Polydipsia frequently occurs in schizophrenia patients. The excessive water loading in polydipsia occasionally induces a hyponatremic state and leads to water intoxication. Whether polydipsia in schizophrenic patients correlates with neuropsychological impairments or structural brain changes is not clear and remains controversial.
Eight polydipsic schizophrenia patients, eight nonpolydipsic schizophrenia patients, and eight healthy controls were recruited. All subjects underwent magnetic resonance imaging (MRI) and neuropsychological testing. Structural abnormalities were analyzed using a voxel-based morphometry (VBM) approach, and patients’ neuropsychological function was assessed using the Brief Assessment of Cognition in Schizophrenia, Japanese version (BACS-J).
No significant differences were found between the two patient groups with respect to the clinical characteristics. Compared with healthy controls, polydipsic patients showed widespread brain volume reduction and neuropsychological impairment. Furthermore, the left insula was significantly reduced in polydipsic patients compared with nonpolydipsic patients. These nonpolydipsic patients performed intermediate to the other two groups in the neuropsychological function test.
It is possible that polydipsia or the secondary hyponatremia might induce left insula volume reduction. Furthermore, this structural brain change may indirectly induce more severe neuropsychological impairments in polydipsic patients. Thus, we suggest that insula abnormalities might contribute to the pathophysiology of polydipsic patients.
Schizophrenia; Polydipsia; Volumetry; MRI; Neuropsychological impairment; Brief assessment of cognition in schizophrenia
Background and Purpose
Oseltamivir is the most widely prescribed anti-influenza medication. However, in rare instances, it has been reported to stimulate behavioural activities in adolescents. The goal of this study was to determine the molecular mechanism responsible for these behavioural activities.
We performed an in vitro assay of MAO-A, the enzyme responsible for neurotransmitter degradation, using either the active form – oseltamivir carboxylate (OC) or the inactive prodrug – oseltamivir ethyl ester (OEE). We also analysed the docking of MAO-A with OEE or OC in silico. Mouse behaviours after OEE or OC administration were monitored using automated video and computer analysis.
OEE, but not OC, competitively and selectively inhibited human MAO-A. The estimated Ki value was comparable with the Km values of native substrates of MAO-A. Docking simulations in silico based on the tertiary structure of MAO-A suggested that OEE could fit into the inner pocket of the enzyme. Behavioural monitoring using automated video analysis further revealed that OEE, not OC, significantly enhanced spontaneous behavioural activities in mice, such as jumping, rearing, sniffing, turning and walking.
Conclusions and Implications
Our multilevel analyses suggested OEE to be the cause of the side effects associated with oseltamivir and revealed the molecular mechanism underlying the stimulated behaviours induced by oseltamivir in some circumstances.
oseltamivir; monoamine oxidase; stimulated behaviour; prodrug
The use of an algorithm may facilitate measurement-based treatment and result in more rational therapy. We conducted a 1-year, open-label study to compare various outcomes of algorithm-based treatment (ALGO) for schizophrenia versus treatment-as-usual (TAU), for which evidence has been very scarce.
In ALGO, patients with schizophrenia (Diagnostic and Statistical Manual of Mental Disorders, fourth edition) were treated with an algorithm consisting of a series of antipsychotic monotherapies that was guided by the total scores in the positive and negative syndrome scale (PANSS). When posttreatment PANSS total scores were above 70% of those at baseline in the first and second stages, or above 80% in the 3rd stage, patients proceeded to the next treatment stage with different antipsychotics. In contrast, TAU represented the best clinical judgment by treating psychiatrists.
Forty-two patients (21 females, 39.0 ± 10.9 years-old) participated in this study. The baseline PANSS total score indicated the presence of severe psychopathology and was significantly higher in the ALGO group (n = 25; 106.9 ± 20.0) than in the TAU group (n = 17; 92.2 ± 18.3) (P = 0.021). As a result of treatment, there were no significant differences in the PANSS reduction rates, premature attrition rates, as well as in a variety of other clinical measures between the groups. Despite an effort to make each group unique in pharmacologic treatment, it was found that pharmacotherapy in the TAU group eventually became similar in quality to that of the ALGO group.
