Double-blind, placebo-controlled trial of pirfenidone in patients with idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a fatal disorder without an effective therapy to date. In a double-blind, randomized, placebo-controlled trial, 107 patients were prospectively evaluated for efficacy of a novel compound, pirfenidone. The difference in the change in the lowest oxygen saturation by pulse oximetry (SpO2) during a 6-minute exercise test, the primary endpoint, from baseline to 6 months was not significant between the two groups (p = 0.0722). In a prespecified subset of patients who maintained a SpO2 greater than 80% during a 6-minute exercise test at baseline, the lowest SpO2 improved during a 6-minute exercise test in the pirfenidone group at 6 and 9 months (p = 0.0069 and 0.0305, respectively). Positive treatment effect was demonstrated in secondary endpoints: (1) change in VC measurements at 9 months (p = 0.0366) and (2) episodes of acute exacerbation of IPF occurring exclusively in the placebo group during the 9 months (p = 0.0031). Significant adverse events were associated with pirfenidone; however, adherence to treatment regimen was similar between pirfenidone and placebo groups. In conclusion, treatment with pirfenidone improved VC and prevented acute exacerbation of IPF during the 9 months of follow-up. Future long-term studies are needed to clarify the overall safety and efficacy of pirfenidone in IPF.     

Prediction and evaluation of brainstem function by auditory brainstem responses in patients with uncal herniation

Serial measurements of auditory brainstem-evoked responses (BERs) were conducted in 15 patients with supratentorial mass lesions. Significant prolongation of the latency of wave V BERs, which originates in the inferior colliculus, occurred when the intracranial pressure (ICP) approached 30 mmHg. In four of five patients whose BERs were measured before pupillary changes, a significant lengthening of wave V latency was observed prior to clinical manifestation of uncal herniation. These results suggest that immediate medical or surgical decompression of ICP should be performed when ICP approaches 30 mmHg with significant prolongation of wave V latency.     

A monoclonal antibody established from the immunization of basal cell carcinoma (BCC) tissues reacts to the intercellular space of BCC and hair follicles

To detail the histogenetic relationship between basal cell carcinoma (BCC) and hair follicles, a monoclonal antibody, coded as MMKB-1 and established from immunization of mice by human basal cell carcinoma (BCC) tissues, was immunohistochemically studied in tissues of BCC and squamous cell carcinoma (SCC) of the skin, as well as in normal human skin tissues. On 1M-NaCl-split normal human skin tissues, it reacted against both the epidermal and the dermal sides of the basement membrane zone (BMZ). This monoclonal antibody reacted to the BMZ and intercellular space (ICS) of the solid, superficial, and fibrosing types of BCC cell nests, but, in SCC tumor cell nests, it reacted exclusively to the BMZ. Immunoelectron microscopic studies revealed that the corresponding antigen of the monoclonal antibody was distributed in the hemidesmosomes and the anchoring fibrils along the BMZ of the normal human skin and the desmosomes of the BCC cell nest. The monoclonal antibody also reacted to the ICS of the lower outer root sheath and hair matrix. We discussed the histogenesis of BCC and hair follicles, referring to the results of the staining patterns of MMKB-1 monoclonal antibody and to other studies suggesting a histogenetic relationship between BCC and hair follicles.     

Phylogenetic analysis of carotenoid-producing marine microorganisms around the coral reefs of the Kerama Islands of Okinawa

Seawater sample from the coral reefs of the Kerama Islands of Okinawa were assessed for the presence of carotenoid-producing bacteria. Results of 16S rDNA analysis of the bacteria obtained from the isolated bacteria showed unique patterns that were different from those of the bacteria obtained from the ordinary marine area. Phylogenetic analysis revealed a slight correlation with the statistical analysis of the PDA chart patterns. The results suggest that useful materials for human health such as carotenoids can be extracted from many carotenoid-producing bacteria such as those found the coral reefs the Kerama Islands.     

