Protein‐bound crotonaldehyde accumulates in the spinal cord of superoxide dismutase‐1 mutation‐associated familial amyotrophic lateral sclerosis and its transgenic mouse model

Growing evidence documents oxidative stress involvement in ALS. We previously demonstrated accumulation of a protein‐bound form of the highly toxic lipid peroxidation product crotonaldehyde (CRA) in the spinal cord of sporadic ALS patients. In the present study, to the determine the role for CRA in the disease processes of superoxide dismutase‐1 (SOD1) mutation‐associated familial ALS (FALS), we performed immunohistochemical and semiquantitative cell count analyses of protein‐bound CRA (P‐CRA) in the spinal cord of SOD1‐mutated FALS and its transgenic mouse model. Immunohistochemical analysis revealed increased P‐CRA immunoreactivity in the spinal cord of the FALS patients and the transgenic mice compared to their respective controls. In the FALS patients, P‐CRA immunoreactivity was localized in almost all of the chromatolytic motor neurons, neurofilamentous conglomerates, spheroids, cordlike swollen axons, reactive astrocytes and microglia, and the surrounding neuropil in the affected areas represented by the anterior horns. In the transgenic mice, P‐CRA immunoreactivity was localized in only a few ventral horn glia in the presymptomatic stage, in almost all of the vacuolated motor neurons and cordlike swollen axons and some of the ventral horn reactive astrocytes and microglia in the onset stage, and in many of the ventral horn reactive astrocytes and microglia in the advanced stage. Cell count analysis on mouse spinal cord sections disclosed a statistically significant increase in the density of P‐CRA‐immunoreactive glia in the ventral horns of the young to old G93A mice compared to the age‐matched control mice. The present results indicate that enhanced CRA formation occurs in motor neurons and reactive glia in the spinal cord of SOD1‐mutated FALS and its transgenic mouse model as well as sporadic ALS, suggesting implications for CRA in the pathomechanism common to these forms of ALS.     

Effects of flutamide as a second-line agent for maximum androgen blockade of hormone refractory prostate cancer

We analyzed clinical effects of flutamide as a second-line agent for maximum androgen blockade (MAB) in patients with relapsing prostate cancer who received bicalutamide as the first-line MAB agent. This study included 13 patients with progressive prostate cancer who had relapsed after first-line MAB, with bicalutamide at 80 mg/day. After checking for antiandrogen withdrawal syndrome, they were given flutamide at 375 mg/day as second-line MAB. The effectiveness of that therapy was evaluated by changes in prostatic specific antigen (PSA) levels, with response defined as a decrease of greater than 50% from the start of therapy. We also compared several factors between responders and non-responders. Nine (69.2%) of the 13 patients showed a decrease in PSA levels, of whom five (38.5%) had a greater than 50% decrease and were defined as responders. The median duration of PSA response was 11.0 months (range 5-20 months). Patients who had a longer duration of response to first-line MAB had a significantly greater response to second-line MAB. For advanced prostate cancer patients who progressed on first-line MAB with bicalutamide, flutamide administration as a second-line antiandrogen was found to be relatively effective, especially for those who showed a longer duration of response to the first-line MAB. Our results confirm previous findings that MAB using flutamide is an effective second-line hormonal therapy.     

Acute encephalopathy associated with nontyphoidal salmonellosis.

The importance of an acute encephalopathy associated with nontyphoidal salmonellosis has recently been recognized, but the disease entity has been poorly established. In this study, we describe two encephalopathic patients associated with nontyphoidal salmonellosis. The patients exhibited a rapid evolution of coma after the onset of lethargy or seizure. Fever and diarrhea due to salmonellosis preceded these events. Secondary factors inducing encephalopathies, such as severe dehydration, sepsis, meningitis, electrolyte or metabolic disturbances, acute renal failure, and multiple organ failure, were excluded in the differential diagnosis at the onset of encephalopathic features. These clinical findings and rapid development of encephalopathic features from localized intestinal infection without any significant abnormalities in a variety of blood tests may suggest a toxic etiology. However, endotoxin was not found in serum from both patients. From these results, we conclude that nontyphoidal salmonellosis can cause a toxic encephalopathy syndrome, like shigellosis or verocytotoxin-producing Escherichia coli infection.     

