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Abstract Background Although the Neer and AO/OTA classifications have been widely accepted, observer reliability studies of these two classifications have questioned their reliability and reproducibility to date. We developed an entirely new classification, the Mitsuzawa classification, for dislocated and displaced proximal humeral fractures and tested all three classifications for their intra- and interobserver reliability. Methods Two experienced shoulder surgeons and two orthopedic residents independently evaluated the Xray (xR) values of 100 proximal humeral fractures (PHFs). The inclusion criteria for PHFs were (1) fracture-dislocation of the glenohumeral joint, (2) severely displaced fracture that required arthroplasty, such as hemi-arthroplasty or reverse shoulder arthroplasty, and (3) age > 18 years. Four reviewers classified all 100 fractures according to the Neer, AO/OTA, and Mitsuzawa classifications on two occasions. The intraobserver reliability was calculated using a Cohen κ statistic, while the interobserver reliability was calculated using a Fleiss κ statistic. Results The average intraobserver agreements for the Neer, AO/OTA, and Mitsuzawa classifications were 0.57 (moderate), 0.67 (substantial), and 0.77 (substantial), respectively. The average interobserver agreements for the Neer, AO/OTA, and Mitsuzawa classifications were 0.49 (moderate), 0.56 (moderate), and 0.73 (substantial), respectively. The most common fracture type in each classification was an anterior dislocated fracture with a greater tuberosity fragment, which corresponded to A3a (57 cases) in the Mitsuzawa classification. Conclusions The Mitsuzawa classification of PHF incorporates different perspectives regarding glenohumeral compatibility, assessment before and after shoulder dislocation reduction, and the degree of displacement of the proximal stump of the humeral shaft. Compared with the Neer and AO/OTA classifications, our new classification system adopted a user-friendly flowchart format and provided satisfactory intra- and interobserver reliability. Level of evidence Level IV.

Abstract Familial adenomatous polyposis (FAP) is an autosomal dominant syndrome caused by germline variants in the APC gene, leading to the development of numerous colorectal polyps and significantly increases the risk of colorectal cancer. A diagnosis is typically made using colonoscopy, and genetic testing can assist in patient surveillance and carrier identification. Recent advances include the use of whole-genome array comparative genomic hybridization (a-CGH), which provides better resolution of genetic imbalances. We aimed to explore the specific features of FAP patients with whole APC gene deletions using high-resolution a-CGH and to compare patient characteristics. Two polyposis patients with whole APC deletions were identified, and the lost genetic sizes ranged from 0.3–1.1 Mb. Nervous abnormalities were a characteristic symptom in a patient with a 1.1 Mb loss. A patient with an approximately 0.3 Mb loss, which included the entire APC gene, presented a polyposis phenotype without intellectual disability. The comparison of genetic losses, with or without intellectual disability, revealed 7 genetic changes. Consequently, EPB41L4A is a candidate gene associated with the neurogenic phenotype.

Abstract After surgery for intradural lesions, dural reconstruction is essential for preventing cerebrospinal fluid (CSF) leakage, which can cause serious complications. However, there is currently no established intraoperative procedure. While hydrophobic polyglycolic acid (PGA) sheets and fibrin glue are effective for dural reconstruction, the usefulness of hydrophilic artificial dura mater made of a porous collagen matrix has also been reported. This study aimed to compare the ability of a fibrin-coated porous collagen matrix and a fibrin-coated PGA sheet to prevent CSF leakage during spinal surgery. This study included 319 patients who underwent surgery for intradural lesions requiring dural reconstruction. Patients in the PGA sheet group (group P) and the porous collagen matrix group (group C) were compared. The median age was 60 years. A total of 319 patients were included, with 219 in Group P and 100 in Group C. CSF leakage occurred in 11 patients (5.0%) in Group P and 0 patients in Group C (P

Abstract BamA is the central component of the essential β-barrel assembly machine (BAM), a conserved multi-subunit complex that dynamically inserts and folds β-barrel proteins into the outer membrane of Gram-negative bacteria. Despite recent advances in our mechanistic and structural understanding of BamA, there are few potent and selective tool molecules that can bind to and modulate BamA activity. Here, we explored in vitro selection methods and different BamA/BAM protein formulations to discover peptide macrocycles that kill Escherichia coli by targeting extreme conformational states of BamA. Our studies show that Peptide Targeting BamA-1 (PTB1) targets an extracellular divalent cation-dependent binding site and locks BamA into a closed lateral gate conformation. By contrast, PTB2 targets a luminal binding site and traps BamA into an open lateral gate conformation. Our results will inform future antibiotic discovery efforts targeting BamA and provide a template to prospectively discover modulators of other dynamic integral membrane proteins.

