Effect of the duration of previous osteoporosis treatment on the effect of romosozumab treatment.

The effect of romosozumab is affected by previous osteoporosis treatment. Here we showed that the duration of the previous treatment just before romosozumab affects the therapeutic effect of romosozumab. Using denosumab and oral bisphosphonates for more than 1 year attenuates the effect of romosozumab. INTRODUCTION: As an anti-sclerostin antibody, romosozumab suppresses bone resorption and stimulates bone formation. We investigated whether the effectiveness of 12 months of romosozumab treatment depended on the duration of previous treatment with teriparatide, denosumab, or oral bisphosphonates. METHODS: In total, 259 osteoporosis patients received subcutaneous injections of romosozumab (210 mg) every 4 weeks during 2019 and 2020. This study was designed as a pre-post comparison. The end points were the percent changes of bone mineral density (BMD) after 12 months of romosozumab treatment. The patients were divided into seven groups depending on the type and duration of previous treatment before starting romosozumab as follows: non-previous treatment group, change from teriparatide used for 1 year or less/more than 1 year, change from denosumab used for 1 year or less/more than 1 year, and change from oral bisphosphonates used for 1 year or less/more than 1 year. RESULTS: The effects of previous treatment with teriparatide on the effectiveness of 12-month romosozumab did not clearly depend on the duration of treatment (p > 0.05). In contrast, the effects of previous treatments with denosumab or oral bisphosphonates on the effectiveness of 12-month romosozumab depended on the previous treatment duration, which was reflected by the differences in percent change of the spine BMD (both p < 0.05), however, there were no significant differences in the percent change of the total hip BMD (both p > 0.05). CONCLUSION: The duration of the previous treatment affected the effectiveness of romosozumab. Using denosumab and oral bisphosphonate for more than 1 year attenuated the effect of romosozumab.

Early clinical effects, safety, and predictors of the effects of romosozumab treatment in osteoporosis patients: one-year study.

Romosozumab is an effective treatment for spine osteoporosis because it reduces the incidence of new fractures and significantly increases the percent change in the spine BMD at 12 months. The percent change in the spine BMD is higher in patients not previously treated with other anti-osteoporosis medications. INTRODUCTION: Romosozumab appeared as a new osteoporosis medication in Japan in 2019. It is an anti-sclerostin antibody, which increases bone formation and suppresses bone resorption. The aim of our study was to elucidate the clinical effects, safety, and predictors of the effects of one-year romosozumab treatment. METHODS: This study was an observational study designed as a pre-post study in 262 patients. Romosozumab (210 mg) was administered subcutaneously once every 4 weeks during 12 months. We focused on incidence of new fractures, safety, bone mineral density (BMD) at the spine and total hip, and bone metabolism markers. RESULTS: There were five cases of new fractures during one-year romosozumab treatment. There were no fatal adverse events. Percent changes from baseline in the spine and total hip BMD after 12 months of romosozumab treatment were 10.67% and 2.04%, respectively. Romosozumab had better effects in cases of severe osteoporosis with low spine BMD, high TRACP-5b, and high iP1NP at the start of romosozumab treatment. The percent change in the spine BMD at 12 months was significantly lower in the group transitioning from bisphosphonates than in the group not previously treated with other anti-osteoporosis medications. CONCLUSION: Romosozumab is an effective treatment for spine osteoporosis because it significantly increases the percent change in the spine BMD at 12 months. The percent change in the spine BMD is higher in patients not previously treated with other anti-osteoporosis medications.

Early clinical effects, safety, and appropriate selection of bone markers in romosozumab treatment for osteoporosis patients: a 6-month study.