The role of cysteinyl leukotrienes in the pathogenesis of asthma: Clinical study of leukotriene antagonist pranlukast for 1 year in moderate and severe asthma

Clinical studies have shown that pranlukast (Ono Pharmaceutical Co., Osaka, Japan) is effective for mild and moderate asthma. However, it is not well known that pranlukast is also effective on moderate and severe persistent asthma in the long term. We studied the effect of pranlukast on moderate and severe asthmatics by evaluating the change of peak expiratory flow (PEF) and therapeutic scores for 1 year before and during pranlukast therapy. We gave pranlukast 225 mg twice daily orally to 25 patients who were receiving more than 400 micrograms/day beclomethasone inhalation and beta 2 stimulant inhalation with or without oral corticosteroid. Pranlukast increased PEF more than 10 L/min in 14 patients in the first 4 weeks. In these 14 patients, 10 patients continued to monitor PEF and kept asthma diaries for 1 year. We compared the data for 1 year before and during the pranlukast therapy. During the pranlukast therapy, PEF significantly increased, puffs of beta 2 stimulant inhalation significantly decreased. The incidence of oral corticosteroid rescue therapy reduced, and the mean daily dose of oral corticosteroid decreased; however, they were not statistically significant. During treatment with pranlukast, no side effect was observed. From these results, we suggest that pranlukast is effective for more than half of the moderate and severe persistent asthmatics, and that the effectiveness continues for more than 1 year.     

Neuropsin is essential for early processes of memory acquisition and Schaffer collateral long-term potentiation in adult mouse hippocampus in vivo

Long-term potentiation (LTP) is thought to be particularly important in the acquisition of hippocampus-associated memory, in part because it develops quickly and persists for indefinite periods. Extracellular proteolysis has been hypothesized to contribute to LTP by modifying adhesive relations of synapses and thus the morphology of excitatory synapses. Here we report that neuropsin (NP), an extracellular serine protease, is critically involved in the formation of both the potentiation effect and hippocampus-dependent forms of memory. NP-knockout mice were significantly impaired in the Morris water maze and Y-mazes and failed to exhibit early phase LTP induced by a single tetanus. Potentiation was also impaired or completely blocked by in vivo application of a specific inhibitor or a neutralizing monoclonal antibody for NP. Intriguingly, recombinant (r-) NP alone, without tetanic stimulation, elicited either long-lasting potentiation or depression, depending on the applied dose. The r-NP-elicited potentiation was occluded by prior induction of LTP, while theta-burst-elicited LTP was occluded by application of r-NP alone, suggesting that the two forms of plasticity have a common signalling pathway. r-NP-elicited potentiation and depression increased phosphorylation at different sites on the GluR1 subunit of the AMPA receptor that had previously been associated with LTP or long-term depression. Thus, we conclude that NP is necessary for establishment of LTP and has a significant role in memory acquisition.     

Quantitative Analysis of Mycobacterial and Propionibacterial DNA in Lymph Nodes of Japanese and European Patients with Sarcoidosis

The cause(s) of sarcoidosis is unknown. Mycobacterium spp. are suspected in Europe and Propionibacterium spp. are suspected in Japan. The present international collaboration evaluated the possible etiological links between sarcoidosis and the suspected bacterial species. Formalin-fixed and paraffin-embedded sections of biopsy samples of lymph nodes, one from each of 108 patients with sarcoidosis and 65 patients with tuberculosis, together with 86 control samples, were collected from two institutes in Japan and three institutes in Italy, Germany, and England. Genomes of Propionibacterium acnes, Propionibacterium granulosum, Mycobacterium tuberculosis, Mycobacterium avium subsp. paratuberculosis, and Escherichia coli (as the control) were counted by quantitative real-time PCR. Either P. acnes or P. granulosum was found in all but two of the sarcoid samples. M. avium subsp. paratuberculosis was found in no sarcoid sample. M. tuberculosis was found in 0 to 9% of the sarcoid samples but in 65 to 100% of the tuberculosis samples. In sarcoid lymph nodes, the total numbers of genomes of P. acnes or P. granulosum were far more than those of M. tuberculosis. P. acnes or P. granulosum was found in 0 to 60% of the tuberculosis and control samples, but the total numbers of genomes of P. acnes or P. granulosum in such samples were less than those in sarcoid samples. Propionibacterium spp. are more likely than Mycobacteria spp. to be involved in the etiology of sarcoidosis, not only in Japanese but also in European patients with sarcoidosis.