Low-grade endometrial stromal sarcoma recurring with multiple bone and lung metastases: report of a case

BACKGROUND: Approximately 50% of patients with low-grade endometrial stromal sarcoma (ESS) develop recurrent disease, mainly in lung or pelvis. Bone metastasis of low-grade ESS is an extremely rare phenomenon. CASE: A 63-year-old Japanese female developed multiple bone and lung metastases 18 years after initial treatment for low-grade ESS. Bone scintigram showed a high uptake area at thoracic spine (Th6, Th8-9 and Th12), right 9th rib, iliac bone, and sacrum. Radiation therapy with Liniac of 4500cGy to the Th6 vertebra and Liniac of 4200cGy to sacrum was performed for the palliation of the pain. Radiotherapy was effective for the pain relief, although the size of recurrent tumor was unchanged. CONCLUSION: This is the first detailed reported case of multiple bone recurrence in a patient with low-grade ESS. The long-term follow-up after treatment is recommended.     

A molecular mechanism for autoinhibition of the tandem SH3 domains of p47phox, the regulatory subunit of the phagocyte NADPH oxidase

The phagocyte NADPH oxidase is a multisubunit enzyme responsible for the production of reactive oxygen species. p47(phox) is a cytosolic component of the NADPH oxidase and plays an important role in the assembly of the activated complex. The structural determination of the tandem SH3 domains of p47(phox) is crucial for elucidation of the molecular mechanism of the activation of p47(phox). We determined the X-ray crystal structure of the tandem SH3 domains with the polybasic/autoinhibitory region (PBR/AIR) of p47(phox). The GAPPR sequence involved in PBR/AIR forms a left-handed polyproline type-II helix (PPII) and interacts with the conserved SH3 binding surfaces of the SH3 domains simultaneously. These SH3 domains are related by a 2-fold pseudosymmetry axis at the centre of the binding groove and interact with the single PPII helix formed by the GAPPR sequence with opposite orientation. In addition, a number of intra-molecular interactions among the SH3 domains, PBR/AIR and the linker tightly hold the architecture of the tandem SH3 domains into the compact structure and stabilize the autoinhibited form synergistically. Phosphorylation of the serine residues in PBR/AIR could destabilize and successively release the intra-molecular interactions. Thus, the overall structure could be rearranged from the autoinhibitory conformation to the active conformation and the PPII ligand binding surfaces on the SH3 domains are now unmasked, which enables their interaction with the target sequence in p22(phox).     

Therapeutic efficacy of once-daily oral administration of a Kunitz-type protease inhibitor, bikunin, in a mouse model and in human cancer

BACKGROUND: Bikunin, a Kunitz-type protease inhibitor, specifically inhibits tumor invasion and metastasis. METHODS: The authors initially evaluated the therapeutic efficacy of once-daily oral administration of different doses of bikunin against human ovarian carcinoma HRA cells growing in the peritonea of nude mice. For the in vivo studies, female 7-week-old nude mice were randomized to 1 of 4 groups: bikunin-treated groups (n = 9 in each group) received 3, 10, or 30 microg/g body weight per day bikunin for 7 days via gastrointestinal gavage, and a control group (n = 9) received the vehicle solution (phosphate-buffered saline) via gastrointestinal gavage. On Day 9, the abdominal cavity was examined by two observers who were blinded to treatment. RESULTS: After oral administration, intact bikunin was detectable in mouse serum specimens at 3 and 6 hours. This was followed by a decline at 12 hours. The mice given bikunin at the highest dose level had a 40% decrease in tumor load. The highest uptake in the tumor was obtained with [125I]bikunin 12 hours postadministration. No effect on either food intake or body weight was observed in the treated versus sham groups. The current study was the first to report the potent activity of once-daily oral administration of bikunin against ovarian carcinoma. Next, the authors performed a Phase I trial to determine the maximum-tolerated dose (MTD) and safety of a once-daily oral administration schedule. The indication was locally advanced uterine cervical carcinoma after definitive treatment. An escalating dose (3, 10, and 30 mg/kg per day) of bikunin was administered orally to nine patients for 7 days. There were no dose-limiting toxicities and the MTD of the bikunin schedule was not defined. The authors also obtained preliminary data on its effect on urokinase-type plasminogen activator expression at the highest dose level. CONCLUSIONS: Once-daily oral administration of bikunin was found to be safe in humans and exhibited signs of biologic activity.     

