Long-term outcomes of the mayo conservative hip system in patients aged 30 years or less with osteonecrosis of the femoral head: mean follow-up of more than 10 years.

INTRODUCTION: Historically, total hip arthroplasty (THA) in very young patients has been associated with lower survivorship. However, the long-term outcomes of THA using short stems for osteonecrosis of the femoral head (ONFH) in very young patients remain unclear. Therefore, this study aimed to investigate the long-term outcomes of the Mayo conservative hip system, a short metaphyseal stabilised stem, in patients with ONFH aged ≦30 years. MATERIALS AND METHODS: We retrospectively reviewed 104 joints in 76 patients with ONFH who underwent THA using the Mayo conservative hip system with a minimum follow-up of 8 years. The mean follow-up period was 12.5 (range, 8-19) years. Patients were categorised into two age groups (≦30 years, n = 21 and > 30 years, n = 83). Radiographic evaluation was used to assess stem sinking, stress shielding, and spot welds. The clinical evaluations were performed using the Japanese Orthopedic Association (JOA) hip score. Postoperative major complication and revision surgery rates were also assessed. RESULTS: The patient characteristics were similar between the two groups, except for the age. Revision surgeries were performed in five cases, with similar implant survival rates between the groups. Dislocations occurred in the older age group alone (four joints). One case of intra-operative periprosthetic femoral fracture was found in the younger age group. Stem sinking of > 3 mm occurred in one and seven joints in the younger and older age groups, respectively. Spot welds were observed in most joints (93.2%) in modified Gruen zones 2 and 6 without significant differences between the groups. Stress shielding showed no significant differences in the frequency of occurrence or location between the two groups. Furthermore,the JOA score showed no significant difference between the two groups. CONCLUSION: The use of short stems in patients aged ≤ 30 years with ONFH showed favourable long-term outcomes.

A novel birnavirus identified as the causative agent of summer atrophy of pearl oyster (Pinctada fucata (Gould)).

The Akoya pearl oyster (Pinctada fucata (Gould)) is the most important species for pearl cultivation in Japan. Mass mortality of 0-year-old juvenile oysters and anomalies in adults, known as summer atrophy, have been observed in major pearl farming areas during the season when seawater temperatures exceed about 20 °C since 2019. In this study, we identified a novel birnavirus as the pathogen of summer atrophy and named it Pinctada birnavirus (PiBV). PiBV was first presumed to be the causative agent when it was detected specifically and frequently in the infected oysters in a comparative metatranscriptomics of experimentally infected and healthy pearl oysters. Subsequently, the symptoms of summer atrophy were reproduced by infection tests using purified PiBV. Infection of juvenile oysters with PiBV resulted in an increase in the PiBV genome followed by the atrophy of soft body and subsequent mortality. Immunostaining with a mouse antiserum against a recombinant PiBV protein showed that the virus antigen was localized mainly in the epithelial cells on the outer surface of the mantle. Although the phylogenetic analysis using maximum likelihood method placed PiBV at the root of the genus Entomobirnavirus, the identity of the bi-segmented, genomic RNA to that of known birnaviruses at the full-length amino acid level was low, suggesting that PiBV forms a new genus. The discovery of PiBV will be the basis for research to control this emerging disease.

Residual deformity after femoral neck fracture affects the location of osteonecrosis of the femoral head.

Aims: The localization of necrotic areas has been reported to impact the prognosis and treatment strategy for osteonecrosis of the femoral head (ONFH). Anteroposterior localization of the necrotic area after a femoral neck fracture (FNF) has not been properly investigated. We hypothesize that the change of the weight loading direction on the femoral head due to residual posterior tilt caused by malunited FNF may affect the location of ONFH. We investigate the relationship between the posterior tilt angle (PTA) and anteroposterior localization of osteonecrosis using lateral hip radiographs. Methods: Patients aged younger than 55 years diagnosed with ONFH after FNF were retrospectively reviewed. Overall, 65 hips (38 males and 27 females; mean age 32.6 years (SD 12.2)) met the inclusion criteria. Patients with stage 1 or 4 ONFH, as per the Association Research Circulation Osseous classification, were excluded. The ratios of anterior and posterior viable areas and necrotic areas of the femoral head to the articular surface were calculated by setting the femoral head centre as the reference point. The PTA was measured using Palm's method. The association between the PTA and viable or necrotic areas of the femoral head was assessed using Spearman's rank correlation analysis (median PTA 6.0° (interquartile range 3 to 11.5)). Results: We identified a negative correlation between PTA and anterior viable areas (rho -0.477; p = 0.001), and no correlation between PTA and necrotic (rho 0.229; p = 0.067) or posterior viable areas (rho 0.204; p = 0.132). Conclusion: Our results suggest that residual posterior tilt after FNF could affect the anteroposterior localization of necrosis.