Efficacy of Enamel Matrix Derivative With Freeze‐Dried Bone Allograft or Demineralized Freeze‐Dried Bone Allograft in Intrabony Defects: A Randomized Trial

Background: Promising clinical outcomes have been reported with the combination of enamel matrix derivative (EMD) and allograft materials. Direct comparison between EMD with a freeze‐dried bone allograft (FDBA) and a demineralized FDBA (DFDBA) was evaluated in one case series study. To date, no randomized controlled trial has been reported. Therefore, a well‐controlled randomized clinical trial was conducted to determine the relative efficacy of EMD/FDBA versus EMD/DFDBA when managing intrabony defects. Methods: A randomized parallel trial was conducted in a private practice from April 2004 to October 2011. Sixty‐nine patients were randomly assigned to one of three groups: EMD/FDBA (EF) intervention group (n = 23), EMD/DFDBA (ED) intervention group (n = 23), and EMD alone without graft material (E) as a negative control group (n = 23). All of the grafting material had minocycline added. Each patient had an intrabony defect. The primary outcomes were the absolute change in probing depth (PD) reduction and clinical attachment level (CAL) gain from baseline to 1‐ and 3‐year follow‐up. Intrabony defects were surgically treated with EMD/FDBA, EMD/DFDBA, or EMD alone. Results: Sixty‐seven patients (EF, n = 21: ED, n = 23; E, n = 23) were analyzed. All groups demonstrated significant improvement in PD reduction and CAL gain from baseline. The changes for PD were as follows (mm, 95% confidence interval [CI]): at 1 year: EF (4.4 mm, 4.0 to 4.7), ED (3.7 mm, 3.4 to 4.0), and E (control) (3.3 mm, 3.0 to 3.6); at 3 years: EF (4.4 mm, 4.1 to 4.8), ED (3.7 mm, 3.4 to 4.0), and E (3.1 mm, 2.8 to 3.4). The changes for CAL were as follows (mm, 95% CI): at 1 year: EF (4.1 mm, 3.8 to 4.5), ED (3.5 mm, 3.0 to 4.0), and E (3.0 mm, 2.5 to 3.6); at 3 years: EF (4.2 mm, 3.7 to 4.7), ED (3.6 mm, 3.1 to 4.1), and E (3.0 mm, 2.5 to 3.5). The intervention groups (EF and ED) showed better treatment outcomes than the control group at 1 and 3 years. Statistically, the two bone‐graft groups were not significantly different from each other at 1 and 3 years. Conclusions: Both EMD/FDBA and EMD/DFDBA interventions resulted in greater soft tissue improvement at 1 and 3 years of follow‐up compared to EMD alone. Both graft materials worked well in managing deep intrabony defects when combined with EMD.     

Hybrid assistive limb (HAL) treatment for patients with severe thoracic myelopathy due to ossification of the posterior longitudinal ligament (OPLL) in the postoperative acute/subacute phase: A clinical trial

Context/Objective: The hybrid assistive limb (HAL) is a wearable exoskeleton robot that assists walking and lower limb movements via real-time actuator control. Our aim was to clarify the safety and feasibility of using the HAL robotic suit for rehabilitation in patients with severe thoracic myelopathy due to ossification of the posterior longitudinal ligament (T-OPLL).

Design: Uncontrolled case series; pre- and post-intervention measurement.

Setting: In-patient rehabilitation unit.

Intervention: HAL training was provided in 60-minuts session, 2–3 sessions per week, for a total of 10 sessions. HAL training was initiated on average 27.5 days post-surgery.

Patients: Eight patients (four males and four females; mean age, 60.9?±?10.2 years) with severe myelopathy, who had undergone posterior decompression with instrumented fusion, were enrolled.

Outcome Measures: Gait speed, step length and cadence were measured along a 10-m walkway every session. The American Spinal Injury Association (ASIA) motor score (lower extremities) and Walking Index for Spinal Cord Injury (WISCI) II were also evaluated at baseline and after 10 sessions. The Japanese Orthopaedic Association (JOA) score was calculated over time after surgery.

Results: All participants completed the 10 training sessions, with no serious adverse effect noted. Gait speed, step length and cadence improved over time. Both the WISCI-II and ASIA motor (lower extremities) scores improved from baseline after 10 sessions. The JOA score improved over time post-surgery.

Conclusion: HAL training can be feasibly initiated in the early postoperative period, without severe adverse events in patients, with T-OPLL-related severe gait disturbance.     