While the results need to be carefully interpreted in light of a hard-to-distinguish treatment manner between the two groups and more studies are necessary, algorithm-based antipsychotic treatments for schizophrenia compared well to treatment-as-usual in this study.
algorithm; open-label clinical trial; measurement-based treatment; schizophrenia; treatment-as-usual
There is an urgent need to determine whether oversulfated chondroitin sulfate (OSCS), a compound contaminating heparin supplies worldwide, is the cause of the severe anaphylactoid reactions that have occurred after intravenous heparin administration in the United States and Germany.
Heparin procured from the Food and Drug Administration, consisting of suspect lots of heparin associated with the clinical events as well as control lots of heparin, were screened in a blinded fashion both for the presence of OSCS and for any biologic activity that could potentially link the contaminant to the observed clinical adverse events. In vitro assays for the activation of the contact system and the complement cascade were performed. In addition, the ability of OSCS to recapitulate key clinical manifestations in vivo was tested in swine.
The OSCS found in contaminated lots of unfractionated heparin, as well as a synthetically generated OSCS reference standard, directly activated the kinin–kallikrein pathway in human plasma, which can lead to the generation of bradykinin, a potent vasoactive mediator. In addition, OSCS induced generation of C3a and C5a, potent anaphylatoxins derived from complement proteins. Activation of these two pathways was unexpectedly linked and dependent on fluid-phase activation of factor XII. Screening of plasma samples from various species indicated that swine and humans are sensitive to the effects of OSCS in a similar manner. OSCS-containing heparin and synthetically derived OSCS induced hypotension associated with kallikrein activation when administered by intravenous infusion in swine.
Our results provide a scientific rationale for a potential biologic link between the presence of OSCS in suspect lots of heparin and the observed clinical adverse events. An assay to assess the amidolytic activity of kallikrein can supplement analytic tests to protect the heparin supply chain by screening for OSCS and other highly sulfated polysaccharide contaminants of heparin that can activate the contact system.
There are very few studies that have investigated host-specificity among tropical herbivorous insects. Indeed, most of the trophic interactions of herbivorous insects in Southeast Asian tropical rainforests remain unknown, and whether polyphagous feeding is common in the herbivores of this ecosystem has not been determined. The present study employed DNA bar coding to reveal the trophic associations of adult leaf-chewing chrysomelid beetles in a Bornean rainforest. Plant material ingested by the adults was retrieved from the bodies of the insects, and a portion of the chloroplast rbcL sequence was then amplified from this material. The plants were identified at the family level using an existing reference database of chloroplast DNA. Our DNA-based diet analysis of eleven chrysomelid species successfully identified their host plant families and indicated that five beetle species fed on more than two families within the angiosperms, and four species fed on several families of gymnosperms and/or ferns together with multiple angiosperm families. These findings suggest that generalist chrysomelid beetles associated with ecologically and taxonomically distant plants constitute a part of the plant-insect network of the Bornean rainforest.
Rickettsia japonica is an obligate intracellular alphaproteobacteria that causes tick-borne Japanese spotted fever, which has spread throughout East Asia. We determined the complete genomic DNA sequence of R. japonica type strain YH (VR-1363), which consists of 1,283,087 base pairs (bp) and 971 protein-coding genes. Comparison of the genomic DNA sequence of R. japonica with other rickettsiae in the public databases showed that 2 regions (4,323 and 216 bp) were conserved in a very narrow range of Rickettsia species, and the shorter one was inserted in, and disrupted, a preexisting open reading frame (ORF). While it is unknown how the DNA sequences were acquired in R. japonica genomes, it may be a useful signature for the diagnosis of Rickettsia species. Instead of the species-specific inserted DNA sequences, rickettsial genomes contain Rickettsia-specific palindromic elements (RPEs), which are also capable of locating in preexisting ORFs. Precise alignments of protein and DNA sequences involving RPEs showed that when a gene contains an inserted DNA sequence, each rickettsial ortholog carried an inserted DNA sequence at the same locus. The sequence, ATGAC, was shown to be highly frequent and thus characteristic in certain RPEs (RPE-4, RPE-6, and RPE-7). This finding implies that RPE-4, RPE-6, and RPE-7 were derived from a common inserted DNA sequence.