High-Degree Valgus Osteotomy for Severe Femoral Head Osteonecrosis After Femoral Neck Fracture with Nonunion: A Case Report.

CASE: A 15-year-old adolescent boy had severe groin pain because of extensive osteonecrosis of the femoral head with collapse, joint space narrowing, and nonunion after a failed internal fixation for femoral neck fracture. We performed a 60° valgus osteotomy that moved the posteromedial small viable portion of the femoral head to the weight-bearing acetabular area. The femoral neck nonunion and the necrosis healed completely, and the spherical contour of the femoral head was regained after postoperative hip joint remodeling. CONCLUSIONS: Good remodeling and congruency were achieved by performing high-degree valgus osteotomy to obtain sufficient viable area below the acetabular roof.

High-degree posterior rotational osteotomy for extensive collapsed femoral head osteonecrosis in teenagers: remodeling and results with a mean of 10-year follow-up.

INTRODUCTION: This study evaluated the effectiveness of high-degree posterior rotational osteotomy for teenagers with extensively collapsed femoral head osteonecrosis. MATERIALS AND METHODS: We reviewed 40 hips in 35 patients with severely collapsed femoral head osteonecrosis treated by this procedure with a mean follow-up period of 9.7 years (range 5-25 years). Thirteen hips had a history of steroid administration. Nine had slipped capital femoral epiphysis. Nine had femoral neck fracture. Two had traumatic dislocation and fracture. Seven had no apparent risk factors. The mean age of the patients (18 women and 17 men) was 14.8 years. All femoral heads were extensively collapsed below the acetabular roof, and 20 hips showed preoperative joint space narrowing (ARCO stage 4). Lateral radiographs of the femoral head revealed extensive lesions from the posterior to anterior portion. The mean degree of posterior rotation was 118° with intentional varus positioning [mean: 19° (range 10-30)]. The pre- and postoperative extent of the viable area of the femoral head was assessed using conventional anteroposterior radiographs and 45-degree flexion radiography. Further collapse, joint space narrowing, femoral head morphology, and congruency with the acetabulum based on the Stulberg classification were assessed using conventional anteroposterior radiographs. The clinical assessment was conducted using the Merle d'Aubigné hip scores at the last follow-up. RESULTS: The viable area of the femoral head on the loaded portion was seen during a short period after operations. The necrotic lesions were gradually improved postoperatively. The mean extent of viable bone below the acetabular roof was 48% at less than 6 months after surgery and 92% at the final follow-up. The mean extent on 45° flexion radiography was 54% at less than 6 months after surgery and 89% at the final follow-up. Further collapse was prevented in 38 hips (95%). In 19 of 20 hips with preoperative narrowing of the joint space, the joint space was first improved, but narrowing progressively observed in 9 of 40 hips at the final follow-up. Thirty-four hips had excellent or good clinical outcomes, whereas 6 had fair or poor outcomes. CONCLUSIONS: We concluded that this procedure is effective at delaying the progression of degeneration if adequate area of viable bone can be moved under the loaded portion of the acetabulum in teenagers with severe femoral head osteonecrosis.

Novel susceptibility loci for steroid-associated osteonecrosis of the femoral head in systemic lupus erythematosus.

