Obesity is an important factor affecting incidence and development of musculoskeletal degenerative changes. In addition, obese patients are considered less favorable surgical candidates for ...decompression surgery in degenerative lumbar spinal canal stenosis and lower limb arthroplasty. The purpose was to assess disease characteristics of lumbar spinal canal stenosis as well as lower limb osteoarthritis, and to investigate surgical times based on body mass index (BMI) in lumbar decompressive surgery and lower limb arthroplasties.
A total of 1161 patients with a diagnosis of lumbar canal stenosis (LCS), hip osteoarthritis (HOA) and knee osteoarthritis (KOA) were enrolled. The present investigation was conducted as a retrospective study using routinely collected data. All patients underwent primary decompressive surgery (laminoplasty: LAM) or lower limb arthroplasty (total hip arthroplasty: THA and total knee arthroplasty: TKA). All of the patients were divided into 3 groups based on BMI (kg/m
) (Group A: ≤ 24.9; Group B: 25-29.9; Group C: ≥ 30) within each disease category. To assess disease characteristics, age, gender, and BMI were evaluated for each disease category. Moreover, surgical times for LAM, THA and TKA were also assessed based on BMI classification.
A total of 269, 470, and 422 patients were allocated to the HOA category, the KOA category, and the LCS category, respectively. The KOA category included the oldest patients and largest BMI, compared to the HOA and the LCS categories. Regarding gender difference, LCS was more common in males than in females, while opposite phenomenon was observed in the HOA and the KOA categories. The heaviest group (Group C) was significantly younger than Groups A or B in TKA and LAM. Surgical time was significantly longer in patients with overweight or obese patients than in those with normal weight in TKA and LAM, while BMI didn't affect the time in THA.
Disease characteristics of the KOA category and the LCS category were notably affected by BMI, and surgical times in TKA and LAM were significantly longer for overweight or obese patients, whereas THA was less affected by BMI concerning disease characteristics and surgical time.
Background
The risk of developing lung cancer is high in patients with interstitial lung disease (ILD), as few treatment options are available. Immune checkpoint inhibitors (ICI) are used for the ...treatment of non‐small cell lung cancer (NSCLC) in clinical practice; however, in patients with preexisting ILD, the risk of ICI‐related pneumonitis is unknown. We evaluated the efficacy and lung toxicity of nivolumab in patients with NSCLC and ILD.
Methods
We retrospectively reviewed the medical records of 216 NSCLC patients who had received nivolumab therapy. The existence of ILD in these patients was determined by lung computed tomography findings; 26 patients had ILD. We evaluated the efficacy of nivolumab by measuring the response rate (RR), progression‐free survival (PFS) duration, and lung toxicity by incidence, severity, and outcome of nivolumab‐related ILD.
Results
The RR and median PFS of the ILD and non‐ILD groups were 27% versus 13% (P = 0.078) and 2.7 (95% confidence interval CI, 1.7–5.3) versus 2.9 months (95% CI 2.1–3.4; P = 0.919), respectively. The incidences of total and severe nivolumab‐related pneumonitis were significantly higher in the ILD group than in the non‐ILD group (31% vs. 12%, P = 0.014 and 19% vs. 5%, P = 0.022, respectively). No death from nivolumab‐related pneumonitis occurred. Over 50% of the patients in both groups with nivolumab‐related pneumonitis showed improvement over time.
Conclusion
Relative to the non‐ILD group, nivolumab‐related pneumonitis was observed more frequently in the ILD group; however, most cases were manageable.
Circulating tumor cells (CTCs) in tumor draining vein blood (DB) are potential sources for liquid biopsy. However, the identification of CTCs in DB of breast cancer has not been attempted. In this ...study, we investigated the feasibility of CTC detection in DB of breast cancer patients using a newly developed filtration-based microfluidic CTC detection device. Samples of peripheral vein blood (PB) and DB drawn from the lateral thoracic vein of the resected breast tissue were collected during the perioperative period. We investigated 41 breast cancer patients who underwent breast surgery with axillary lymph node dissection. DB was successfully collected in 36 patients (87.8%), with a mean amount of 0.85 ml. CTCs were detected in 58.3% of PB samples and 80.6% of DB samples. DB had significant higher number of CTCs compared with PB (p < 0.001). CTCs were detected in 75.0% of DB samples and 50.0% of PB samples from patients achieving pathological complete response after neoadjuvant chemotherapy. These results suggest that abundant CTCs are released into the DB of breast cancer patients, indicating that CTCs in DB would be alternative sources for liquid biopsy and potential indicators for monitoring of treatment response and prognosis in breast cancer patients.
