Nucleolar Disaggregation in Guinea Pig Hepatic Cells with Methionine or Ethionine and Its Reversal with Adenine

The effects of methionine and ethionine on the fine structure of hepatic cell nucleoli of guinea pigs and rats were investigated. A single intraperitoneal injection of methionine into guinea pigs results in the disruption of nucleolonema as early as 2 hours after the injection. By 4 hours, nucleoli show complete fragmentation consisting of many small fragments and small remnants of nucleoli. Large aggregates of interchromatinic granules and condensation of chromatin appear in the nucleoplasm. These changes are remarkably similar to the lesions induced by ethionine in the liver of the rat or the guinea pig. The methionine-induced nuclear and nucleolar lesions persist up to 10 hours after the injection. The administration of adenine 4 hours after the methionine injection reverses the nucleolar lesions by 8 hours. The appearance of incompletely reconstructed nucleoli with twisted ropelike structures suggests a pattern of recovery very similar to the adenine-induced nucleolar reformation in ethionine-treated rats. Injecting methionine into rats induced no nucleolar abnormalities. It is suggested that the mechanism of nucleolar fragmentation induced by methionine or ethionine is related to the accumulation of S-adenosyl compounds with concomitant ATP deficiency in the liver.