Osteonecrosis of the femoral head (ONFH) involves necrosis of bone and bone marrow of the femoral head caused by ischemia with unknown etiology. Previous genetic studies on ONFH failed to produce consistent results, presumably because ONFH has various causes with different genetic backgrounds and the underlying diseases confounded the associations. Steroid-associated ONFH (S-ONFH) accounts for one-half of all ONFH, and systemic lupus erythematosus (SLE) is a representative disease underlying S-ONFH. We performed a genome-wide association study (GWAS) to identify genetic risk factors for S-ONFH in patients with SLE. We conducted a two-staged GWAS on 636 SLE patients with S-ONFH and 95 588 non-SLE controls. Among the novel loci identified, we determined S-ONFH-specific loci by comparing allele frequencies between SLE patients without S-ONFH and non-SLE controls. We also used Korean datasets comprising 148 S-ONFH cases and 37 015 controls to assess overall significance. We evaluated the functional annotations of significant variants by in silico analyses. The Japanese GWAS identified 4 significant loci together with 12 known SLE susceptibility loci. The four significant variants showed comparable effect sizes on S-ONFH compared with SLE controls and non-SLE controls. Three of the four loci, MIR4293/MIR1265 [odds ratio (OR) = 1.99, P-value = 1.1 × 10-9)], TRIM49/NAALAD2 (OR = 1.65, P-value = 4.8 × 10-8) and MYO16 (OR = 3.91, P-value = 4.9 × 10-10), showed significant associations in the meta-analysis with Korean datasets. Bioinformatics analyses identified MIR4293, NAALAD2 and MYO16 as candidate causal genes. MIR4293 regulates a PPARG-related adipogenesis pathway relevant to S-ONFH. We identified three novel susceptibility loci for S-ONFH in SLE.

Structural and functional analyses of calcium ion response factors in the mantle of Pinctada fucata.

The pearl oyster, Pinctada fucata, is cultured for pearl production in Japan. The shell of the pearl oyster consists of calcium carbonate and a small amount of organic matrix. Despite many studies of the shell matrix proteins, the mechanism by which calcium elements are transported from the mantle to the shell remains unclear. Investigating the molecular mechanism of calcium transportation, we prepared artificial seawater with a high concentration of calcium ions (10ASW) to induce calcification in the pearl oyster. When pearl oysters were cultured in 10ASW, unusual nanoparticles were precipitated on the surface of the nacreous layer. SDS-PAGE and 2D-PAGE analyses revealed that some calcium-sensing proteins (Sarcoplasmic Ca-binding Protein (Pf-SCP) and Pf-filamin A) might be related to the synthesis of these nanoparticles. The recombinant proteins of Pf-SCP can bind to calcium ions and accumulate nanoparticles of calcium carbonate crystals. However, transcriptomic analysis of the pearl oysters grown in 10ASW showed that the matrix protein genes in the shell did not differ before and after treatment with 10ASW. These results suggest that, despite increasing calcium transportation to the shell, treatment with a high concentration of calcium ions does not induce formation of the organic framework in the shell microstructure. These findings offer meaningful insights into the transportation of calcium elements from the mantle to the shell.

Genome-wide Association Study of Idiopathic Osteonecrosis of the Femoral Head.

Idiopathic osteonecrosis of the femoral head (IONFH) is an ischemic disorder that causes bone necrosis of the femoral head, resulting in hip joint dysfunction. IONFH is a polygenic disease and steroid and alcohol have already known to increase its risk; however, the mechanism of IONFH remains to be elucidated. We performed a genome-wide association study using ~60,000 subjects and found two novel loci on chromosome 20q12 and 12q24. Big data analyses identified LINC01370 as a candidate susceptibility gene in the 20q12 locus. Stratified analysis by IONFH risk factors suggested that the 12q24 locus was associated with IONFH through drinking capacity. Our findings would shed new light on pathophysiology of IONFH.

Comparison between component designs with different femoral head size in metal-on-metal total hip arthroplasty; multicenter randomized prospective study.

BACKGROUNDS/AIMS: We prospectively studied 78 prostheses with conventional femoral head and 86 prostheses with large head (Magnum) of metal-on-metal total hip arthroplasty (MoM THA) with two years follow-up. METHODS: Clinical outcomes and blood metal ion were evaluated. RESULTS: There were no significant differences of clinical outcomes between groups. 1.17 ± 1.01 µg/L of blood cobalt ion in Magnum was significantly lower than 1.99 ± 2.34 µg/L in conventional group. No dislocation was observed in Magnum while one dislocation in conventional group. MoM THA with large head is useful if the implants are positioned in appropriate alignment, however longer follow-up will be necessary. CLINICAL TRIAL REGISTRATION: NCT01010763 (registered on ClinicalTrials.gov).