Bacillus cereus (B. cereus) is a pathogen in opportunistic infections. Here we show that Bacillus cereus sphingomyelinase (Bc-SMase) is a virulence factor for septicemia. Clinical isolates produced ...large amounts of Bc-SMase, grew in vivo, and caused death among mice, but ATCC strains isolated from soil did not. A transformant of the ATCC strain carrying a recombinant plasmid containing the Bc-SMase gene grew in vivo, but that with the gene for E53A, which has little enzymatic activity, did not. Administration of an anti-Bc-SMase antibody and immunization against Bc-SMase prevented death caused by the clinical isolates, showing that Bc-SMase plays an important role in the diseases caused by B. cereus. Treatment of mouse macrophages with Bc-SMase resulted in a reduction in the generation of H(2)O(2) and phagocytosis of macrophages induced by peptidoglycan (PGN), but no effect on the release of TNF-α and little release of LDH under our experimental conditions. Confocal laser microscopy showed that the treatment of mouse macrophages with Bc-SMase resulted in the formation of ceramide-rich domains. A photobleaching analysis suggested that the cells treated with Bc-SMase exhibited a reduction in membrane fluidity. The results suggest that Bc-SMase is essential for the hydrolysis of SM in membranes, leading to a reduction in phagocytosis.
Limited salvage chemotherapies are available for relapsed/refractory acute myeloid leukemia. Herein, we described successful reinduction chemotherapy, involving a combination of clofarabine, ...cyclophosphamide, and etoposide, in a 12-year-old male with relapsed acute myeloid leukemia prior to allogeneic bone marrow transplantation from his father. Although treatment with a combination of fludarabine, cytarabine, granulocyte colony-stimulating factor, idarubicin, and gemtuzumab ozogamicin had no positive effects, the aforementioned clofarabine-based chemotherapy induced complete remission and allowed the transplantation to go ahead. The abovementioned regimen may be useful for induction chemotherapy prior to hematopoietic stem cell transplantation for refractory/relapsed acute myeloid leukemia.
Neuronal intranuclear inclusion disease (NIID) is a neurodegenerative disorder, characterized by the presence of eosinophilic inclusions (NIIs) within nuclei of central and peripheral nervous system ...cells. This study aims to identify the components of NIIs, which have been difficult to analyze directly due to their insolubility. In order to establish a method to directly identify the components of NIIs, we first analyzed the huntingtin inclusion-rich fraction obtained from the brains of Huntington disease model mice. Although the sequence with expanded polyglutamine could not be identified by liquid-chromatography mass spectrometry, amino acid analysis revealed that glutamine of the huntingtin inclusion-rich fraction increased significantly. This is compatible with the calculated amino acid content of the transgene product. Therefore, we applied this method to analyze the NIIs of diseased human brains, which may have proteins with compositionally biased regions, and identified a serine-rich protein called hornerin. Since the analyzed NII-rich fraction was also serine-rich, we suggested hornerin as a major component of the NIIs. A specific distribution of hornerin in NIID was also investigated by Matrix-assisted laser desorption/ionization imaging mass spectrometry and immunofluorescence. Finally, we confirmed a variant of hornerin by whole-exome sequencing and DNA sequencing. This study suggests that hornerin may be related to the pathological process of this NIID, and the direct analysis of NIIs, especially by amino acid analysis using the NII-rich fractions, would contribute to a deeper understanding of the disease pathogenesis.
Retrospective case series.
The aim of this study was to compare the utility and cost-effectiveness of multilevel lateral interbody fusion (LIF) combined with posterior spinal fusion (PSF) (L group) ...and conventional PSF (with transforaminal lumbar interbody fusion) (P group) in adult spinal deformity (ASD) surgery.
The clinical and radiographic outcomes of multilevel LIF for ASD have been reported favorable; however, the cost benefit of LIF in conjunction with PSF is still controversial.
Retrospective comparisons of 88 surgically treated ASD patients with minimum 2-year follow-up from a multicenter database (L group n = 39 and P group n = 49) were performed. Demographic and radiographic data, health-related quality of life (HRQoL), and the direct hospitalization cost for the initial surgery and 2-year total hospitalization cost were analyzed.
Analyses of sagittal spinal alignment showed no significant difference between the two groups at baseline and 2 years post-operation. Surgical time was longer in the L group (L vs. P: 354 vs. 268 minutes, P < 0.01), whereas the amount of blood loss was greater in the P group (494 vs. 678 mL, P = 0.03). The HRQoL was improved similarly at 2 years post-operation (L vs. P: SRS-22 total score, 3.86 vs. 3.80, P = 0.54), with comparable revision rates (L vs. P: 18% vs. 10%, P = 0.29). The total direct cost of index surgery was significantly higher in the L group (65,937 vs. 49,849 USD, P < 0.01), which was mainly due to the operating room cost, including implant cost (54,466 vs. 41,328 USD, P < 0.01). In addition, the 2-year total hospitalization cost, including revision surgery, was also significantly higher in the L group (70,847 vs. 52,560 USD, P < 0.01).
LIF with PSF is a similarly effective surgery for ASD when compared with conventional PSF. However, due to the significantly higher cost, additional studies on the cost-effectiveness of LIF in different ASD patient cohorts are warranted.
3.
