High-dose (9 MU) long-term (60 weeks) alfa-interferon therapy for chronic hepatitis patients infected with HCV genotype 1b

Summary.  Efficacy of standard regimens (e.g., 3–6 MU for 24 weeks) of alfa-IFN therapy for chronic hepatitis C has been limited, particularly in patients with HCV/1b. To see if higher-dose longer term treatment is more effective, we tried a 9 MU 60-week regimen. HCV/1b-infected chronic hepatitis patients received 9 MU IFNα2a everyday but Sunday for 2 weeks and thrice a week for next 10 weeks, and 76 patients became HCV RNA-negative while 81 remained positive. The RNA-negative patients were then randomized to receive 3 MU (group I, n=37) or 9 MU (group II, n=39) for 48 weeks. Of the RNA-positive patients, only those with normal ALT received another 9 MU 48-week treatment (group III, n=45). Sustained responders (SR) were defined as those with negative RNA and normal ALT 6 months after the therapy. SR rates based on intent-to-treat principle did not differ significantly between groups I and II (30% vs 41%), but those based on the protocol-compatible cases showed a significant difference (32% vs 56%, p=0.034). SR rate in group III was significantly lower than those in group II. Adverse effects of IFN, developed more frequently in groups II and III than in group I, were mostly reversible. In conclusion, our results encourage 9 MU 60-week IFNα treatment in HCV/1b-infected patients with careful attention to adverse effects, and suggest that the treatment should be discontinued if HCV RNA does not disappear within 12 weeks. Received February 18, 1998 Accepted March 19, 1998     

Enhancement of an inhibitory input to the feeding central pattern generator in Lymnaea stagnalis during conditioned taste-aversion learning

To study the neuronal mechanism of a conditioned taste-aversion (CTA) learning in the pond snail Lymnaea stagnalis, we examined the synaptic connection between the neuron 1 medial (N1M) cell and the cerebral giant cell (CGC), the former is an interneuron in central pattern generator for the feeding response and the latter is a regulatory neuron to the central pattern generator. Inhibitory postsynaptic potential (IPSP) which was evoked in the N1M cell by activation of the CGC was larger and lasted longer in the conditioned animal than that in the control animal. The electrical properties of the cell body of CGC and the responses of the CGC to the chemosensory inputs were not changed during the CTA learning. These results, together with the previous report indicating the existence of excitatory projection from the N1M cell to the feeding motoneuron, suggest that enhanced IPSP in the N1M cell may underlie the suppression of feeding responses in the Lymnaea CTA learning.     

AN ELECTRON MICROSCOPIC STUDY ON THE RETICULOENDOTHELIAL CELLS IN THE LYMPH NODES

In an attempt to clarify the cytological characteristics of the RES cells in the lymph nodes and their embryological correlations, lymph nodes and lymph node anlages of germ-free rats, nude mice, and human fetuses were light and electron microscopically examined. On the basis of differences of intracellular organelles, their behaviors for reticulum fibers and of endogenous peroxidatic activity, histiocytes should be reasonably distinguished from the cells conventionally called reticulum cells. Reticulum cells and histiocytes respectively are destined to differentiate in different directions from the early stage of development of the lymph node anlage. Sinus endothelial cells are ontogenetically originated and differentiated from the endothelial lining cells of lymphatic vessels. Primitive reticular cells are differentiated into mature reticulum cells in the lymph nodes, they transform into the lympho-reticular cells, further into lymphoblasts, and finally develop into medium-sized lymphocytes.     

Neuropeptides stimulate production of interleukin-1β, interleukin-6, and tumor necrosis factor-α in human dental pulp cells

Objective:Orthodontic tooth movement causes inflammatory reactions in the periodontal membrane and dental pulp. It has been reported that substance P (SP) and calcitonin gene-related peptide (CGRP), both sensory neuropeptides, are manifested in the dental pulp of rats during experimental tooth movement, suggesting that they might be involved in the dental pulp inflammation during orthodontic tooth movement. However, the relationships between neuropeptides and pro-inflammatory cytokines have not been fully elucidated.Materials and methods:Human dental pulp (HDP) fibroblasts were prepared from 6 healthy young volunteers (3 males, 3 females; 15–25 years old) during the course of orthodontic treatment. HDP cells were incubated for 24 h in fresh medium containing 2% FCS in the presence of various concentrations of CGRP (10^–12 to 10^–4 M) and SP (10^–12 to 10^–4 M), and the levels of interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF)- present in the media were determined using commercially available high-sensitivity enzyme-linked immunosorbent assay kit.Results:We examined the effects of stimulation by these neuropeptides on the production of inflammatory cytokines in HDP fibroblasts, and found that the levels of IL-1, IL-6, and TNF- increased in a time- and concentration-dependent manner. However, the neuropeptides did not act synergistically to increase cytokine secretion in HDP cells or significantly modify LPS-induced cytokine production by HDP cells.Conclusions:Our results suggest that human pulp fibroblasts may be involved in the progress of inflammation in pulp tissue during orthodontic tooth movement, as they produced large amounts of IL-1, IL-6, and TNF- following stimulation with neuropeptides.Received 2 March 2003; returned for revision 14 July 2003; accepted by M.J. Parnham 17 December 2003     