Breath-holding spells in somatoform disorder

Breath-holding spells (BHS) are commonly seen in childhood. However, there are no case reports of BHS occurring in adolescents or young adults. We report two young adult cases and discuss the pathogensis, both physically and psychologically. BHS occurred for 1-2 minutes after hyperventilation accompanied by cyanosis in both cases. Oxygen saturation was markedly decreased. Each patient had shown distress and a regressed state psychologically. These cyanotic BHS occurred after hyperventilation, and we considered that a complex interplay of hyperventilation followed by expiratory apnea increased intrathoracic pressure and respiratory spasm. Breath-holding spells can occur beyond childhood.     

Hippocampal volume and first major depressive episode after cancer diagnosis in breast cancer survivors

OBJECTIVE: Patients experiencing their first major depressive episode after receiving a diagnosis of cancer are frequently seen in clinical oncology settings; however, little is known about the neurobiological basis of the first episode. In previous studies, a smaller hippocampus than in healthy comparison subjects has been observed in patients with a history of recurrent and prolonged major depressive episodes. The purpose of the present study was to investigate whether there is an association between hippocampal volume and a first major depressive episode after cancer diagnosis in cancer survivors. METHOD: The subjects were 68 female cancer survivors who had undergone breast cancer surgery 3 or more years earlier (mean interval=4.3 years, SD=0.9). The hippocampal volume and delayed recall function of the 17 cancer survivors who had their first major depressive episode after receiving their cancer diagnosis and the 51 with no history of major depressive episode at any time during their lives were measured by magnetic resonance imaging and the Wechsler Memory Scale-Revised, respectively. RESULTS: The mean duration of the major depressive episode after cancer diagnosis was 11.9 weeks (SD=14.2). There were no significant differences in left or right hippocampal volume or in delayed recall function between the cancer survivors with and without a major depressive episode after cancer diagnosis. CONCLUSIONS: First major depressive episodes after cancer diagnosis in female cancer survivors do not appear to be associated with hippocampal volume. However, a longitudinal study with healthy comparison subjects is needed to draw a definite conclusion.     

Assessment of social networks between developmental physicians and welfare facilities/specialists for children with intellectual disabilities in Japan

The social networks between Japanese child neurologists and welfare facilities/specialists for children with mental retardation (MR) were assessed. A total of 113 physicians answered our mail-in questionnaire. Most of the doctors had various connections with nursery homes for children with MR or severe motor and intellectual disabilities (SMID) and with public health centers, and often collaborated with teachers of schools and kindergartens. On the other hand, most physicians had little relation with residential and vocational facilities for adults with MR, and with specialists in residential or community care. There was a statistical correlation between the number of facilities or collaborated specialists and the number of persons seen by each physician; however, the physicians' experience and affiliations had no relation. In view of 'social participation', physicians who usually see children with developmental disorders can play an important role in decision making of their life-style with their families.     