Human mesenchymal stem/stromal cells suppress spinal inflammation in mice with contribution of pituitary adenylate cyclase-activating polypeptide (PACAP).

BACKGROUND: Adult human mesenchymal stem/stromal cells (hMSCs) from bone marrow have been reported to exhibit beneficial effects on spinal cord injury (SCI). A neuropeptide, pituitary adenylate cyclase-activating polypeptide (PACAP) is known to decrease neuronal cell death and inflammatory response after ischemia, SCI, and other neuronal disorders. Recently, we found that expression of the gene for mouse PACAP (Adcyap1) was greater in animals receiving hMSCs with neural injury such as ischemia. However, the association of PACAP with hMSCs to protect nerve cells against neural injuries is still unclear. METHODS: Wild-type and PACAP-gene-deficient (Adcyap1 (+/-) ) mice were subjected to spinal cord transection, and hMSCs (5 × 10(5) cells) were injected into the intervertebral spinal cord on day 1 post-operation (p.o.). Locomotor activity, injury volume, retention of hMSCs, mouse and human cytokine genes (which contribute to macrophage (MΦ) and microglial activation), and Adcyap1 were evaluated. RESULTS: hMSCs injected into wild-type mice improved locomotor activity and injury volume compared with vehicle-treated mice. In contrast, non-viable hMSCs injected into wild-type mice, and viable hMSCs injected into Adcyap1 (+/-) mice, did not. Wild-type mice injected with hMSCs exhibited increased Adcyap1 expression, and observed PACAP immunoreaction in neuron-like cells. Gene expression levels for IL-1, tumor necrosis factor α (TNFα), interleukin-10 (IL-10), and transforming growth factor ß (TGFß) decreased, while that for interleukin-4 (IL-4) increased, in hMSC-injected wild-type mice. In contrast, IL-1, TGFß, and IL-4 gene expression levels were all abolished in hMSC-injected Adcyap1 (+/-) mice on day 7 post-operation. Moreover, the mice-implanted hMSCs increased an alternative activating macrophage/microglial marker, arginase activity. The human gene profile indicated that hMSCs upregulated the gene of IL-4 and growth factors which were reported to enhance Adcyap1 expression. Finally, we demonstrated that hMSCs express human ADCYAP1 and its receptor gene after the inflammation-related interferon-γ (IFNγ) in vitro. CONCLUSIONS: These results suggest that hMSCs attenuate the deleterious effects of SCI by reducing associated inflammatory responses and enhancing IL-4 production. This effect could be mediated in part by cell-cell cross-talk involving the neuropeptide PACAP.

Early repair of necrotic lesion of the femoral head after high-degree posterior rotational osteotomy in young patients-a study evaluated by volume measurement using magnetic resonance imaging.

We investigated the repair of femoral head necrosis with extensive necrotic lesions treated by high-degree posterior rotational osteotomy (HDPRO) in young adults and adolescents (mean age; 30.8 years) using magnetic resonance imaging (MRI). HDPRO was performed on 72 hips from 66 cases, and of those, 60 hips from 60 cases were included in this study for data analysis. All cases had extensive collapsed lesion preoperative anteroposterior radiographs. In total, 34 hips were male and 26 were females. In total, 19 had a history of steroid administration, 11 had a previous femoral neck fracture, 7 had no particular etiologic factor, and 4 had a followed slipped capital femoral epiphysis. Antero-inferior viable areas were transferred to the loaded portion below the acetabular roof by this operation. The mean posterior rotational angle was 118.5°. MRI was taken after 1 month, 6 months and 1-year post-operatively. Post-operative necrotic lesion volume compared with the preoperative necrotic lesion volume was defined as lesion volume ratio (%). The reduction of necrotic volume was observed over time, and at 1 year post-operatively, it was 19.4% for patients in their teens, 35.3% for those in twenties, 42.8% for those in their thirties and 59.5% for those in their forties. From this study, we concluded that the extensive necrotic lesions decreased in size within a short period after HDPRO in young patients.

Costal osteochondral autograft for reconstruction of advanced-stage osteochondritis dissecans of the capitellum.