We report an 85-year-old man who underwent transarterial embolization (TAE) for an infected internal iliac artery aneurysm. The patient presented with fever and left lower abdominal pain. Computed tomography (CT) revealed the expansion of a left internal iliac artery aneurysm. We planned surgical treatment for an infected internal iliac artery aneurysm; however, the patient's age and general condition made the surgery high-risk. Therefore, we performed emergency TAE. The patient was administered antibiotics for 4 weeks and discharged on day 33 after the procedure with good progression. A 3-year follow-up CT scan showed aneurysm reduction and no recurrent infections. This case report highlights that TAE can be a treatment option for patients with an infected artery aneurysm.

In the present study, the effects of dietary supplementation with a mixed fermented loquat leaf tea residue (MFL) were evaluated on muscle α-tocopherol concentration and drip loss of Tsushima-Jidori crossbred chicken. MFL contained significantly less β-carotene, α-tocopherol, and total catechin than that of residues of green tea leaf infusion, although total polyphenol was significantly higher and 1,1-diphenyl-2-picrylhydrazyl radical-scavenging activity tended to be higher, indicating increased antioxidant properties. A total of 120 male Tsushima-Jidori crossbred chickens were divided into two groups at 62 days of age. The control group was fed a basal diet (commercial finisher diet containing 16.5% crude protein and 12.77 MJ/kg metabolizable energy) and the test group was fed a basal diet supplemented with MFL at a concentration of 1.0% until 90 days of age. Body mass, body mass gain, feed intake, and tissue mass did not significantly differ between the two groups. Dietary supplementation with MFL significantly increased breast muscle α-tocopherol concentration and reduced muscle drip loss. This was accompanied by a lower muscle K-value, which indicated the freshness of the meat. These results suggested that dietary supplementation with MFL improved the shelf life and water-holding capacity of breast muscles of Tsushima-Jidori crossbred chickens.

B-cell acute lymphoblastic leukemia (B-ALL) is the most common type of cancer found in children. Although the overall survival rates are now >80%, 15%-20% of pediatric patients relapse, with survival rates subsequently dropping to 5%-10%. Cmpd10357, 3-amino-5-arylamino-6-chloro-N- (diaminomethylene) pyrazine-2-carboximide, is a highly potent, cell-permeant compound recently shown to have cytotoxic effects on solid tumors, including human breast cancer and high-grade gliomas, independent of their proliferative status. Cmpd10357 demonstrated concentration-dependent cytotoxicity in two human B-ALL cell lines, JM1 and Reh, at half-maximal inhibitory concentrations (IC50) of 3.2 and 3.3 μM, respectively. Cmpd10357, at a dose of 5 mg/kg, significantly prolonged survival in our B-ALL xenograft mouse model, with a median survival time of 49.0 days compared with 45.5 days in the control group (p < 0.05). The cytotoxicity of Cmpd10357 demonstrated caspase-independent, nonapoptotic cancer cell demise associated with the nuclear translocation of apoptosis-inducing factor (AIF). The cytotoxicity of Cmpd10357 in B-ALL cells was inhibited by Necrostatin-1 but not by Necrosulfonamide. These studies suggest that an AIF-mediated, caspase-independent necrosis mechanism of Cmpd10357 in B-ALL could be used in combination with traditional apoptotic chemotherapeutic agents.

Compound 10357 is an amiloride derivative with potential promise as an adjunct to current chemotherapeutics. This study investigates the therapeutic efficacy of Compound 10357 in B-Cell Acute Lymphoblastic Leukemia (B-ALL).