AIM: To evaluate the protective effects of fucoidan on oxidative stress-induced barrier disruption in human intestinal epithelial cells.
METHODS: In Caco-2 cell monolayer models, the disruption of barrier function by oxidative stress is mediated by H2O2. The integrity of polarized Caco-2 cell monolayers was determined by measuring the transepithelial resistance (TER) and permeability was estimated by measuring the paracellular transport of FITC-labeled 4-kDa dextran (FD4). The protective effects of fucoidan on epithelial barrier functions on polarized Caco-2 cell monolayers were evaluated by TER and FD4 flux. The expression of tight junction (TJ) proteins was assessed using reverse-transcription polymerase chain reaction (RT-PCR) and immunofluorescence staining.
RESULTS: Without H2O2 treatment, fucoidan significantly increased the TER compared to control (P < 0.05), indicating a direct enhancement of intestinal epithelial barrier function. Next, H2O2 disrupted the epithelial barrier function in a time-dependent manner. Fucoidan prevented the H2O2-induced destruction in a dose-dependent manner. Fucoidan significantly decreased H2O2-induced FD4 flux (P < 0.01), indicating the prevention of disruption in paracellular permeability. RT-PCR showed that Caco-2 cells endogenously expressed claudin-1 and -2, and occludin and that H2O2 reduced the mRNA expression of these TJ proteins. Treatment with fucoidan attenuated the reduction in the expressions of claudin-1 and claudin-2 but not occludin. Immunofluorescence staining revealed that the expression of claudin-1 was intact and high on the cell surface. H2O2 disrupted the integrity of claudin-1. Treatment with fucoidan dramatically attenuated the expression of claudin-1.
CONCLUSION: Fucoidan enhanced intestinal epithelial barrier function by upregulating the expression of claudin-1. Thus, fucoidan may be an appropriate therapy for the treatment of inflammatory bowel diseases.
Fucoidan; Tight junction; Intestinal epithelial cells; Oxidative stress; Inflammatory bowel diseases
It is believed that the type of educational environment in teaching hospitals may affect the performance of medical knowledge base among residents, but this has not yet been proven.
We aimed to investigate the association between the hospital educational environment and the performance of the medical knowledge base among resident physicians in Japanese teaching hospitals.
To assess the knowledge base of medicine, we conducted the General Medicine InTraining Examination (GM-ITE) for second-year residents in the last month of their residency. The items of the exam were developed based on the outcomes designated by the Japanese Ministry of Health, Labor, and Welfare. The educational environment was evaluated using the Postgraduate Hospital Educational Environment Measure (PHEEM) score, which was assessed by a mailed survey 2 years prior to the exam. A mixed-effects linear regression model was employed for the analysis of variables associated with a higher score.
Twenty-one teaching hospitals participated in the study and a total of 206 residents (67 women) participated and completed the exam. There were no residents who declined to participate in the exam. The mean GM-ITE score was 58 (standard deviation 8.4). The mixed-effects linear regression analysis showed that a higher PHEEM score was associated with a higher GM-ITE score (P = 0.02). Having a department of general medicine, and hospital location in a provincial community (versus an urban setting), were also shown to have a significant relationship with the higher score (P = 0.03, and P = 0.02, respectively).