BACKGROUND: Advanced-stage osteochondritis dissecans of the capitellum affecting the lateral wall may result in osteoarthritis, and suitable treatment is needed to avoid permanent deformation and impaired function. We aimed to assess postoperative outcomes of costal osteochondral autograft for treatment of this condition. METHODS: We included 22 young overhead athletes (mean age, 13.9 years) with advanced osteochondritis dissecans of the humeral capitellum who underwent costal osteochondral autograft. All patients had elbow pain and wide-range articular cartilage lesions. We evaluated clinical and radiographic outcomes at a mean follow-up of 27 months (range, 12-77 months). RESULTS: All patients achieved rapid functional improvement and returned to their former sports activity levels. The baseball players were able to play catch within 62 to 164 days (mean, 107 days) and returned to full pitching activity within 123 to 339 days (mean, 226 days). We assessed mean elbow function by the clinical rating system of Timmerman and Andrews and the Japanese Orthopaedic Association sports score; the scores improved from 121.5 and 53.7 points preoperatively to 169.2 points and 86.1 points, respectively, at the time of follow-up. Four patients required additional minor surgical procedures, including screw removal, loose body removal, and shaving off of spur formation. No patient showed obvious radiographic changes of osteoarthritis. All patients were satisfied with the final outcomes and had good functional recovery. CONCLUSION: Costal osteochondral autograft gave satisfactory results for advanced osteochondritis dissecans of the humeral capitellum with extensive lesions affecting the lateral wall.

PACAP stimulates functional recovery after spinal cord injury through axonal regeneration.

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuroprotective peptide expressed in the central nervous system. Although many studies have shown a neuroprotective effect of PACAP, the mechanism of PACAP in the treatment of spinal cord injury (SCI) is yet to be elucidated. The purpose of this study was to examine the efficacy and underlying mechanism of PACAP in a mouse SCI model where PACAP was delivered via a biodegradable hydrogel. When PACAP or saline was delivered immediately after SCI, the functional motor recovery 14 days after SCI was significantly improved in the PACAP group compared with that in the saline group. Expression levels of messenger RNA (mRNA) for collapsin response mediator protein 2 (CRMP2), a factor related to axonal regeneration, were increased in the PACAP group 14 days after SCI compared with those in the saline group. A significantly increased number of CRMP2-positive cells were observed around the injury lesion in the PACAP group, while CRMP2 co-labeling with neuronal and oligodendrocyte markers was detected in intact spinal cord. Fourteen days after SCI, anterograde tracing revealed that a significantly increased number of neuronal fibers extended caudally from the lesion epicenter in the PACAP group. These results suggest that PACAP stimulates functional motor recovery after SCI through axonal regeneration mediated by CRMP2.

Proprioceptive illusions created by vibration of one arm are altered by vibrating the other arm.

There is some evidence that signals coming from both arms are used to determine the perceived position and movement of one arm. We examined whether the sense of position and movement of one (reference) arm is altered by increases in muscle spindle signals in the other (indicator) arm in blindfolded participants (n = 26). To increase muscle spindle discharge, we applied 70-80 Hz muscle vibration to the elbow flexors of the indicator arm. In a first experiment, proprioceptive illusions in the vibrated reference arm in a forearm position-matching task were compared between conditions in which the indicator arm elbow flexors were vibrated or not vibrated. We found that the vibration illusion of arm extension induced by vibration of reference arm elbow flexors was reduced in the presence of vibration of the indicator elbow flexors. In a second experiment, participants were asked to describe their perception of the illusion of forearm extension movements of the reference arm evoked by vibration of reference arm elbow flexors in response to on/off and off/on transitions of vibration of non-reference arm elbow flexors. When vibration of non-reference arm elbow flexors was turned on, they reported a sensation of slowing down of the illusion of the reference arm. When it was turned off, they reported a sensation of speeding up. To conclude, the present study shows that both the sense of limb position and the sense of limb movement of one arm are dependent to some extent on spindle signals coming from the other arm.

Pearl microstructure and expression of shell matrix protein genes MSI31 and MSI60 in the pearl sac epithelium of Pinctada fucata by in situ hybridization.