In leukemia, a distinct subpopulation of cancer-initiating cells called leukemia stem cells (LSCs) is believed to drive population expansion and tumor growth. Failing to eliminate LSCs may result in disease relapse regardless of the amount of non-LSCs destroyed. The first step in targeting and eliminating LSCs is to identify and characterize them. Acute precursor B lymphoblastic leukemia (B-ALL) cells derived from patients were incubated with fluorescent glucose analog 2-(N-(7-Nitrobenz-2-oxa-1, 3-diazol-4-yl) Amino)-2-Deoxyglucose (NBDG) and sorted based on NBDG uptake. Cell subpopulations defined by glucose uptake were then serially transplanted into mice and evaluated for leukemia initiating capacity. Gene expression profiles of these cells were characterized using RNA-Sequencing (RNA-Seq). A distinct population of NBDG-low cells was identified in patient B-ALL samples. These cells are a small population (1.92% of the entire leukemia population), have lower HLA expression, and are smaller in size (4.0 to 7.0 μm) than the rest of the leukemia population. All mice transplanted with NBDG-low cells developed leukemia between 5 and 14 weeks, while those transplanted with NBDG-high cells did not develop leukemia (p ≤ 0.0001-0.002). Serial transplantation of the NBDG-low mouse model resulted in successful leukemia development. NBDG-medium (NBDG-med) populations also developed leukemia. Interestingly, comprehensive molecular characterization of NBDG-low and NBDG-med cells from patient-derived xenograft (PDX) models using RNA-Seq revealed a distinct profile of 2,162 differentially-expressed transcripts (DETs) (p

Invasive candidiasis is rare but is associated with high mortality in immunocompromised or critically ill patients. Here, we present a case of a 55-year-old man with untreated diabetes who was diagnosed with coronavirus disease 2019 and subsequently developed invasive candidiasis. The patient presented with fever, tachycardia, and tachypnea. Chest computed tomography revealed multiple consolidations mainly distributed around the bronchovascular bundles with bronchiectatic cavity formation, which initially raised suspicion for invasive pulmonary aspergillosis. However, subsequent testing confirmed Candida albicans infection; hence, we changed the antifungal agents effective for invasive candidiasis. This improved the patient's respiratory status, and he was then successfully weaned from mechanical ventilation. This case report highlights the importance of considering invasive candidiasis in the differential diagnosis of patients with bronchiectatic cavities on chest computed tomography, particularly in immunocompromised or critically ill patients with risk factors for invasive candidiasis.

Abstract Background Cesarean section often requires an urgent transfusion load due to decreased blood pressure after spinal anesthesia. This prospective randomized study aimed to investigate whether a preoperative oral rehydration solution (ORS) stabilized perioperative circulatory dynamics. Methods Sixty-three parturients scheduled for cesarean section under combined spinal epidural anesthesia (CSEA) were randomly allocated to one of three groups: Group O received 500 mL ORS before bedtime and 500 mL 2 h before CSEA; Group M received mineral water instead of ORS; and Group C had no fluid intake (controls). After entering the operating room, stomach size was measured using ultrasound. Blood samples were obtained, and CSEA was induced. Vasopressors were administered when systolic blood pressure was 20%. As a vasopressor, phenylephrine (0.1 mg) was administered at ≥ 60 beats/min heart rate or ephedrine (5 mg) at

Abstract Seasonal changes are more robust and dynamic at higher latitudes than at lower latitudes, and animals sense seasonal changes in the environment and alter their physiology and behavior to better adapt to harsh winter conditions. However, the genetic basis for sensing seasonal changes, including the photoperiod and temperature, remains unclear. Medaka (Oryzias latipes species complex), widely distributed from subtropical to cool-temperate regions throughout the Japanese archipelago, provides an excellent model to tackle this subject. In this study, we examined the critical photoperiods and critical temperatures required for seasonal gonadal development in female medaka from local populations at various latitudes. Intraspecific differences in critical photoperiods and temperatures were detected, demonstrating that these differences were genetically controlled. Most medaka populations could perceive the difference between photoperiods for at least 1 h. Populations in the Northern Japanese group required 14 h of light in a 24 h photoperiod to develop their ovaries, whereas ovaries from the Southern Japanese group developed under 13 h of light. Additionally, Miyazaki and Ginoza populations from lower latitudes were able to spawn under short-day conditions of 11 and 10 h of light, respectively. Investigation of the critical temperature demonstrated that the Higashidori population, the population from the northernmost region of medaka habitats, had a critical temperature of over 18 °C, which was the highest critical temperature among the populations examined. The Miyazaki and the Ginoza populations, in contrast, were found to have critical temperatures under 14 °C. When we conducted a transplant experiment in a high-latitudinal environment using medaka populations with different seasonal responses, the population from higher latitudes, which had a longer critical photoperiod and a higher critical temperature, showed a slower reproductive onset but quickly reached a peak of ovarian size. The current findings show that low latitudinal populations are less responsive to photoperiodic and temperature changes, implying that variations in this responsiveness can alter seasonal timing of reproduction and change fitness to natural environments with varying harshnesses of seasonal changes. Local medaka populations will contribute to elucidating the genetic basis of seasonal time perception and adaptation to environmental changes.