Our 6-month study showed the usefulness of romosozumab for preventing fractures and its safety. It was effective in patients with low baseline spine BMD, high TRACP-5b, and high iP1NP. Percent change from baseline of TRACP-5b and iP1NP after 1 month correlated with that from baseline of BMD after four to 6-month treatment. INTRODUCTION: Romosozumab appeared as a new osteoporosis medication in Japan in 2019. It is an anti-sclerostin antibody which increases bone formation and suppresses bone resorption. In this study, we analyzed the actual clinical effects, adverse effects, and the optimal way to evaluate the treatment. METHODS: Romosozumab was administered as subcutaneous injection of 210 mg once every 4 weeks. We conducted pre-post study in 185 patients treated for 6 months. We focused on the incidence of new vertebral fractures, safety, bone mineral density (BMD) at the spine and total hip, and bone metabolism markers. We evaluated BMD before romosozumab treatment and after 4 to 6 months and performed the serum analysis before romosozumab treatment, after 1, 3, and 6 months. RESULTS: There was no new fracture during treatment, and there was no fatal adverse event including cardiovascular disease. Since percent changes from baseline of the spine and total hip BMD were 6.34% and 1.53% after 4- to 6-month treatment, the treatment was effective for spine osteoporosis. Tartrate-resistant acid phosphatase 5b (TRACP-5b) and intact type I procollagen N-terminal propeptide (iP1NP) had significant changes during romosozumab treatment (p < 0.05). Percent change from baseline of TRACP-5b and iP1NP after 1 month correlated with percent change from baseline of BMD after 4 to 6 months of treatment. CONCLUSION: Romosozumab is effective in preventing fractures and useful for increasing the spine BMD. Also, romosozumab is relatively safe to use. It is especially effective in patients with low baseline spine BMD, high TRACP-5b, and high iP1NP.

Review of renal carcinoid tumor with focus on clinical and pathobiological aspects.

Renal carcinoid tumor is a rare neoplasm. In this article, we review this neoplasm with a focus on clinical and pathobiological aspects. The majority of patients present in the fourth to seventh decades, but there is no gender predilection. Clinically, patients with renal carcinoid tumor frequently present with abdominal, back or flank pain. This tumor is occassionally associated with horseshoe kidney and/or mature cystic teratoma located in the kidney. Macroscopically, these tumors are well demarcated with a lobulated appearance and yellow or tan-brown color cut surface. Microscopically, these tumors are composed of monomorphic round to polygonal cells with granular amphophilic to eosinophilic cytoplasm. Tumor cells are arranged in trabecular, ribbon-like, gyriform, insular, glandular and solid patterns. The nuclei are round to oval and with evenly distributed nuclear chromatin, frequently with a "salt and pepper"-pattern. Immunohistochemically, tumor cells demonstrate immuno-labeling for chromogranin A and synaptophysin. Ultrastructurally, the neoplastic cells contain abundant dense core neurosecretory granules. In previous genetic studies, abnormalities of chromosomes 3 or 13 have been reported. The clinical behavior of renal carcinoid tumors is variable, but is more indolent than most renal cell carcinomas. Further investigations are warranted in order to elucidate the critical genetic abnormalities responsible for the pathogenesis of this rare entity in renal neoplastic pathology.

Combined therapeutic application of botulinum toxin type A, low-frequency rTMS, and intensive occupational therapy for post-stroke spastic upper limb hemiparesis.

BACKGROUND: For spastic upper limb hemiparesis after stroke, we developed triple-element protocol of botulinum toxin type A (BoNTA) injection, low-frequency repetitive transcranial magnetic stimulation (LF-rTMS), and intensive occupational therapy (OT). Aim. To investigate the safety and feasibility of the protocol. Design. A preliminary study. Setting. At a university hospital. Population. Fourteen post-stroke patients with spastic upper limb hemiparesis (mean age: 54.9±9.2 years, time after onset: 87.1±48.2 months, ±SD). METHODS: In all patients, BoNTA was injected into spastic muscles of the affected upper limb (maximum total dose: 240 units). Four weeks later, they were hospitalized to receive 22 sessions of 20-min LF-rTMS and 120-min intensive OT daily over 15 days. Motor function of the affected upper limb was evaluated mainly using Fugl-Meyer Assessment (FMA), Wolf Motor Function Test (WMFT), motor activity log (MAL), and the severity of spasticity was measured with modified Ashworth scale (MAS) at BoNTA injection, discharge and four weeks post-discharge. RESULTS: All patients completed the protocol without any adverse effects. The FMA score and MAL scores, but not WMFT performance time, improved significantly at discharge. The MAS score of all examined muscles decreased significantly between BoNTA and discharge. The beneficial effect of the protocol on motor function and spasticity was almost maintained until four weeks after discharge. CONCLUSION: The protocol is safe and feasible, although further larger studies are needed to confirm its efficacy. CLINICAL REHABILITATION IMPACT: The protocol is a potentially useful neurorehabilitative approach for this patient population.