Expression patterns of the shell matrix protein genes MSI31 and MSI60 in the pearl sac epithelium were examined by in situ hybridization 38 days after implantation, and related to pearl quality. A pearl sac that produced a nacreous pearl showed very weak expression of MSI31 and strong expression of MSI60. A pearl sac, which yielded a prismatic pearl, strongly expressed MSI31 and very weakly expressed MSI60. In a complex pearl, whose surface consisted of a mosaic of both nacreous and prismatic layers, the expression pattern of MSI31 and MSI60 similarly corresponded to the underlying surface structures of the pearl. A nacreous pearl whose pearl sac showed strong MSI31 expression had an entirely nacreous surface composed of a laminar structure with unusual tablet growth at the corresponding site. MSI31 and MSI60 are the major components of the shell matrix proteins of the nacreous and prismatic layers. Clearly, high expression of MSI31 does not always result in prismatic secretion. These observations cannot be explained solely on the basis of the expression patterns of MSI31 and MSI60. We propose that, in addition to the MSI genes that form the prismatic and nacreous layers, upstream from these genes there are regulatory master genes that determine whether a nacreous layer (aragonite) or a prismatic layer (calcite) is formed.

CO2 homeostasis is maintained in conscious humans by regulation of tidal volume, but not of respiratory rhythm.

Automatic regulation of tidal volume (VT) maintains CO2 homeostasis when spontaneous respiratory rhythm is replaced with a cortically triggered rhythm. We examined whether automatic regulation of respiratory frequency (fR) could maintain CO2 homeostasis at rest if the VT is cortically designated in experiments performed in 21 conscious humans. First, volitionally controlled fR at levels lower than baseline resulted in a larger VT, maintaining end-tidal CO2 fraction constant at eupneic levels. However, when fR was volitionally controlled at levels higher than baseline, end-tidal CO2 fraction decreased unexpectedly. Next, when the VT was volitionally constrained but fr was freely chosen, end-tidal CO2 fraction decreased. The present study revealed some limitations in the control of CO2 homeostasis by automatic regulation of fR, probably because respiratory rhythm is susceptible to non-metabolic factors. This study also showed the importance of automatic regulation of VT in maintaining CO2 homeostasis at rest. Nevertheless, automatic regulation of VT was incomplete when fR was volitionally imposed at high levels.

Interaction between vibration-evoked proprioceptive illusions and mirror-evoked visual illusions in an arm-matching task.

We studied the influence of false proprioceptive information generated by arm vibration and false visual information provided by a mirror in which subjects saw a reflection of another arm on perception of arm position, in a forearm position-matching task in right-handed subjects (n = 17). The mirror was placed between left and right arms, and arranged so that the reflected left arm appeared to the subjects to be their unseen right (reference) arm. The felt position of the right arm, indicated with a paddle, was influenced by vision of the mirror image of the left arm. If the left arm appeared flexed in the mirror, subjects felt their right arm to be more flexed than it was. Conversely, if the left arm was extended, they felt their right arm to be more extended than it was. When reference elbow flexors were vibrated at 70-80 Hz, an illusion of extension of the vibrated arm was elicited. The illusion of a more flexed reference arm evoked by seeing a mirror image of the flexed left arm was reduced by vibration. However, the illusion of extension of the right arm evoked by seeing a mirror image of the extended left arm was increased by vibration. That is, when the mirror and vibration illusions were in the same direction, they reinforced each other. However, when they were in opposite directions, they tended to cancel one another. The present study shows the interaction between proprioceptive and visual information in perception of arm position.

Neuroprotective effect of endogenous pituitary adenylate cyclase-activating polypeptide on spinal cord injury.

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuroprotective peptide expressed in the central nervous system. To date, changes in the expression and effect of endogenous PACAP have not been clarified with respect to spinal cord injury (SCI). The aim of this study was to elucidate the expression pattern and function of endogenous PACAP on the contusion model of SCI using heterozygous PACAP knockout (PACAP(+/-)) and wild-type mice. Real-time polymerase chain reaction methods revealed that the level of PACAP mRNA increased gradually for 14 days after SCI and that PAC1R mRNA levels also increased for 7 days compared with intact control mice. PACAP and PAC1R immunoreactivities colabeled with a neuronal marker in the intact spinal cord. Seven days after SCI, PAC1R immunoreactivity was additionally co-expressed with an astrocyte marker. Wild-type mice gradually recovered motor function after 14 days, but PACAP(+/-) mice showed significantly impaired recovery from 3 days compared with wild-type mice. The injury volume at day 7 in PACAP(+/-) mice, and the number of single-stranded DNA-immunopositive cells as a marker of neuronal cell death at day 3 were significantly higher than values measured in wild-type mice. These data suggest that endogenous PACAP is upregulated by SCI and has a neuroprotective effect on the damaged spinal cord.