Development of analysis of drugs and toxic substances that can play an immediate role in emergency medical service: what is to be analyzed?

Our laboratory was capable of analyzing less than 20 drugs and toxic substances at the time of the establishment of the Center in 1994. Since the poisoning crimes in 1998, such as the curry poisoning with arsenic in Wakayama, the sodium azide poisoning in Niigata, and the potassium cyanide poisoning in Nagano, we have introduced methods for rapid qualitative analysis of arsenic compounds, cyanides and azides, and developed methods for qualitative analysis of three types of surfactants (cationic, anionic, and nonionic) on the basis of the statistics for intoxication patients transferred to the Center. In 1999, the Analysis Method Investigation Committee of the Japanese Society for Clinical Toxicology requested individual medical institutions to analyze 15 selected intoxicating substances, focusing on the following three aspects. 1. Intoxication with a high degree of fatality. 2. Intoxication where analysis plays an immediate role in treatment. 3. Intoxication with a high frequency of requests by clinical physicians for analysis. The selected substances included methanol, barbital drugs, benzodiazepines, tricyclic or tetracyclic antidepressants, methamphetamine, acetaminophen, salicylic acid, bromovalerylurea, organophosphorus pesticides, carbamate pesticides, paraquat, glufosinate, cyanides, arsenic, and theophylline. Responding to the Committee's request, out laboratory has been making efforts so that analysis of drugs and intoxicating substances can play an immediate role in emergency medical service, giving the highest priority to the aforementioned 15 substances. As a result, anyone of us can now rapidly analyze about 35 substances, including those listed by the Society, day and night.     

Lymph node necrosis in systemic lupus erythematosus. A histopathological and immunohistochemical study of four cases

The lymph node lesions of lupus lymphadenitis are characterized by necrosis sometimes accompanied by hematoxylin bodies, but only a few immunohistological analyses of this unique lesion have been reported. In this study we investigated the immunopathogenesis of these lesions. Lymph node specimens from four patients were analyzed immunohistochemically by applying recently developed monoclonal antibodies to immunocompetent cells. Necrosis occupied almost the entire lymph node in two cases (extensive type), whereas small foci of necrosis were found in the paracortex in the remaining two (localized type). No hematoxylin body formation was detected in any of the samples. Necrosis of the small muscular arteries, arterioles and venules was seen in the necrotic areas in all four cases. In one case of the localized type, necrotizing angitis was seen in a few arterioles and venules in the non-necrotic area. By immunohistology, amorphous depositions of immunoglobulins and C3 were demonstrated in the walls of the arterioles and venules in two cases. Our findings indicate that vasculitis due to local deposition of immune complexes in the blood vessels may play an important role in the pathogenesis of necrosis in lupus lymphadenitis.     

Dual Bar homeo box genes of Drosophila required in two photoreceptor cells, R1 and R6, and primary pigment cells for normal eye development.

In the Bar mutation of Drosophila, ommatidial differentiation is known to be suppressed in the anterior portion of the eye. Our structural analysis shows that the Bar region contains a pair of homeo box genes, BarH1 and BarH2. These genes encode polypeptides similar in size and sequence and share a common homeo domain that is identical in sequence except for putative trans-activator-binding sites. We also show, by mosaic analysis and immunostaining with anti-BarH1/BarH2 antibodies, that BarH1 and BarH2 are not only specifically coexpressed but also functionally required in R1/R6 prephotoreceptors and primary pigment cells in developing ommatidia. In R1/R6, the expression of BarH1 and BarH2 appears to be regulated by rough and glass gene products. BarH1 and BarH2 proteins are essential to normal lens formation, formation of three types of pigment cells, and elimination of excess cells from mature ommatidia. Taken together, our results suggest that Bar homeo domain proteins may play key roles in the fate-determination processes of pigment cells and cone cells.