Nicotinic acetylcholine receptors expressed in the ventralposterolateral thalamic nucleus play an important role in anti-allodynic effects.

BACKGROUND AND PURPOSE: Much interest is currently being focused on the anti-nociceptive effects mediated by nicotinic acetylcholine (nACh) receptors, including their location and mechanism of action. The purpose of this study was to elucidate these issues using 5-iodo-3-(2(S)-azetidinylmethoxy)pyridine (5IA), a nACh receptor agonist, and [(125)I]5IA. EXPERIMENTAL APPROACH: We partially ligated the sciatic nerve of Sprague-Dawley rat to induce neuropathic pain [Seltzer's partial sciatic nerve ligation (PSL) model]. We then examined the changes in nACh receptor density in the CNS using [(125)I]5IA autoradiography and the involvement of nACh receptors in anti-nociceptive effects in the region where changes occurred. KEY RESULTS: Autoradiographic studies showed that the accumulation of [(125)I]5IA and the number of nACh receptors in the thalamus of PSL rats were increased about twofold compared with those in the sham-operated rats. No change was observed in other brain regions. Rats injected in the ventral posterolateral thalamic nucleus (VPL) with 5IA demonstrated a significant and dose-dependent anti-allodynic effect and this effect was completely antagonized by mecamylamine, injected with 5IA, into the VPL. The blockade of nACh receptors in the VPL by mecamylamine decreased by 70% the anti-allodynic effect of 5IA, given i.c.v. Moreover, mecamylamine given intra-VPL by itself, induced significant hyperalgesia. CONCLUSIONS AND IMPLICATIONS: Our findings suggest that the nACh receptors expressed in the VPL play an important role in the anti-allodynic effects produced by exogenous and endogenous agonists.

Systemic overexpression of IFN-gamma and IL-5 exacerbates early phase reaction and conjunctival eosinophilia, respectively, in experimental allergic conjunctivitis.

AIMS/BACKGROUND: To investigate how systemic overexpression of IL-4, IL-5 and IFN-gamma affects the severity of experimental conjunctivitis (EC) in mice. METHODS: The tibialis anterior muscle of naive BALB/c mice was electroporated with IL-4, IL-5, IFN-gamma or a control gene, and then the mice blood and conjunctivas were harvested to measure the eosinophil content in these tissues. To evaluate the effects of cytokine gene electroporation on the early-phase reaction (EPR), cytokine gene-electroporated ragweed (RW)-immunised mice were intravenously injected with Evans Blue (EB) and then challenged with RW in eye-drops. Thirty minutes later, their conjunctivas were harvested to extract EB and evaluate the EPR. Additionally, 24 h after RW challenge, conjunctivas were harvested from cytokine gene-electroporated RW-immunised mice, which had not received intravenous injection of EB, to measure conjunctival eosinophilia. RESULTS: Significantly more eosinophils were detected in the blood and conjunctivas of IL-5-electroporated mice in which EC was not induced. The intensity of the EPR was significantly greater in IFN-gamma-electroporated mice. Significantly greater eosinophil infiltration was seen in the conjunctivas of IL-5-electroporated EC-developing mice. CONCLUSIONS: It appears that systemic IL-5 and IFN-gamma play different roles in the development of EC.

DNA probes for identifying chromosomes 5, 6, and 7 of Schistosoma mansoni.

Schistosoma mansoni has a genome of 270 Mb contained on 8 pairs of chromosomes. C-banding has been a useful technique in identifying the 7 autosomal and sex chromosomes. However, even with C-banding, S. mansoni chromosomes 5, 6, and 7 are difficult to discriminate from each other, because of their small sizes, morphological similarity, and poor banding patterns. We have identified probes that specifically paint chromosomes 5, 6, and 7 of S. mansoni with the use of chromosome microdissection and the degenerate oligonucleotide-primed polymerase chain reaction (DOP-PCR). Exact chromosome identification is required for accurate chromosome mapping of genomic clones and genetic elements, which is an essential component of the schistosome genome project.