We found that the performance of the medical knowledge base of resident physicians was significantly associated with the educational environment of their hospitals. Improvement of the educational environment in teaching hospitals might be crucial for enhancing the performance of resident physicians in Japan.
outcome-based education; postgraduate medical education; educational environment; general medicine; provincial hospital
A 44-year-old man presenting to our hospital emergency room with abdominal pain was hospitalized for hyperlipidemic acute pancreatitis. A pig-tail catheter was placed percutaneously to drain an abscess on day 22. Although the abscess improved gradually and good clinical progress was seen, pancreatic duct disruption was strongly suspected and endoscopic retrograde cholangiopancreatography was performed on day 90. An endoscopic nasopancreatic drainage tube was placed, but even with concurrent use of a somatostatin analogue, treatment was ineffective. Surgical treatment was elected, but was subsequently postponed as the abscess culture was positive for extended-spectrum β-lactamase-producing Escherichia coli and methicillin-resistant Staphylococcus aureus. Drainage tubography showed a small fistula of the colon at the splenic flexure on day 140. Colonoscopy was performed on day 148. After indigo carmine had been injected, a fistula into the splenic flexure of the colon showed blue staining. The over-the-scope clip (OTSC) system was used to seal the fistula and complete closure was shown. A liquid diet was started on day 159 and was smoothly upgraded to a full diet. Following removal of the pancreatic stent on day 180, drainage volume immediately decreased and the percutaneous drain was removed. On day 189, computed tomography showed no exacerbation of the abscess and the patient was discharged on day 194. This case of colonic fistula caused by severe acute pancreatitis was successfully treated using the OTSC system, avoiding the need for an open procedure.
Colonic fistula; Endoscopic treatment; Pancreatic duct disruption; Severe acute pancreatitis
Plasticity related gene-1 (PRG-1) is a brain-specific membrane protein related to lipid phosphate phosphatases, which acts in the hippocampus specifically at the excitatory synapse terminating on glutamatergic neurons. Deletion of prg-1 in mice leads to epileptic seizures and augmentation of EPSCs, but not IPSCs. In utero electroporation of PRG-1 into deficient animals revealed that PRG-1 modulates excitation at the synaptic junction. Mutation of the extracellular domain of PRG-1 crucial for its interaction with lysophosphatidic acid (LPA) abolished the ability to prevent hyperexcitability. As LPA application in vitro induced hyperexcitability in wild-type but not in LPA2 receptor-deficient animals, and uptake of phospholipids is reduced in PRG-1-deficient neurons, we assessed PRG-1/LPA2 receptor-deficient animals, and found that the pathophysiology observed in the PRG-1-deficient mice was fully reverted. Thus, we propose PRG-1 as an important player in the modulatory control of hippocampal excitability dependent on presynaptic LPA2 receptor signaling.
Few controlled trials compared second-generation antipsychotics (SGAs) with first-generation antipsychotics (FGAs) regarding relapse prevention in schizophrenia. We conducted a systematic review/meta-analysis of randomized trials, lasting ≥6 months comparing SGAs with FGAs in schizophrenia. Primary outcome was study-defined relapse; secondary outcomes included relapse at 3, 6 and 12 months, treatment failure, hospitalization, and dropout due to any cause, non-adherence and intolerability. Pooled relative risk (RR) [+/−95%CIs] was calculated using random-effects model, with numbers-needed-to-treat (NNT) calculations where appropriate. Across 23 studies (n=4,504, mean duration=61.9+/−22.4 weeks), none of the individual SGAs outperformed FGAs (mainly haloperidol) regarding study-defined relapse, except for isolated, single trial-based superiority, and except for risperidone's superiority at 3 and 6 months when requiring >/=3 trials. Grouped together, however, SGAs prevented relapse more than FGAs (29.0% vs. 37.5%, RR=0.80, CI:0.70–0.91, p=.0007, I2=37%; NNT=17, CI:10–50, p=.003). SGAs were also superior regarding relapse at 3, 6 and 12 months (p=.04, p<.0001, p=.0001), treatment failure (p=.003) and hospitalization (p=.004). SGAs showed trend-level superiority for dropout due to intolerability (p=.05). Superiority of SGAs regarding relapse was modest (NNT=17), but confirmed in double-blind trials, first- and multi-episode patients, using preferentially or exclusively raw or estimated relapse rates, and for different haloperidol equivalent-comparator doses. There was no significant heterogeneity or publication bias. The relevance of the somewhat greater efficacy of SGAs over FGAs on several relevant outcomes depends on whether SGAs form a meaningful group and whether mid- or low-potency FGAs differ from haloperidol. Regardless, treatment selection needs to be individualized considering patient- and medication-related factors.
