Efficacy, safety, and pharmacokinetics of multiple administration of infliximab in Behçet's disease with refractory uveoretinitis

OBJECTIVE: Beh?et's disease (BD) with uveoretinitis is a chronic refractory disease accompanied by ocular attacks. As the decrease in visual acuity due to ocular attack is seriously life-threatening, development of a new drug is anticipated. Since tumor necrosis factor-a (TNF-a) is involved in the symptoms of BD, particularly the activity of ocular symptoms, suppression of TNF-a might be effective in treating BD with uveoretinitis. We conducted a clinical trial of infliximab, an anti-TNF-a chimeric monoclonal antibody, in patients with BD. METHODS: In this open label trial, the efficacy, safety, and pharmacokinetics of repeated administration of infliximab were evaluated in 13 patients with BD accompanied by refractory uveoretinitis. Infliximab was administered 4 times at Weeks 0, 2, 6, and 10 at doses of either 5 or 10 mg/kg by intravenous drip infusion. Frequency of ocular attacks was used as the primary index for evaluation of efficacy, with visual acuity and extraocular symptoms as secondary indices. RESULTS: The mean numbers of ocular attacks, converted to frequency per 14 weeks, were 3.96 times for the 5 mg/kg group and 3.79 times for the 10 mg/kg group during the observation period. Following treatment with infliximab, they decreased to 0.98 times and 0.16 times, respectively. A serious adverse event, tuberculosis, was observed in one case in the 10 mg/kg group. Serum infliximab concentration increased with dosage. CONCLUSION: Administration of infliximab in patients with BD with refractory uveoretinitis suppressed the frequency of ocular attacks, and multiple administration was well tolerated, suggesting that infliximab is effective for this condition.     

Two-generation reproduction toxicity study in rats with methoxychlor

A two-generation reproduction toxicity study was conducted in rats with a reference estrogenic pesticide, methoxychlor, to validate the sensitivity and competency of current guidelines recommended by the United States Environmental Protection Agency; Japanese Ministry of Agriculture, Forestry and Fisheries; and Organisation for Economic Co-operation and Development for predicting reproductive toxicity of the test compound based on estrogenic endocrine disrupting effects. Both sexes of SD rats were exposed to methoxychlor in the diet at concentrations of 0, 10, 500 and 1500 ppm for two successive generations. The present study has successfully detected estrogenic activities and reproductive toxicities of methoxychlor, as well as its systemic toxicity. Body weights, body weight gains and food consumption of both sexes of animals were suppressed significantly in the 500 and 1500 ppm groups. Typical reproductive toxicities observed in females of these groups included, but were not limited to, prolonged estrous cycle, reduced fertility, decreased numbers of implantation sites and newborns, decreased ovary weights and/or increased incidences of cystic ovary. Uterine weights of weanlings increased significantly in these groups, suggesting that the sensitivity of this parameter for predicting estrogenic ability of the test compound is comparable to that of the uterotrophic assay. Reproductive toxicities of methoxychlor seemed less potent in males than in females. Methoxychlor delayed preputial separation and significantly reduced sperm counts and reproductive organ weights of males of the 500 and/or 1500 ppm groups; however, most males that failed to impregnate females in the same group showed normal fertility when they were re-mated with untreated females. Neither systemic nor reproductive toxicities appeared in the 10 ppm group.     

LDL-apheresis reduces P-Selectin, CRP and fibrinogen -- possible important implications for improving atherosclerosis

Although it is known that LDL-apheresis improves coronary artery stenosis (CAS) as well as ischemic limbs seen in patients with peripheral arterial occlusive disease (PAOD), the underlying mechanisms remain still unknown. LDL-apheresis might exert its favorable action through anti-inflammatory effects. We studied whether or not serum or plasma levels of P-selectin, high sensitivity C-reactive protein (hsCRP), monocyte chemoattractant protein-1 (MCP-1) or fibrinogen could be reduced in patients with PAOD before and after 10 sessions of LDL-apheresis. Sixteen patients (12 patients with hemodialysis, HD) with PAOD were enrolled in the present study. LDL-apheresis was carried out 10 times (treated plasma of 3000 mL) over 5 weeks. Serum levels of P-selectin were significantly reduced from 516 +/- 153 to 290 +/- 52 ng/mL before and after 10-sessions of LDL-apheresis, respectively (P < 0.05). Likewise, serum levels of hsCRP decreased from 9.118 +/- 2.649 to 5.587 +/- 2.445 mg/L (P < 0.01); and plasma fibrinogen levels statistically decreased from 196 +/- 9.82 to 149 +/- 7.97 mg/dL (P < 0.01), whereas serum levels of MCP-1 were not significantly changed. The favorable actions of LDL-apheresis might include anti-inflammatory effects, which could lead to an improvement of CAS and PAOD. Moreover, this intervention might be applicable for patients with atherosclerotic cardiovascular disorders, particularly in patients with HD.     