Renal leiomyoma: an immunohistochemical, ultrastructural and comparative genomic hybridization study.

Renal leiomyoma is a rare neoplasm. We report such a case in a 57-year-old Japanese woman who was found to have a mass in the left kidney. The histological examination disclosed the proliferation of spindle cells showing a benign appearance. Entrapped tubular cells were observed in the peripheral area of the tumor. The immunohistochemical examination of spindle neoplastic cells showed a positive reaction for alpha smooth muscle actin, h-caldesmon, l-caldesmon, calponin, muscle actin, myosin and desmin. Additionally, the ultrastructural examination of the tumor showed membrane caveolae and myofilaments in the cytoplasm. This tumor was considered to show a differentiation into smooth muscle cells. The comparative genomic hybridization of the tumor detected the combined losses of chromosomes 4, 6, 12 and 14 which has not been previously described in renal tumors. Finally, the immunohistochemical panel of smooth muscle markers and ultrastructural and genetic study may be useful in diagnosing renal leiomyoma.

IGF-I gene transfer by electroporation promotes regeneration in a muscle injury model.

The goal of this study was to determine whether insulin-like growth factor-I (IGF-I) gene delivery by electroporation promotes repair after muscle injury. An injury-repair model was created using mice in which a hamstring muscle was cut and sutured. A total of 50 microg of IGF-I DNA or green fluorescent protein (GFP) DNA (both in pCAGGS) was injected into the lesion and introduced into muscle cells by electrostimulation using an electric pulse generator. The number of regenerating muscle fibers in the IGF-I DNA group was significantly more than that in the GFP DNA group at 2 weeks after injection. The diameter of regenerating muscle fibers from the IGF-I DNA group was larger than that of the GFP DNA group at 4 weeks after injection. There was no significant difference in the serum IGF-I concentration between the IGF-I DNA group and the GFP DNA group at 1, 2, and 4 weeks after injection. However, muscle IGF-I concentration in the IGF-I DNA injection group was significantly greater than that in the GFP DNA injection group at 2 weeks after injection. These results demonstrated that the effects of enhanced IGF-I production were local and limited to the injected area. The ratio (injected/uninjected; intact) of the amplitude of compound muscle action potentials (CMAP) in the IGF-I DNA injection group was greater than that in the GFP DNA injection group at 4 weeks after injection and of the control group. In conclusion, IGF-I gene transfer by electroporation proved to be a simple, safe, inexpensive, and effective method to promote the regeneration of injured muscles in our injury model.

A small asymptomatic intracranial aneurysm in an elderly woman that ruptured soon after discovery.

A 78-year-old woman underwent magnetic resonance (MR) imaging to assess the deterioration of her right hemiparesis initially caused by putaminal hemorrhage that occurred 5 years prior to referral. MR imaging detected an anterior communicating artery aneurysm but no new lesion was seen that might have caused the deterioration was observed. Hemiparesis improved within several days and she was referred for endovascular treatment of the aneurysm. Digital subtraction angiography demonstrated a 4.4 mm long aneurysm at the A1-A2 junction of her left anterior cerebral artery. Information on the risk associated with treatment caused her to hesitate. Three days after discharge and 40 days after the discovery of the aneurysm it ruptured, causing severe subarachnoid hemorrhage. The patient died on the following day.

Thickening of sphenoid sinus mucosa during the acute stage of pituitary apoplexy.

The authors treated two patients with pituitary apoplexy in whom magnetic resonance (MR) images were obtained before and after the episode. Two days after the apoplectic episodes, MR imaging demonstrated marked thickening of the mucosa of the sphenoid sinus that was absent in the previous studies. The relevance of this change in the sphenoid sinus was investigated. Retrospective evaluations were performed using MR images obtained in 14 consecutive patients with classic pituitary apoplexy characterized by acute onset of severe headache. The mucosa of the sphenoid sinus had thickened predominantly in the compartment just beneath the sella turcica, in nine of 11 patients, as ascertained on MR images obtained within 7 days after the onset of apoplectic symptoms. This condition improved spontaneously in all four patients who did not undergo transsphenoidal surgery. The sphenoid sinus mucosa appeared to be normal on MR images obtained from three patients at the chronic stage (> 3 months after onset). The incidence of sphenoid sinus mucosal thickening during the acute stage was significantly higher in the patients with apoplexy than that in the 100 patients without apoplexy. A histological study conducted in four patients who underwent transsphenoidal surgery during the early stage showed that the subepithelial layer of the sphenoid sinus mucous membrane was obviously swollen. The sphenoid sinus mucosa thickens during the acute stage of pituitary apoplexy. This thickening neither indicates infectious sinusitis nor rules out the choice of the transsphenoidal route for surgery.

