TAFRO syndrome: 2 cases and review of the literature.

Recently, more than ten cases of thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly (TAFRO) syndrome or Castleman-Kojima disease exhibiting such symptoms as thrombocytopenia, anasarca, fever, reticulin fibrosis and organomegaly have been reported in Japan. We have found two cases of TAFRO syndrome and have reviewed another eighteen previously reported cases. Histological findings of the lymph nodes and levels of interleukin 6 (IL-6) and vascular endothelial growth factor in both serum/plasma and effusions are important characteristics for diagnosing this syndrome.

A case of sepsis caused by Streptococcus canis in a dog owner: a first case report of sepsis without dog bite in Japan.

A 91-year-old dog-owning woman with a history of hypertension and femoral neck fracture consulted our hospital with fever and femur pain with redness. Laboratory test results showed leukocytosis with 85% neutrophils and high values of C-reactive protein and procalcitonin. In addition, growth of Gram-positive streptococcus was observed in two independent blood culture sets. The isolated bacterium was identified as Streptococcus canis on the basis of biochemical properties and sequencing analyses of the 16S rRNA gene. The patient recovered completely without critical illness following prompt antimicrobial treatment with ceftriaxone. S. canis, a ß-hemolytic Lancefield group G streptococcus, is in general isolated from various animal sources, but its isolation from a human clinical sample is extremely rare. Since ß-hemolytic streptococci can cause severe infectious diseases such as necrotizing fasciitis, it is absolutely necessary to start antimicrobial treatment immediately. It is necessary to identify pathogenic bacteria carefully and to obtain information on a patient's background, including history of contact with an animal, when S. canis is isolated.

Small proliferative adipocytes: identification of proliferative cells expressing adipocyte markers.

It has been thought that adipocytes lack proliferative ability and do not revert to precursor cells. However, numerous findings that challenge this notion have also been reported. The idea that adipocytes dedifferentiate to fibroblast-like cells with increasing cell number was reported in 1975. This possibility has been ignored despite knowledge gained in the 1990s regarding adipocyte differentiation. Several studies on proliferation and dedifferentiation of adipocytes have been published, most of which were conducted from the perspective of regenerative medicine. However, the concept of proliferation of adipocytes remains unclear. In this study, we postulate a new population of adipocytes, which consist of small sized cells (less than 20 µm in diameter) expressing adipocyte markers, such as adiponectin and peroxisome proliferator-activated receptor γ (PPARγ), but not possessing large lipid droplets. These cells show marked ability to incorporate 5-bromo-2'-deoxyuridine (BrdU), for which reason we termed them "small proliferative adipocytes (SPA)". In addition, SPA are observed in the stromal vascular fraction. Since SPA are morphologically different from mature adipocytes, we regarded them as committed progenitor cells. When proliferation of adipocytes in vivo is assessed by measuring BrdU incorporation and expression levels of proliferating cell nuclear antigen (PCNA) in isolated fractions of adipocytes from adipose tissues, subcutaneous SPA proliferate less actively than visceral SPA. Treatment with pioglitazone increases the number of proliferating SPA in subcutaneous, but not visceral, fat, suggesting that SPA may be important in regulating systemic insulin sensitivity and glucose metabolism.

The role of small proliferative adipocytes in the development of obesity: comparison between Otsuka Long-Evans Tokushima Fatty (OLETF) rats and non-obese Long-Evans Tokushima Otsuka (LETO) rats.

Obesity consists of hypertrophy and hyperplasia of adipocytes. Although the number of adipocytes is influenced by anatomical location, nutritional environment, hormone and genetic variation, it has been thought to be determined by the proliferation of precursor cells and subsequent differentiation. However, our recent research has identified the population of small adipocytes less than 20 µm in diameter, exhibiting tiny or no lipid droplets and expressing adipocyte marker proteins (small proliferative adipocytes: SPA) in isolated adipocytes. Notably, 5-bromo-2'-deoxyuridine (BrdU) incorporation and proliferating cell nuclear antigen (PCNA) expression were detected in these cells. In this study, we investigated the role of SPA in development of adipose tissue using genetically obese diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats and their non-obese and non-diabetic littermates, Long-Evans Tokushima Otsuka (LETO) rats. Proliferation of SPA was determined by measurement of PCNA at the protein level in isolated fractions of adipocytes with collagenase digestion. In general, expression levels of PCNA rose, reached a maximum, and declined in adipose tissues during aging. The expression levels of PCNA were maximum in epididymal fat at 32 w and 12 w of age in LETO and OLETF, respectively. They reached the maximum at 20 w of age both in LETO and OLETF in mesenteric fat. Although the PCNA expression level was higher in OLETF in the early period, it reversed later. Enlargement of adipocytes developed during aging, which was enhanced when the expression levels of PCNA declined. These results suggest that proliferation of SPA may prevent adipocyte hypertrophy and the resultant development of metabolic disorders.

