Essential role of IRAK-4 protein and its kinase activity in Toll-like receptor-mediated immune responses but not in TCR signaling

Interleukin-1 receptor-associated kinase 4 (IRAK-4) was reported to be essential for the Toll-like receptor (TLR)- and T cell receptor (TCR)-mediated signaling leading to the activation of nuclear factor kappaB (NF-kappaB). However, the importance of kinase activity of IRAK family members is unclear. In this study, we investigated the functional role of IRAK-4 activity in vivo by generating mice carrying a knockin mutation (KK213AA) that abrogates its kinase activity. IRAK-4(KN/KN) mice were highly resistant to TLR-induced shock response. The cytokine production in response to TLR ligands was severely impaired in IRAK-4(KN/KN) as well as IRAK-4(-/-) macrophages. The IRAK-4 activity was essential for the activation of signaling pathways leading to mitogen-activated protein kinases. TLR-induced IRAK-4/IRAK-1-dependent and -independent pathways were involved in early induction of NF-kappaB-regulated genes in response to TLR ligands such as tumor necrosis factor alpha and IkappaBzeta. In contrast to a previous paper (Suzuki, N., S. Suzuki, D.G. Millar, M. Unno, H. Hara, T. Calzascia, S. Yamasaki, T. Yokosuka, N.J. Chen, A.R. Elford, et al. 2006. Science. 311:1927-1932), the TCR signaling was not impaired in IRAK-4(-/-) and IRAK-4(KN/KN) mice. Thus, the kinase activity of IRAK-4 is essential for the regulation of TLR-mediated innate immune responses.     

Intraperitoneal seeding of ruptured hepatocellular carcinoma: case report

We report a solitary intraperitoneal recurrence in a long-term survivor after rupture of hepatocellular carcinoma. Ultrasonography demonstrated the finding of a lobulated mass with a "mosaic" appearance. The patient underwent resection of this implant and is currently disease free. We emphasize the importance of periodic surveillance of disseminated metastases of this condition.     

Caregiver burden and burnout. A guide for primary care physicians

Caregiver burden and burnout are important, prevalent, and preventable. Physicians aware of the symptoms and signs can better assess, identify, prevent, and intervene in these situations. Such efforts result in improved quality of life for both patients and their loved ones.     

Kupffer cell function in chronic liver injury and after partial hepatectomy

The reticuloendothelial system (RES) plays an important role in the biological defense system. In the liver, Kupffer cells are the main constituent of the RES, and when their function is impaired postoperative complications may more often occur. By using^99mTc-labeled human serum albumin millimicrospheres (^99mTc-HSA-MM) combined with assessment of single photon emission computed tomography (SPECT), we have attempted to determine the function of Kupffer cells independently of the hepatic blood flow. First, Kupffer cell function in rats with chronic liver injury caused by CCl₄ was studied. The hepatic uptake rate in chronic liver injury was decreased, and a reduced phagocytic activity of the Kupffer cells was noted. The parameter concerning Kupffer cell degradation, the excretion rate (k), was markedly decreased in the early period of chronic liver injury. Changes in Kupffer cell function after 30% and 70% hepatectomy were also studied. After 30% hepatectomy, the excretion rate was decreased on the first postoperative day (POD), and it was increased beyond that found after sham operation on the 3rd POD. In contrast, slower recovery of uptake rate was demonstrated. After 70% hepatectomy, both uptake and excretion rates were markedly reduced, and recovery was prolonged beyond the 5th POD. The hepatic uptake was not parallel with the excretion rate in either experiment. These results suggest that the method that measures the hepatic excretion rate may provide a better assessment of Kupffer cell function than the current uptake measurement with radiolabeled colloid.     

DNA vaccine against hamster oral papillomavirus-associated oral cancer

Previously we developed a carcinogenesis model involving the combination of 9,10-dimethyl-1,2-benzanthracene (DMBA) application with physical wounding of hamster lingual mucosa. The presence of a novel hamster oral papillomavirus (HOPV) was demonstrated and its genome sequenced. In the present study, this HOPV hamster model was used to test whether vaccination with the L1 gene could prevent the development of oral carcinoma. DNA plasmids encoding the L1 gene or the vector alone were injected intramuscularly into 20 vaccinated and 20 control hamsters, respectively. The lingual tips of the hamsters were painted with DMBA for 8 weeks. A portion of the lingual tips was excised, and the tips were then painted daily with DMBA until the animals were killed 13 days later. All control hamsters developed lingual carcinoma, whereas 12 of the L1-vaccinated hamsters showed no lesions. These results suggest that immunization with L1 DNA vaccines may prevent the development of papillomavirus-associated oral cancer.     

A patient with recurrent hepatic encephalopathy and chronic renal failure treated successfully with long-term hemodialysis

A 38-year-old man suffering from chronic recurrent hepatic enchephalopathy due to liver cirrhosis complicated with chronic renal failure had been maintained well by regular hemodialysis treatment for 14 months. Only four episodes of hepatic encephalopathy occurred in that period. Each of four episodes of disturbed consciousness was accompanied by slightly elevated blood ammonia levels. Energetic serial dialysis for 5-7 days was necessary for its recovery. The factors causing hepatic encephalopathy did not appear to be easily dialysable as compared with those of uremic coma. It is concluded that the hemodialysis is quite an effective treatment for the recurrent type of hepatic encephalopathy.     

The relationship between usual coffee consumption and serum C-reactive protein level in a Japanese female population

BACKGROUND: Usual coffee consumption may decrease insulin resistance and type 2 diabetes incidence, and reduce cardiovascular disease risk. As a mechanism, coffee-induced lower levels of C-reactive protein (CRP), a marker for the development of these diseases, can be considered. The associations between coffee consumption and CRP should be established by studies on various populations, yet studies in Japanese people, who do not necessarily consume as much coffee daily, are limited. METHODS: In total, 459 community-living Japanese women, aged 23-83 years, were investigated. Clinical data including age, body mass index, blood pressure, HbA(1c), serum high sensitive CRP (hsCRP) and lifestyle habits, such as coffee consumption, were included in the analyses. All analyses were performed in two groups of the population, i.e., age < 60 and > or = 60 years. RESULTS: Significantly lower levels of hsCRP were observed in the group of > or = 1 cup/day than in that of < 1 cup/day in the respective groups of < 60 years (p = 0.001) and > or = 60 years (p < 0.0001). In multiple regression analysis, coffee consumption was significantly, independently and inversely correlated to log-hsCRP in the respective groups of < 60 years (p = 0.017) and > or = 60 years (p < 0.0001). CONCLUSIONS: It was noteworthy that the benefits of coffee consumption, even if > or = 1 cup/day, on serum hsCRP levels were confirmed in Japanese women, following similarly to other ethnic data.