Concomitant pituitary adenoma and Rathke's cleft cyst.

We reviewed the clinical, radiological and surgical findings in patients with both pituitary adenoma and Rathke's cleft cyst. We retrospectively selected patients with both lesions from the 374 patients in whom a sellar/juxtasellar lesion was detected on MRI at 1.5 tesla. All patients received intravenous contrast medium. Concomitant pituitary adenoma and Rathke's cleft cyst were found in eight patients (2.1 %). The frequency of the combination was 3.5 % of pituitary adenomas and 11% of Rathke's cleft cysts. Symptoms were always due to the adenoma, secreting adrenocorticotrophin in two patients and growth hormone in six. The adenoma was larger in five patients, and the cyst in three. The cysts gave variable signal. The adenoma was adjacent to the cyst in seven patients, and enclosed it in the other patient. As a result of experience with MRI, concomitant pituitary adenoma and Rathke's cleft cyst are now known not to be as rare as thought previously. When a non-enhancing cyst-like structure is demonstrated in a patient with pituitary adenoma, the possibility of a coexisting Rathke's cleft cyst should be considered.

Reticular erythematous mucinosis syndrome with an infiltration of factor XIIIa+ and hyaluronan synthase 2+ dermal dendrocytes.

We report a patient with reticular erythematous mucinosis (REM) syndrome. Content of hyaluronan in lesional skin was approximately 2.9-fold higher than in the patient's uninvolved skin, but its synthetic activity in fibroblasts explanted from lesional skin remained unchanged. Immunohistochemical study using antifactor XIIIa (anti-FXIIIa) antibody demonstrated that the number of FXIIIa+ cells in the lesional skin was significantly increased compared with those in the patient's uninvolved skin and in normal control skin samples (P < 0.01). As hyaluronan is considered to be synthesized by hyaluronan synthase (HAS), which is composed of three genetically distinct isoforms (HAS1, HAS2 and HAS3), the cells responsible for the accumulation of hyaluronan in lesional skin were immunohistochemically examined using antibodies for HAS1, HAS2 and HAS3. The specific antibody for HAS2 was found to react with some populations of FXIIIa+ cells in the involved skin, and the number of HAS2+ cells was significantly increased in the involved skin (P < 0.01). The results suggest that accumulation of hyaluronan in REM may be related to populations of FXIIIa+/HAS2+ dermal dendrocytes rather than to dermal fibroblasts.

Characterization of cryptic flagellin genes in Shigella boydii and Shigella dysenteriae.

Flagellin (fliC) genes of 12 Shigella boydii and five Shigella dysenteriae strains were characterized. Though these strains are nonmotile, the cryptic fliCSB gene, cloned from S. boydii strain C3, is functional for expression of flagellin. It consists of 1,704 bp, and encodes 568 amino acid residues (57,918 Da). The fliCSD gene from S. dysenteriae strain 16 consists of 1,650 bp encoding 549 amino acid residues (57,591 Da) and contains an IS1 element inserted in its 3' end. The two genes are composed of the 5'-constant, central variable and 3'-constant sequences, like other known fliC genes. The two genes share high homology in nucleotide and amino acid sequences with each other and also with the Escherichia coli fliCE gene, indicating that both genes are closely related to the fliCE gene. Comparison of the central variable sequences of six different fliC genes showed that the fliCSB and fliCSD genes share low homology in amino acid sequence with the other fliC genes, suggesting that they encode antigenic determinants intrinsic to respective subgroups. However, Southern blotting using as probes the central variable sequences of several fliC genes showed that four of 12 S. boydii strains have a fliC gene similar to that of Shigella flexneri, and that among five fliC genes from S. dysenteriae strains, one is similar to that of S. flexneri, two are similar to that of S. boydii, and only one is unique to S. dysenteriae. Some of these variant alleles were verified by immunoblotting with flagellins produced from cloned fliC genes. The presence of variant fliC alleles in S. boydii and S. dysenteriae indicates that subdivision into subgroups does not reflect the ancestral flagella H antigenic relationships. These data will be useful in considering the evolutionary divergence of the Shigella spp..