Effect of nematode Trichinella infection on glucose tolerance and status of macrophage in obese mice.

We investigated the effect of Trichinella infection on glucose tolerance and (pro- or anti-inflammatory) macrophage status in adipose tissue. Ob/ob mice and high fat-fed mice (obesity model) and C57/BL mice (control mice) were orally infected with (infected group) or without (uninfected group) 400 Trichinella per mouse. Four weeks later, the mice were subjected to investigation, which showed that fasting plasma glucose levels decreased in the infected group of C57/BL and ob/ob mice. Glucose tolerance, evaluated with intraperitoneal GTT, improved in the infected group of ob/ob mice and high fat-fed mice compared with the uninfected groups. Additional assay included anti-inflammatory macrophage (M2) markers and pro-inflammatory macrophage (M1) markers, with the aim to explore the effect of Trichinella infection on adipose tissue inflammation, since our previous study identified anti-inflammatory substances in secreted proteins by Trichinella. The result showed that mRNA levels of M2 markers, such as CD206, arginase and IL-10, increased, whereas M1 markers, such as CD11c, iNOS and IL-6, decreased in the stromal vascular fraction (SVF) isolated from epididymal fat in ob/ob mice. Residential macrophages obtained from the peritoneal lavage exhibited lower M1 markers and higher M2 markers levels in the infected group than in the uninfected group. Trichinella infection increases the ratio of M2/M1 systemically, which results in an improvement in pro-inflammatory state in adipose tissue and amelioration of glucose tolerance in obese mice.

Pioglitazone enhances small-sized adipocyte proliferation in subcutaneous adipose tissue.

The possibility that mature adipocytes proliferate has not been fully investigated. In this study, we demonstrate that adipocytes can proliferate. 5-bromo-2'-deoxyuridine (BrdU)-labeled adipocyte like cells, most of which were less than 30 µm in diameter, were observed in adipose tissue. Proliferating cell nuclear antigen (PCNA) was simultaneously detected in BrdU-labeled nuclei. Observation of individual mature adipocytes of smeared specimens on glass slides revealed that small sized adipocytes more frequently incorporated BrdU. Cultured mature adipocytes using the ceiling-cultured method showed clustering of proliferating cells in small-sized adipocytes. These small cultured adipocytes, but not large ones, extensively incorporated BrdU. Quantified analysis of BrdU incorporation demonstrated that mature visceral adipocytes, including epididymal, mesenteric and perirenal adipocytes, proliferated more actively than subcutaneous ones. On the other hand, treatment with pioglitazone (Pio), a ligand of peroxisome proliferator-activated receptor γ, containing food for 2w, elevated BrdU incorporation and expression of PCNA in mature adipocytes isolated from subcutaneous, but not visceral adipose tissue. Moreover, Pio induced increased BrdU-labeled small-sized subcutaneous adipocytes, which was associated with an increased number of total small adipocytes in subcutaneous adipose tissue. In conclusion, mature adipocytes have a subgroup representing the potential to replicate, and this proliferation is more active in visceral adipocytes. Treatment with Pio increases proliferation in subcutaneous adipocytes. These results may explain the mechanism of Pio-induced hyperplasia especially in subcutaneous adipocytes.

Elevated mitochondrial biogenesis in skeletal muscle is associated with testosterone-induced body weight loss in male mice.

Androgen reduces fat mass, although the underlying mechanisms are unknown. Here, we examined the effect of testosterone on heat production and mitochondrial biogenesis. Testosterone-treated mice exhibited elevated heat production. Treatment with testosterone increased the expression level of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α), ATP5B and Cox4 in skeletal muscle, but not that in brown adipose tissue and liver. mRNA levels of genes involved in mitochondrial biogenesis were elevated in skeletal muscle isolated from testosterone-treated male mice, but were down-regulated in androgen receptor deficient mice. These results demonstrated that the testosterone-induced increase in energy expenditure is derived from elevated mitochondrial biogenesis in skeletal muscle.