Imidazole dipeptides possess important bioregulatory properties in animals. This study aimed to evaluate the effect of high ambient temperature on muscle imidazole dipeptides (carnosine, anserine, and balenine) in broiler chickens. Sixteen 14-day-old male broiler chickens were divided into two groups, which were reared under thermoneutral (25 ± 1 °C) or cyclic high ambient temperature (35 ± 1 °C for 8 h/day) for 4 weeks. Chickens exposed to cyclic high ambient temperatures displayed lower skeletal muscle anserine and carnosine content than control chickens. Balenine could not be detected in the pectoral muscle of either group. The pectoral muscles of broiler chickens kept under cyclic high-temperature exhibited significantly lower mRNA expression of carnosine synthase 1, which synthesizes carnosine and anserine; but a significantly higher mRNA expression of carnosinase 2, which degrades carnosine and anserine. Our results suggest that heat exposure decreases pectoral imidazole dipeptide content in broiler chickens. This may be attributed to a lower expression of imidazole dipeptide-synthesizing genes, but higher levels of genes involved in their degradation.

BackgroundRenal medullary carcinoma (RMC) is a rare but aggressive tumor often complicated by early lung metastasis with few treatment options and very poor outcomes. There are currently no verified RMC patient-derived xenograft (PDX) mouse models established from metastatic pleural effusion (PE) available to study RMC and evaluate new therapeutic options.MethodsRenal tumor tissue and malignant PE cells from an RMC patient were successfully engrafted into 20 NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice. We evaluated the histopathological similarity of the renal tumor and PE PDXs with the original patient renal tumor and PE, respectively. We then evaluated the molecular integrity of the renal tumor PDXs between passages, as well as the PE PDX compared to two generations of renal tumor PDXs, by microarray analysis. The therapeutic efficacy of sunitinib and temsirolimus was tested in a serially-transplanted generation of 27 PE PDX mice.ResultsThe pathologic characteristics of the patient renal tumor and patient PE were retained in the PDXs. Gene expression profiling revealed high concordance between the two generations of renal tumor PDXs (RMC-P0 vs. RMC-P1, r=0.865), as well as between the first generation PE PDX and each generation of the renal tumor PDX (PE-P0 vs. RMC-P0, r=0.919 and PE-P0 vs. RMC-P1, r=0.843). A low number (626) of differentially-expressed genes (DEGs) was seen between the first generation PE PDX and the first generation renal tumor PDX. In the PE-P1 xenograft, sunitinib significantly reduced tumor growth (p

Microorganisms in marine subsurface sediments substantially contribute to global biomass. Sediments warmer than 40°C account for roughly half the marine sediment volume, but the processes mediated by microbial populations in these hard-to-access environments are poorly understood. We investigated microbial life in up to 1.2-kilometer-deep and up to 120°C hot sediments in the Nankai Trough subduction zone. Above 45°C, concentrations of vegetative cells drop two orders of magnitude and endospores become more than 6000 times more abundant than vegetative cells. Methane is biologically produced and oxidized until sediments reach 80° to 85°C. In 100° to 120°C sediments, isotopic evidence and increased cell concentrations demonstrate the activity of acetate-degrading hyperthermophiles. Above 45°C, populated zones alternate with zones up to 192 meters thick where microbes were undetectable.