Differentiation stages of eosinophils characterized by hyaluronic acid binding via CD44 and responsiveness to stimuli.

To characterize interleukin (IL)-5-induced eosinophils, we examined the expression of CD44, very late antigen (VLA)-4, and the IL-5 receptor alpha chain, as well as the levels of eosinophil peroxidase and the generation of superoxide. Eosinophils were prepared from IL-5-transgenic mice, then characterized using electron microscopy to determine their responses to stimuli. Whereas CD44 densities remained almost constant, the level of VLA-4 increased in parallel with eosinophil maturation. Although a subset of IL-5-induced eosinophils with high side scatter recovered from bone marrow and rare ones found in blood recognized hyaluronic acid (HA), most did not have this property. Bone marrow eosinophils with high side scatter and lower density contained eosinophil peroxidase, not only in granules, but also in membranous structures for 30% of this population. This population developed HA-binding ability in response to IL-3, IL-4, IL-5, granulocyte-macrophage colony-stimulating factor, macrophage inflammatory protein (MIP)-2, monocyte chemotactic protein (MCP)-1, eotaxin, nerve growth factor (NGF), and opsonized zymosan (OZ). Peripheral blood eosinophils acquired HA-binding ability in response to the same stimuli, but their responses were less than those of bone marrow eosinophils with high levels of side scatter. However, splenic eosinophils did not respond to these stimuli. Although peripheral blood eosinophils did not proliferate when stimulated by IL-5, these were the only cells that released eosinophil peroxidase in response to IL-4, MIP-2, MCP-1, eotaxin, NGF, and OZ. With the exception of a subset of bone marrow eosinophils, the ability to acquire HA binding, but not the ability to generate superoxide, correlated with eosinophil peroxidase activity and major basic protein accumulation in the granules of maturing cells.

Photodynamic therapy targeted to tumor-induced angiogenic vessels.

Cancer photodynamic therapy (PDT) with benzoporphyrin derivative monoacid ring A (BPD-MA, verteporfin) may be effective not only by being directly cytotoxic to tumor cells, but also by being cytotoxic to the endothelium of tumor neovasculature. In the present study, we investigated the effect of PDT with an experimental liposomal formulation of BPD-MA on tumor-induced angiogenic vessels using a murine dorsal air sac model. First, hemostasis of neovasculature was examined by varying the regimen of PDT. Laser irradiation at 15 min after injection of 2 mg/kg liposomal BPD-MA (15 min PDT) caused complete blocking of blood flow in neovasculature. In contrast, PDT did not inhibit blood flow when the irradiation occurred 3 h after the injection of liposomal BPD-MA (3 h PDT). Next, the antitumor effect of PDT on Meth A sarcoma-bearing mice was investigated by using the hemostasis-inducing regimen. Tumor growth was strongly inhibited after the 15 min PDT with BPD-MA at a dose of 0.5-2 mg/kg. In contrast, 3 h PDT with BPD-MA at a dose of 2 mg/kg suppressed tumor growth only partially. The current study indicates that 15 min PDT causes strong suppression of tumor growth, perhaps through damaging endothelial cells in the tumor neovasculature rather than through a direct cytotoxic effect on tumor cells.

Eosinophil-induced liver injury: an experimental model using IL-5 transgenic mice.