Schizophrenia; Antipsychotics; Relapse Prevention; Maintenance; Long-term treatment; Meta-analysis
Decoy receptor 3 (DcR3) is a soluble secreted protein that belongs to the tumor necrosis factor receptor (TNFR) superfamily. DcR3 inhibits the Fas ligand (FasL)/Fas apoptotic pathway by binding to FasL, competitively with Fas receptor. Previous studies have reported that overexpression of DcR3 has been detected in various human malignancies and that DcR3 functions as a ‘decoy’ for FasL to inhibit FasL-induced apoptosis. In addition, recent studies have revealed that DcR3 has ‘non-decoy’ functions to promote tumor cell migration and invasion, suggesting that DcR3 may play important roles in tumor progression by decoy and non-decoy functions. We have previously reported that overexpression of DcR3 was observed in human malignant fibrous histiocytoma (MFH), however, the roles of DcR3 in MFH have not been studied. In the present study, to elucidate the roles of DcR3 in tumor progression of MFH, we examined the effects of DcR3 inhibition on cell apoptosis, migration and invasion in human MFH cells. siRNA knockdown of DcR3 enhanced the FasL-induced apoptotic activity and significantly decreased cell migration and invasion with a decrease in the activation of phosphatidylinositol 3 kinase (PI3K)/Akt and matrix metalloproteinase (MMP)-2. The findings in this study strongly suggest that DcR3 plays important roles in tumor progression of human MFH by decoy as well as non-decoy functions and that DcR3 may serve as a potent therapeutic target for human MFH.
DcR3; apoptosis; migration; invasion; matrix metalloproteinase
Demyelination is generally regarded as a consequence of oligodendrocytic cell death. Oligodendrocyte processes that form myelin sheaths may, however, degenerate and regenerate independently of the cell body, in which case cell death does not necessarily occur. We provide here the first evidence of retraction and regeneration of oligodendrocyte processes with no cell death in vitro, using time-lapse imaging. When processes were severed mechanically in vitro, the cells did not undergo cell death and the processes regenerated in 36 h. In a separate experiment, moderate N-methyl-D-aspartate (NMDA) stimuli caused process retraction without apparent cell death, and the processes regained their elaborate morphology after NMDA was removed from the culture medium. These results strongly suggest that demyelination and remyelination can take place without concomitant cell death, at least in vitro. Process regeneration may therefore become a target for future therapy of demyelinating disorders.
The senescence marker protein-30 (SMP30) is a 34 kDa protein originally identified in rat liver that shows decreased levels with age. Several functional studies using SMP30 knockout (Smp30Y/−) mice established that SMP30 functions as an antioxidant and protects against apoptosis. To address the potential role of SMP30 in nonalcoholic fatty liver disease (NAFLD) pathogenesis, we established Smp30Y/− mice on a Leprdb/db background (Leprdb/dbSmp30Y/− mice).