Several lines of evidence have revealed that newly emerging transformed cells are often eliminated from the epithelium, though the underlying molecular mechanisms of this cancer preventive phenomenon ...still remain elusive. In this study, using mammalian cell culture systems we have identified plectin, a versatile cytoskeletal linker protein, as a novel regulator for apical extrusion of RasV12-transformed cells. Plectin is accumulated in RasV12 cells when they are surrounded by normal epithelial cells. Similarly, cytoskeletal proteins tubulin, keratin, and Epithelial Protein Lost In Neoplasm (EPLIN) are also accumulated in the transformed cells surrounded by normal cells. Knockdown or functional disruption of one of these molecules diminishes the accumulation of the others, indicating that the accumulation process of the individual protein mutually depends on each other. Furthermore, plectin-knockdown attenuates caveolin-1 (Cav-1) enrichment and PKA activity in RasV12 cells and profoundly suppresses the apical extrusion. These results indicate that the plectin-microtubules-EPLIN complex positively regulates apical elimination of RasV12-transformed cells from the epithelium in a coordinated fashion. Further development of this study would open a new avenue for cancer preventive medicine.
Systemic branched‐chain amino acid (BCAA) metabolism is dysregulated in cardiometabolic diseases. We previously demonstrated that upregulated AMP deaminase 3 (AMPD3) impairs cardiac energetics in a ...rat model of obese type 2 diabetes, Otsuka Long‐Evans‐Tokushima fatty (OLETF). Here, we hypothesized that the cardiac BCAA levels and the activity of branched‐chain α‐keto acid dehydrogenase (BCKDH), a rate‐limiting enzyme in BCAA metabolism, are altered by type 2 diabetes (T2DM), and that upregulated AMPD3 expression is involved in the alteration. Performing proteomic analysis combined with immunoblotting, we discovered that BCKDH localizes not only to mitochondria but also to the endoplasmic reticulum (ER), where it interacts with AMPD3. Knocking down AMPD3 in neonatal rat cardiomyocytes (NRCMs) increased BCKDH activity, suggesting that AMPD3 negatively regulates BCKDH. Compared with control rats (Long‐Evans Tokushima Otsuka LETO rats), OLETF rats exhibited 49% higher cardiac BCAA levels and 49% lower BCKDH activity. In the cardiac ER of the OLETF rats, BCKDH‐E1α subunit expression was downregulated, while AMPD3 expression was upregulated, resulting in an 80% lower AMPD3‐E1α interaction compared to LETO rats. Knocking down E1α expression in NRCMs upregulated AMPD3 expression and recapitulated the imbalanced AMPD3‐BCKDH expressions observed in OLETF rat hearts. E1α knockdown in NRCMs inhibited glucose oxidation in response to insulin, palmitate oxidation, and lipid droplet biogenesis under oleate loading. Collectively, these data revealed previously unrecognized extramitochondrial localization of BCKDH in the heart and its reciprocal regulation with AMPD3 and imbalanced AMPD3‐BCKDH interactions in OLETF. Downregulation of BCKDH in cardiomyocytes induced profound metabolic changes that are observed in OLETF hearts, providing insight into mechanisms contributing to the development of diabetic cardiomyopathy.
The present study revealed previously unrecognized extramitochondrial localization of branched‐chain α‐keto acid dehydrogenase (BCKDH) and its reciprocal regulation with AMPD3 in cardiomyocytes and imbalanced AMPD3‐BCKDH interactions in a rat model of type 2 diabetes, Otsuka Long‐Evans‐Tokushima fatty (OLETF). Downregulation of BCKDH in cardiomyocytes induced profound metabolic changes that are observed in OLETF hearts, providing insight into mechanisms contributing to the development of diabetic cardiomyopathy.
Cardiac myosin light chain kinase (cMLCK) plays an obligatory role in maintaining the phosphorylation levels of regulatory myosin light chain (MLC2), which is thought to be crucial for regulation of ...cardiac function. To test this hypothesis, the role played by ventricular MLC2 (MLC2v) phosphorylation was investigated in the phenylephrine-induced increase in twitch tension using the naturally-occurring mouse strain, C57BL/6N, in which cMLCK is down regulated.
By Western blot and nanoLC-MS/MS analysis, cMLCKs with molecular mass of 61-kDa (cMLCK-2) and/or 86-kDa were identified in mice heart. Among various mouse strains, C57BL/6N expressed cMLCK-2 alone and the closest relative strain C57BL/6J expressed both cMLCKs. The levels of MLC2v phosphorylation was significantly lower in C57BL/6N than in C57BL/6J. The papillary muscle twitch tension induced by electrical field stimulation was smaller in C57BL/6N than C57BL/6J. Phenylephrine had no effect on MLC2v phosphorylation in either strains but increased the twitch tension more potently in C57BL/6J than in C57BL/6N. Calyculin A increased papillary muscle MLC2v phosphorylation to a similar extent in both strains but increased the phenylephrine-induced inotropic response only in C57BL/6N. There was a significant positive correlation between the phenylephrine-induced inotropic response and the levels of MLC2v phosphorylation within ranges of 15-30%.
We identified a new isoform of cMLCK with a molecular mass of 61kDa(cMLCK-2) in mouse heart. In the C57BL/6N strain, only cMLCK-2 was expressed and the basal MLC2v phosphorylation levels and the phenylephrine-induced inotropic response were both smaller. We suggest that a lower phenylephrine-induced inotropic response may be caused by the lower basal MLC2v phosphorylation levels in this strain.
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