BACKGROUND/AIMS: In certain liver diseases, activated eosinophils are considered to be important effector cells in addition to T-cell-mediated cytotoxicity. No experimental model, however, has been developed for in vivo analysis of the cytotoxic mechanisms. METHODS: Interleukin-5 (IL-5) transgenic mice (C3H/HeN-TgN(IL-5)Imeg), which exhibit marked eosinophilia without liver injury, were injected once with 25 microg of lipopolysaccharide (LPS) intraperitoneally. The mice were sacrificed weekly and eosinophilic injuries were assessed microscopically. To clarify the role of Kupffer cells and tumor necrosis factor-alpha (TNF-alpha) in the liver injury, gadolinium chloride (GdCl3) and anti-TNF-alpha neutralizing antibody were administrated before the LPS injection. RESULTS: Two weeks after injection, transgenic mice exhibited marked infiltration of eosinophils and extensive lobular necrosis. Transmigration of eosinophils through vascular endothelium and degranulation of eosinophil cytotoxic granules in inflamed areas were observed. These eosinophilic injuries were transient, but liver-specific. Pre-administration of GdCl3 and anti-TNF-alpha markedly reduced the hepatic inflammation, suggesting that LPS-activated Kupffer cells play a key role in producing the cytotoxicity of eosinophils by releasing TNF-alpha. CONCLUSIONS: We have established an experimental model of eosinophil-induced liver injury using IL-5 transgenic mice. Since this model is simple and highly reproducible, it will be useful for analysis of in vivo cytotoxic mechanisms of eosinophils.

A new theory of phylogeny inference through construction of multidimensional vector space.

Here, a new theory of molecular phylogeny is developed in a multidimensional vector space (MVS). The molecular evolution is represented as a successive splitting of branch vectors in the MVS. The end points of these vectors are the extant species and indicate the specific directions reflected by their individual histories of evolution in the past. This representation makes it possible to infer the phylogeny (evolutionary histories) from the spatial positions of the end points. Search vectors are introduced to draw out the groups of species distributed around them. These groups are classified according to the nearby order of branches with them. A law of physics is applied to determine the species positions in the MVS. The species are regarded as the particles moving in time according to the equation of motion, finally falling into the lowest-energy state in spite of their randomly distributed initial condition. This falling into the ground state results in the construction of an MVS in which the relative distances between two particles are equal to the substitution distances. The species positions are obtained prior to the phylogeny inference. Therefore, as the number of species increases, the species vectors can be more specific in an MVS of a larger size, such that the vector analysis gives a more stable and reliable topology. The efficacy of the present method was examined by using computer simulations of molecular evolution in which all the branch- and end-point sequences of the trees are known in advance. In the phylogeny inference from the end points with 100 multiple data sets, the present method consistently reconstructed the correct topologies, in contrast to standard methods. In applications to 185 vertebrates in the alpha-hemoglobin, the vector analysis drew out the two lineage groups of birds and mammals. A core member of the mammalian radiation appeared at the base of the mammalian lineage. Squamates were isolated from the bird lineage to compose the outgroup, while the other living reptilians were directly coupled with birds without forming any sister groups. This result is in contrast to the morphological phylogeny and is also different from those of recent molecular analyses.

Intrasellar rhabdomyosarcoma: case report.

OBJECTIVE AND IMPORTANCE: There has been only one reported case of an intrasellar rhabdomyosarcoma, the origin of which was in the para-nasal sinus. The authors encountered a patient with an intrasellar rhabdomyosarcoma with no evidence of tumor at any additional sites. CLINICAL PRESENTATION: A 28-year-old otherwise healthy man complaining of headache exhibited left abducent nerve palsy and left visual disturbance. The patient was diagnosed as having a sellar tumor invading the left cavernous sinus. INTERVENTION: Near total removal of the tumor was achieved via a trans-sphenoidal approach. Histologically, the tumor was composed of small, round-to-elongated undifferentiated cells and large spindle cells with myoblastic features. Immunohistochemically, tumor cells were positive for antibodies against desmin, myoglobin, and alpha-smooth muscle actin. The tumor was identified as an embryonal rhabdomyosarcoma on the basis of the above pathological findings. Systemic investigation, including the nasal and para-nasal regions, failed to detect any additional tumors. Postoperative local radiation therapy and chemotherapy with the use of ifosfamide, etoposide, and vincristine brought about complete initial remission. CONCLUSION: Rhabdomyosarcoma should be considered in the differential diagnosis of a primary intrasellar neoplasm.