Research Design/Principal Findings
Male Leprdb/dbSmp30Y/− mice were fed a standard diet (340 kcal/100 g, fat 5.6%) for 16 weeks whereupon the lipid/lipoprotein profiles, hepatic expression of genes related to lipid metabolism and endoplasmic reticulum stress markers were analyzed by HPLC, quantitative RT-PCR and western blotting, respectively. Changes in the liver at a histological level were also investigated. The amount of SMP30 mRNA and protein in livers was decreased in Leprdb/dbSmp30Y/+ mice compared with Leprdb/+Smp30Y/+ mice. Compared with Leprdb/dbSmp30Y/+ mice, 24 week old Leprdb/dbSmp30Y/− mice showed: i) increased small dense LDL-cho and decreased HDL-cho levels; ii) fatty liver accompanied by numerous inflammatory cells and increased oxidative stress; iii) decreased mRNA expression of genes involved in fatty acid oxidation (PPARα) and lipoprotein uptake (LDLR and VLDLR) but increased CD36 levels; and iv) increased endoplasmic reticulum stress.
Our data strongly suggest that SMP30 is closely associated with NAFLD pathogenesis, and might be a possible therapeutic target for NAFLD.
Hypertension induces cardiovascular hypertrophy and fibrosis. Infiltrated macrophages are critically involved in this process. We recently reported that inhibition of prolyl hydroxylase domain protein 2 (PHD2), which hydroxylates the proline residues of hypoxia‐inducible factor‐α (HIF‐α) and thereby induces HIF‐α degradation, suppressed inflammatory responses in macrophages. We examined whether myeloid‐specific Phd2 deletion affects hypertension‐induced cardiovascular remodeling.
Methods and Results
Myeloid‐specific PHD2‐deficient mice (MyPHD2KO) were generated by crossing Phd2‐floxed mice with LysM‐Cre transgenic mice, resulting in the accumulation of HIF‐1α and HIF‐2α in macrophage. Eight‐ to ten‐week‐old mice were given NG‐nitro‐L‐arginine methyl ester (L‐NAME), a nitric oxide synthase inhibitor, and Angiotensin II (Ang II) infusion. L‐NAME/Ang II comparably increased systolic blood pressure in control and MyPHD2KO mice. However, MyPHD2KO mice showed less aortic medial and adventitial thickening, and macrophage infiltration. Cardiac interstitial fibrosis and myocyte hypertrophy were also significantly ameliorated in MyPHD2KO mice. Transforming growth factor‐β and collagen expression were decreased in the aorta and heart from MyPHD2KO mice. Echocardiographic analysis showed that left ventricular hypertrophy and reduced ejection fraction induced by L‐NAME/Ang II treatment in control mice were not observed in MyPHD2KO mice. Administration of digoxin that inhibits HIF‐α synthesis to L‐NAME/Ang II‐treated MyPHD2KO mice reversed these beneficial features.
Phd2 deletion in myeloid lineage attenuates hypertensive cardiovascular hypertrophy and fibrosis, which may be mediated by decreased inflammation‐ and fibrosis‐associated gene expression in macrophages. PHD2 in myeloid lineage plays a critical role in hypertensive cardiovascular remodeling.
fibrosis; hypertrophy; hypoxia; macrophages; migration
Cells recognize and respond to changes in intra- and extracellular mechanical conditions to maintain their mechanical homeostasis. Linear contractile bundles of actin filaments and myosin II known as stress fibres (SFs) mediate mechanical signals. Mechanical cues such as excessive stress driven by myosin II and/or external force may damage SFs and induce the local transient accumulation of SF-repair complexes (zyxin and VASP) at the damaged sites. Using an atomic force microscope mounted on a fluorescence microscope, we applied mechanical damage to cells expressing fluorescently tagged cytoskeletal proteins and recorded the subsequent mobilization of SF-repair complexes. We found that a LIM protein, paxillin, transiently accumulated at the damaged sites earlier than zyxin, while paxillin knockdown did not affect the kinetics of zyxin translocation. The C-terminal half of paxillin, comprising four-tandem LIM domains, can still translocate to damaged sites on SFs, suggesting that the LIM domain is essential for the mechanosensory function of paxillin. Our findings demonstrate a crucial role of the LIM domain in mechanosensing LIM proteins.