The effect of a newly synthesized indazole compound, TAS-3-124, on experimental autoimmune disease

The effects of a newly synthesized compound, 6-acetoamido-1-acetyl-1-indazole (TAS-3-124), on autoimmune diseases were studied. We used animal models of collagen-induced arthritis (CIA) in mice and experimental autoimmune encephalomyelitis (EAE) in rats to evaluate the efficacy of TAS-3-124. TAS-3-124 at doses of 100 and 300 mg/kg p.o. inhibited the development of CIA, decreasing the swelling of fore- and hind-limbs and bone destruction in knee joints. This agent also suppressed the delayed type hypersensitivity reaction (DTH) against type II collagen. These effects were confirmed by histopathological examination and measurement of the expression of mRNA of proinflammatory cytokines in the knee joint. In addition, TAS-3-124 at a dose of 300 mg/kg inhibited the development of EAE and the DTH to myelin basic protein (MBP) in rats. Moreover, TAS-3-124 inhibited the production of proinflammatory cytokines including interleukin (IL)-1beta, tumor necrosis factor (TNF)-alpha and IL-6 but not T cell derived cytokines in mice. These demonstrate the efficacy of TAS-3-124 against experimental autoimmune disease, probably due to the suppression of the production of proinflammatory cytokines in the pathological lesion.     

Cell-specific expression of NADPH-dependent cytosolic 3,5,3'-triiodo-L-thyronine-binding protein (p38CTBP)

We have previously shown that cytosolic 3,5,3'-triiodo-L-thyronine (T3)-binding protein (CTBP) possesses a high affinity for T3 binding in the presence of nicotinamide adenine dinucleotide phosphate in vitro, and that p38CTBP increases intracellular content of T3, and suppresses T3-mediated transactivity. Screening of mRNA expression in 73 different human tIssues has demonstrated that p38CTBP mRNA is expressed at high levels in brain and heart. We have examined the intracellular localization and tissue-specific distribution of this protein by using a specific antibody against human p38CTBP. Western blotting and immunoprecipitation studies have shown that the antibody recognizes human p38CTBP. Interaction of p38CTBP with the antibody did not affect the T3-binding activity of p38CTBP, and its dimer formation in vitro. Western blotting analysis has shown that p38CTBP is expressed in brain and heart predominantly, similar to the distribution of mRNA. Immunohistochemical studies have demonstrated p38CTBP in neural cells and cardiac muscle cells. p38CTBP localizes in cytoplasm rather than in nuclei in neural cells. The evidence for the presence of tIssue-specific localization of p38CTBP has indicated that p38CTBP has a tIssue-specific function, such as the regulation of T3 delivery from cytoplasm to nuclei.     

Dissemination of the phage-associated novel superantigen gene speL in recent invasive and noninvasive Streptococcus pyogenes M3/T3 isolates in Japan

In Japan, more than 10% of streptococcal toxic shock-like syndrome (TSLS) cases have been caused by Streptococcus pyogenes M3/T3 isolates since the first reported TSLS case in 1992. Most M3/T3 isolates from TSLS or severe invasive infection cases during 1992 to 2001 and those from noninvasive cases during this period are indistinguishable in pulsed-field gel electropherograms. The longest fragments of these recent isolates were 300 kb in size, whereas those of isolates recovered during or before 1973 were 260 kb in size. These 260- and 300-kb fragments hybridized to each other, suggesting the acquisition of an about 40-kb fragment by the recent isolates. The whole part of the acquired fragment was cloned from the first Japanese TSLS isolate, NIH1, and its nucleotide sequence was determined. The 41,796-bp fragment is temperate phage phiNIH1.1, containing a new superantigen gene speL near its right attachment site. The C-terminal part of the deduced amino acid sequence of speL has 48 and 46% similarity with well-characterized erythrogenic toxin SpeC and the most potent superantigen, SmeZ-2, respectively. None of 10 T3 isolates recovered during or before 1973 has speL, whereas all of 18 M3/T3 isolates recovered during or after 1992 and, surprisingly, Streptococcus equi subsp. equi ATCC 9527 do have this gene. Though plaques could not be obtained from phiNIH1.1, its DNA became detectable from the phage particle fraction upon mitomycin C induction, showing that this phage is not defective. A horizontal transfer of the phage carrying speL may explain the observed change in M3/T3 S. pyogenes isolates in Japan.