ARID1A expression in gastric adenocarcinoma:Clinicopathological significance and correlation with DNA mismatch repair status

AIM:To analyze the mismatch repair(MMR)status and the ARID1A expression as well as their clinicopathological significance in gastric adenocarcinomas.METHODS:We examined the expressions of MMR proteins and ARID1A by immunohistochemistry in consecutive 489 primary gastric adenocarcinomas.The results were further correlated with clinicopathological variables.RESULTS:The loss of any MMR protein expression,indicative of MMR deficiency,was observed in 38cases(7.8%)and was significantly associated with an older age(68.6±9.2 vs 60.4±11.7,P0.001),a female sex(55.3%vs 31.3%,P=0.004),an antral location(44.7%vs 25.7%,P=0.021),and a differentiated histology(57.9%vs 39.7%,P=0.023).Abnormal ARID1A expression,including reduced or loss of ARID1A expression,was observed in 109 cases(22.3%)and was significantly correlated with lymphatic invasion(80.7%vs 69.5%,P=0.022)and lymph node metastasis(83.5%vs 73.7%,P=0.042).The tumors with abnormal ARID1A expression more frequently indicated MMR deficiency(47.4%vs 20.2%,P0.001).A multivariate analysis identified abnormal ARID1A expression as an independent poor prognostic factor(HR=1.36,95%CI:1.01-1.84;P=0.040).CONCLUSION:Our observations suggest that the AIRD1A inactivation is associated with lymphatic invasion,lymph node metastasis,poor prognosis,and MMR deficiency in gastric adenocarcinomas.     

Immunomodulatory Effect of Linezolid on Methicillin-Resistant Staphylococcus aureus Supernatant-Induced MUC5AC Overexpression in Human Airway Epithelial Cells

Linezolid is the first member of the oxazolidinones and is active against drug-resistant Gram-positive pathogens, such as methicillin-resistant Staphylococcus aureus (MRSA). Additionally, linezolid shows an immunomodulatory effect, such as inhibition of inflammatory cytokine production. In this study, we examined the effect of linezolid on MRSA-induced MUC5AC overexpression in airway epithelial cells. In this study, an MRSA supernatant was used to avoid the direct effect of linezolid on MRSA. MUC5AC protein production was significantly increased with a 40-fold dilution of MRSA supernatant. At the mRNA level, MUC5AC gene expression was significantly increased 6 and 9 h after stimulation. In an inhibition study, linezolid significantly reduced MRSA-induced MUC5AC protein and mRNA overexpression at concentrations of 5 and 20 μg/ml, which were the same as the trough and peak concentrations in human epithelial lining fluid. In an analysis of cell signaling, among the mitogen-activated protein kinase inhibitors, only the extracellular signal-regulated protein kinase 1/2 (ERK1/2) inhibitor reduced the MUC5AC protein production to the same level as that of the control; on Western blot analysis, only ERK1/2 was phosphorylated by the MRSA supernatant. In addition, the ERK1/2 phosphorylation was inhibited by linezolid. MUC5AC and MUC5B are the major barrier that traps inhaled microbial organisms, particulates, and foreign irritants. However, in patients with chronic respiratory diseases, pathogen-induced MUC5AC overexpression causes many problems, and control of the overexpression is important. Thus, this study revealed that linezolid showed a direct immunomodulatory effect in airway epithelial cells.     

Reversible protruded lesion regarded as idiopathic appendiceal intussusception

A patient with a reversible protruded lesion regarded as idiopathic appendiceal intussusception was investigated in this study. The patient was a 78‐year‐old male, who consulted our department as a result of positive occult blood in his stool sample. There was no associated pain, nausea, vomiting, fever, chill or anorexia. He had no prior surgical history. Total colonoscopy detected a sigmoidal polyp and a protruded lesion in the caecum. The protruded lesion (about 12 mm in diameter) covered with normal mucosa was diagnosed as a benign submucosal tumor at that time. The periodic follow‐up colonoscopy showed an orifice on top of the protuberance. Further detailed observation revealed that the lesion reduced by itself, and resulted in showing a normal orifice of the appendix; however, afterwards it protruded again. These observations led to the diagnosis of the lesion as type B of Atkinson's classification in appendiceal intussusception. To our knowledge, approximately 200 cases of appendiceal intussusception have been documented in scientific reports worldwide. In Japan, only 10 cases of idiopathic appendiceal intussusception have been described. This case is considered to be important for presenting the initial stage of the complete intussusception of the appendix.