Repair of stress fibres; Mechanosensors; LIM domains
Dipeptidyl peptidase-4 (DPP-4) inhibitors have recently emerged as a new class of antidiabetic that show favorable results in improving glycemic control with a minimal risk of hypoglycemia and weight gain. Teneligliptin, a novel DPP-4 inhibitor, exhibits a unique structure characterized by five consecutive rings, which produce a potent and long-lasting effect. Teneligliptin is currently used in cases showing insufficient improvement in glycemic control even after diet control and exercise or a combination of diet control, exercise, and sulfonylurea- or thiazolidine-class drugs. In adults, teneligliptin is orally administered at a dosage of 20 mg once daily, which can be increased up to 40 mg per day. Because the metabolites of this drug are eliminated via renal and hepatic excretion, no dose adjustment is necessary in patients with renal impairment. The safety profile of teneligliptin is similar to those of other available DPP-4 inhibitors. However, caution needs to be exercised when administering teneligliptin to patients who are prone to QT prolongation. One study has reported that the postprandial blood glucose-lowering effects of teneligliptin administered prior to breakfast were sustained throughout the day, and the effects observed after dinner were similar to those observed after breakfast or lunch. Thus, although clinical data for this new drug are limited, this drug shows promise in stabilizing glycemic fluctuations throughout the day and consequently suppressing the progression of diabetic complications. However, continued evaluation in long-term studies and clinical trials is required to evaluate the efficacy and safety of the drug as well as to identify additional indications for its clinical use.
teneligliptin; DPP-4 inhibitor; diabetes
Various clinical reports suggest etanercept (ETN) has some efficacy in bone formation in rheumatoid arthritis (RA). To examine this effect, we investigated the gene expression of cytokines relevant to osteoblast/osteoclast differentiation, and evaluated histomorphometric findings in mature rats with collagen-induced arthritis (CIA).
Total RNA was extracted from knee joints with CIA after ETN or placebo administration.
Subsequently, realtime-PCR was carried out to quantify the mRNAs encoding Wnt-1,
Dickkopf-1 (DKK-1), receptor activator of nuclear factor kappa-B ligand (RANKL),
osteoprotegelin (OPG) and TNF (tumor necrosis factor)-alpha. In histomorphometric analysis,
the infiltrating pannus volume and pannus surface, and the following items in contact with
pannus surface were measured: osteoclast number, osteoid surface, osteoid volume and labeling
surface. These were evaluated in the distal femur with CIA with or without ETN
TNF-alpha, RANKL and OPG mRNA expressions, linked to osteoclastogenesis, were not
significantly different with or without ETN administration. ETN administration significantly
increased Wnt-1 mRNA expression, the osteoblast promoter, and decreased DKK-1 mRNA expression,
the Wnt signal inhibitor. In histomorphometric analysis, pannus volume, pannus surface and
osteoclast number, parameters of bone destruction, were not significantly different among
groups. Osteoid volume, osteoid surface and labeling surface, parameters of bone formation,
increased significantly with ETN administration.
Our results suggest that ETN suppresses DDK-1 expression, and, as a result, Wnt expression
is promoted and osteoblastogenesis becomes more active, independent of the regulation of
osteoclast activity. Marked bone formation is attributed to the fact that ETN directly
promotes osteoblastogenesis, not as a result of suppressing osteoclastogenesis.
bone formation; Dickkopf-1; etanercept; rheumatoid arthritis; Wnt
Cervical disorders in rheumatoid arthritis (RA) patients have been an important problem
for a long time. Although the recent progression of the treatment strategies for RA might change
the progression of atlantoaxial vertical subluxation (VS) in RA patients, to reveal the risk factors
for VS progression should be important at present. Osteoporosis (OP) and RA share the same risk
factors. The purposes of this study were to identify the progression of VS in RA, and to evaluate
the relationship between the VS development and OP.