Both alleles of PSF1 are required for maintenance of pool size of immature hematopoietic cells and acute bone marrow regeneration

Hematopoietic stem cells (HSCs) have a very low rate of cell division in the steady state; however, under conditions of hematopoietic stress, these cells can begin to proliferate at high rates, differentiate into mature hematopoietic cells, and rapidly reconstitute ablated bone marrow (BM). Previously, we isolated a novel evolutionarily conserved DNA replication factor, PSF1 (partner of SLD5-1), from an HSC-specific cDNA library. In the steady state, PSF1 is expressed predominantly in CD34(+)KSL (c-kit(+)/Sca-1(+)/Lineage(-)) cells and progenitors, whereas high levels of PSF1 expression are induced in KSL cells after BM ablation. In 1-year-old PSF1(+/-) mice, the pool size of stem cells and progenitors is decreased. Whereas young PSF1(+/-) mutant mice develop normally, are fertile, and have no obvious differences in hematopoiesis in the steady state compared with wild-type mice, intravenous injection of 5-fluorouracil (5-FU) is lethal in PSF1(+/-) mice, resulting from a delay in induction of HSC proliferation during ablated BM reconstitution. Overexpression studies revealed that PSF1 regulates molecular stability of other GINS components, including SLD5, PSF2, and PSF3. Our data indicate that PSF1 is required for acute proliferation of HSCs in the BM of mice.     

Usefulness of a single radial immunodiffusion method for the immediate diagnosis of abnormal fibrinogenemia in the laboratory

Patients with dysfibrinogenemia demonstrate a low concentration of plasma fibrinogen. However, many cases remain a symptomatic and are incidentally identified on a pre-operative or screening test for pregnancy. Therefore, urgent diagnosis is desirable. To diagnose this abnormality, it is important to demonstrate a discrepancy between test results by the Clauss and immunologic methods. We use a single radial immunodiffusion (SRID) method to measure the fibrinogen level immunologically. We present one dysfibrinogenemia case diagnosed by SRID. The present case was 23 year-old pregnant female. She demonstrated a low plasma level of fibrinogen (91 mg/dl by the Clauss method) on a pre-delivery-screening test in the 39th week of pregnancy. We suspected dysfibrinogenemia, and measured the fibrinogen level immunologically with SRID. Briefly, we dissolved agar in 10% PBS solution and added 1 mg/ml anti-fibrinogen antibody. Then, patient plasma and 50-200 mg/dl of control plasma were placed on the agar overnight. The immunoreactive fibrinogen level in this patient was 400 mg/dl. Therefore, we diagnosed her as dysfibrinogenemia. She did not have a bleeding episode during the normal vaginal delivery even through fibrinogen was not transfused. The SRID method is readily available, and requires only an anti-fibrinogen antibody and agar, both of which are usually stocked by a general laboratory. The practical method and application described in this report provide instructive information for hospital laboratories.     

Affect recognition, empathy, and dysosmia after traumatic brain injury

Neumann D, Zupan B, Babbage DR, Radnovich AJ, Tomita M, Hammond F, Willer B. Affect recognition, empathy, and dysosmia after traumatic brain injury.ObjectiveTo investigate if olfaction is associated with affect recognition and empathy deficits after traumatic brain injury (TBI). Prior research has shown that TBI often leads to loss of smell. We hypothesized a relationship with emotion perception, because the neural substrates of the olfactory system overlap with the ventral circuitry of the orbital frontal cortex, which play a critical role in affective responses, such as empathy.DesignComparative study investigating differences between participants with TBI who had impaired olfaction (dysosmia) with those with normal olfaction (normosmia).SettingPostacute rehabilitation facilities in the United States, Canada, and New Zealand.ParticipantsParticipants (N=106) in the current study were a convenience sample of adults with moderate to severe TBI who were tested for olfactory function as part of a larger, related study on affect recognition. On average, participants were 11.5 years postinjury.InterventionsNot applicable.Main Outcome MeasuresOlfaction (Brief Smell Identification Test), facial affect recognition (Diagnostic Assessment of Nonverbal Affect 2–Adult Faces [DANVA2-AF]), vocal affect recognition (Diagnostic Assessment of Nonverbal Affect 2–Adult Paralanguage [DANVA2-AP]), emotional inference (Emotional Inference from Stories Test [EIST]), and empathy (Interpersonal Reactivity Index [IRI]).ResultsFifty-six percent of participants were dysosmic and only 36% of these participants were aware of their deficit. Participants with dysosmia performed significantly poorer on the DANVA2-AF (P=.003), DANVA2-AP (P=.007), EIST (P=.016), and IRI (P=.013). Medium effect sizes were found for all measures. Dysosmia had a sensitivity value of 86.4% for detecting facial affect recognition impairments and 67.8% for vocal affect recognition impairments.ConclusionsThis study shows that olfactory deficits may be indicative of affect recognition impairments and reduced empathy. Early knowledge of affect recognition and empathy deficits would be valuable so that treatment could be implemented predischarge.     

Expression pattern changes and function of RANKL during mouse lymph node microarchitecture development

Receptor activator of nuclear factor kappa-B ligand (RANKL) expression was examined during the development of mouse fetal peripheral lymphoid organs. A shift in the expression pattern was detected during the transition from lymphoid tissue inducer (LTi) cells to lymphoid tissue organizer (LTo) cells in the lymph node (LN) anlagen but not in the Peyer's patch anlagen. In order to understand the functional impact of these changes in the fetal expression of RANKL, the RANKL function was blocked by a blocking antibody. Excess anti-RANKL antibody was administered to pregnant mice between 13.5 and 16.5 dpc and was found to completely block LN anlagen development, suggesting that RANKL function during this period is critical for LN development. In addition, small amounts of anti-RANKL antibodies were injected directly into the amniotic space at 13.5 dpc, resulting in perturbed B-cell follicle formation and high endothelial venule differentiation after birth. These results suggest that RANKL expression on LTi cells during the early phase of LN development is critical for the development LN microarchitecture.