Salusin-ß accelerates inflammatory responses in vascular endothelial cells via NF-κB signaling in LDL receptor-deficient mice in vivo and HUVECs in vitro.

The bioactive peptide salusin-ß is highly expressed in human atheromas; additionally, infusion of antiserum against salusin-ß suppresses the development of atherosclerosis in atherogenic mice. This study examined the roles of salusin-ß in vascular inflammation during atherogenesis. Infusion of antiserum against salusin-ß attenuated the induction of VCAM-1, monocyte chemoattractant protein (MCP)-1, and IL-1ß and as well as nuclear translocation of NF-κB in aortic endothelial cells (ECs) of LDL receptor-deficient mice, which led to the prevention of monocyte adhesion to aortic ECs. In vitro experiments indicated that salusin-ß directly enhances the expression levels of proinflammatory molecules, including VCAM-1, MCP-1, IL-1ß, and NADPH oxidase 2, as well as THP-1 monocyte adhesion to cultured human umbilical vein ECs (HUVECs). Both salusin-ß-induced VCAM-1 induction and monocyte/HUVEC adhesion were suppressed by pharmacological inhibitors of NF-κB, e.g., Bay 11-7682 and curcumin. Furthermore, the VCAM-1 induction was significantly prevented by the phosphatidylinositol 3-kinase (PI3K) inhibitor LY-294002, whereas it was accelerated by the ERK inhibitor, U-0126. Treatment of HUVECs with salusin-ß, but not with salusin-α, accelerated oxidative stress and nuclear translocation of NF-κB as well as phosphorylation and degradation of IκB-α, an endogenous inhibitor of NF-κB. Thus, salusin-ß enhanced monocyte adhesion to vascular ECs through NF-κB-mediated inflammatory responses in ECs, which can be modified by PI3K or ERK signals. These findings are suggestive of a novel role of salusin-ß in atherogenesis.

Interleukin-1 participates in the classical and alternative activation of microglia/macrophages after spinal cord injury.

BACKGROUND: Microglia and macrophages (MG/MΦ) have a diverse range of functions depending on unique cytokine stimuli, and contribute to neural cell death, repair, and remodeling during central nervous system diseases. While IL-1 has been shown to exacerbate inflammation, it has also been recognized to enhance neuroregeneration. We determined the activating phenotype of MG/MΦ and the impact of IL-1 in an in vivo spinal cord injury (SCI) model of IL-1 knock-out (KO) mice. Moreover, we demonstrated the contribution of IL-1 to both the classical and alternative activation of MG in vitro using an adult MG primary culture. METHODS: SCI was induced by transection of the spinal cord between the T9 and T10 vertebra in wild-type and IL-1 KO mice. Locomotor activity was monitored and lesion size was determined for 14 days. TNFα and Ym1 levels were monitored to determine the MG/MΦ activating phenotype. Primary cultures of MG were produced from adult mice, and were exposed to IFNγ or IL-4 with and without IL-1ß. Moreover, cultures were exposed to IL-4 and/or IL-13 in the presence and absence of IL-1ß. RESULTS: The locomotor activity and lesion area of IL-1 KO mice improved significantly after SCI compared with wild-type mice. TNFα production was significantly suppressed in IL-1 KO mice. Also, Ym1, an alternative activating MG/MΦ marker, did not increase in IL-1 KO mice, suggesting that IL-1 contributes to both the classical and alternative activation of MG/MΦ. We treated primary MG cultures with IFNγ or IL-4 in the presence and absence of IL-1ß. Increased nitric oxide and TNFα was present in the culture media and increased inducible NO synthase was detected in cell suspensions following co-treatment with IFNγ and IL-1ß. Expression of the alternative activation markers Ym1 and arginase-1 was increased after exposure to IL-4 and further increased after co-treatment with IL-4 and IL-1ß. The phenotype was not observed after exposure of cells to IL-13. CONCLUSIONS: We demonstrate here in in vivo experiments that IL-1 suppressed SCI in a process mediated by the reduction of inflammatory responses. Moreover, we suggest that IL-1 participates in both the classical and alternative activation of MG in in vivo and in vitro systems.