Eighty female patients with RA and 18 female patients with OP were retrospectively analyzed.
The RA patients were divided into VS (10 patients) and non-VS groups (70 patients). Morphological
parameters on coronal reconstructed computed tomography images were evaluated. Three-dimensional
analysis was used to measure volumes and volumetric bone mineral densities (vBMDs)
at the upper cervical spine (UCS).
The VS group had higher age, longer RA symptom duration, and lower BMD at the lumbar spine
compared to the non-VS group. Volumes and vBMDs at the UCS in RA group were greater than those
in the OP group. In accordance with VS development, the lateral masses at the UCS became shorter,
the C1 facet angle became sharper, and the volumes at the UCS decreased. However, there was no
statistically significant relationship between vBMDs at the UCS and the VS development.
The C1 facet angle became sharper with VS progression. Although 3-dimensional analysis revealed
that decreases in the volumes at the UCS were associated with VS development, no significant
relationship between OP and the VS development was observed.
bone mineral density; osteoporosis; rheumatoid arthritis; vertical subluxation
Mice lacking the prion protein (PrPC) gene (Prnp), Ngsk Prnp0/0 mice, show late-onset cerebellar Purkinje cell (PC) degeneration because of ectopic overexpression of PrPC-like protein (PrPLP/Dpl). Because PrPC is highly expressed in cerebellar neurons (including PCs and granule cells), it may be involved in cerebellar synaptic function and cerebellar cognitive function. However, no studies have been conducted to investigate the possible involvement of PrPC and/or PrPLP/Dpl in cerebellum-dependent discrete motor learning. Therefore, the present cross-sectional study was designed to examine cerebellum-dependent delay eyeblink conditioning in Ngsk Prnp0/0 mice in adulthood (16, 40, and 60 weeks of age). The aims of the present study were two-fold: (1) to examine the role of PrPC and/or PrPLP/Dpl in cerebellum-dependent motor learning and (2) to confirm the age-related deterioration of eyeblink conditioning in Ngsk Prnp0/0 mice as an animal model of progressive cerebellar degeneration. Ngsk Prnp0/0 mice aged 16 weeks exhibited intact acquisition of conditioned eyeblink responses (CRs), although the CR timing was altered. The same result was observed in another line of PrPc-deficient mice, ZrchI PrnP0/0 mice. However, at 40 weeks of age, CR incidence impairment was observed in Ngsk Prnp0/0 mice. Furthermore, Ngsk Prnp0/0 mice aged 60 weeks showed more significantly impaired CR acquisition than Ngsk Prnp0/0 mice aged 40 weeks, indicating the temporal correlation between cerebellar PC degeneration and motor learning deficits. Our findings indicate the importance of the cerebellar cortex in delay eyeblink conditioning and suggest an important physiological role of prion protein in cerebellar motor learning.
To classify the defects of the skull base, we present a new concept that is intuitive, simple to use, and consistent with subsequent reconstructive procedures. The centers of defects are determined in the anterior (I) or middle (II) skull base. The defects are classified as localized in the defect's center (Ia, IIa) or extended horizontally (Ib, IIb) or vertically (Ic, IIc) from the defect's center. Accompanying defects of the orbital contents and skin are indicated by “O” and “S,” respectively. An algorithm for selecting subsequent reconstructive procedures was based on the classification. Using the new system, we retrospectively reclassified 90 skull base defects and examined how the defect classifications were related to the reconstructive flaps used and postoperative complications. All defects were reclassified with the new system without difficulty or omission. The mean correlation rate was high (88%) between the flaps indicated by the new classification and the flaps that had actually been used. The rate of postoperative complications tended to be higher with Ia, Ic, and IIb defects and combined defects. Our new classification concept can be used to classify defects and to help select flaps used for subsequent reconstructive procedures.
skull base; skull base defect; classification; reconstructive surgery