Novel bile acid biosynthetic pathways are enriched in the microbiome of centenarians.

Centenarians have a decreased susceptibility to ageing-associated illnesses, chronic inflammation and infectious diseases1-3. Here we show that centenarians have a distinct gut microbiome that is enriched in microorganisms that are capable of generating unique secondary bile acids, including various isoforms of lithocholic acid (LCA): iso-, 3-oxo-, allo-, 3-oxoallo- and isoallolithocholic acid. Among these bile acids, the biosynthetic pathway for isoalloLCA had not been described previously. By screening 68 bacterial isolates from the faecal microbiota of a centenarian, we identified Odoribacteraceae strains as effective producers of isoalloLCA both in vitro and in vivo. Furthermore, we found that the enzymes 5α-reductase (5AR) and 3ß-hydroxysteroid dehydrogenase (3ß-HSDH) were responsible for the production of isoalloLCA. IsoalloLCA exerted potent antimicrobial effects against Gram-positive (but not Gram-negative) multidrug-resistant pathogens, including Clostridioides difficile and Enterococcus faecium. These findings suggest that the metabolism of specific bile acids may be involved in reducing the risk of infection with pathobionts, thereby potentially contributing to the maintenance of intestinal homeostasis.

Prognostic factors of idiopathic hypereosinophilic syndrome: A nationwide survey in Japan.

Idiopathic hypereosinophilic syndrome (iHES) is a condition wherein persistent hypereosinophilia associated with end-organ damage occurs without any known causes. Due to the rarity of the disease, insufficient knowledge has been accumulated. We therefore conducted a retrospective, multicentre, nationwide survey on iHES in Japan. A total of 57 patients were identified. For 43 patients who received any treatment, all cases were first treated with corticosteroids. An eosinophil percentage of less than 30% in the bone marrow and the absence of oedema were identified as factors associated with steroid dependency. The 5-year overall survival was 88.2%, and five patients died during follow-up; factors associated with worse overall survival were age >50, haemoglobin <12 g/dL, activated partial thromboplastin time >34 s, the presence of dyspnoea, the presence of thrombotic tendency and the presence of renal failure. Given the rarity of fatalities in our cohort, time-to-next-treatment (TTNT) was further analysed; the presence of renal failure, splenomegaly and lung abnormalities were associated with worse TTNT. Our nationwide study not only demonstrated clinical characteristics and the outcome of patients with iHES but also for the first time revealed clinical factors associated with steroid dependency and duration of first-line corticosteroid efficacy.

Direct evaluation of cohesin-mediated sister kinetochore associations at meiosis I in fission yeast.

Kinetochores drive chromosome segregation by mediating chromosome interactions with the spindle. In higher eukaryotes, sister kinetochores are separately positioned on opposite sides of sister centromeres during mitosis, but associate with each other during meiosis I. Kinetochore association facilitates the attachment of sister chromatids to the same pole, enabling the segregation of homologous chromosomes toward opposite poles. In the fission yeast, Schizosaccharomyces pombe, Rec8-containing meiotic cohesin is suggested to establish kinetochore associations by mediating cohesion of the centromere cores. However, cohesin-mediated kinetochore associations on intact chromosomes have never been demonstrated directly. In the present study, we describe a novel method for the direct evaluation of kinetochore associations on intact chromosomes in live S. pombe cells, and demonstrate that sister kinetochores and the centromere cores are positioned separately on mitotic chromosomes but associate with each other on meiosis I chromosomes. Furthermore, we demonstrate that kinetochore association depends on meiotic cohesin and the cohesin regulators Moa1 and Mrc1, and requires mating-pheromone signaling for its establishment. These results confirm cohesin-mediated kinetochore association and its regulatory mechanisms, along with the usefulness of the developed method for its analysis. This article has an associated First Person interview with the first author of the paper.

Isolated massive pleural effusion as a manifestation of chronic graft versus host disease successfully treated with corticosteroid.

Isolated pleural effusion is a rare manifestation of chronic graft versus host disease (cGVHD) after hematopoietic stem cell transplantation (HSCT). We herein report a 58-year-old woman presenting with massive pleural effusion approximately 1 year after allogeneic HSCT, who was successfully treated with corticosteroid. She had discontinued tacrolimus approximately 1 month before she presented with pleural effusion, which was attributed to cGVHD after a thorough exclusion process. This case illustrates a unique manifestation of atypical cGVHD and highlights the need for prompt therapy initiation.

Usefulness of the preoperative thoracic inlet angle in comparison to the T1 slope for predicting cervical kyphosis after laminoplasty.

PURPOSE: Thoracic inlet angle (TIA) is a sagittal radiographic parameter with a constant value regardless of posture and is significantly correlated with the sagittal balance of the cervical spine. However, the practical use of TIA has not been studied. This study aimed to investigate the usefulness of the preoperative TIA for predicting the development of kyphotic deformity after cervical laminoplasty in comparison to the preoperative T1 slope (T1S). METHODS: A total of 98 patients who underwent cervical laminoplasty without preoperative kyphotic alignment were included (mean age, 73.7 years; 41.8% female). Radiography was evaluated before surgery and at the 2-year follow-up examination. The cervical sagittal parameters were measured on standing radiographs, and the TIA was measured on T2-weighted MRI in a supine position. Cervical alignment with a C2-C7 angle of ≥ 0° was defined as lordosis, and that with an angle of < 0° was defined as kyphosis. RESULTS: Postoperative kyphosis occurred in 11 patients (11.2%). Preoperatively, the kyphosis group showed significantly lower values in the T1S (23.5° vs. 30.3°, p = 0.034) and TIA (76.1° vs. 81.8°, p = 0.042). We performed ROC curve analysis to clarify the impact of the preoperative TIA and T1S on kyphotic deformity after laminoplasty. The optimal cutoff angles for TIA and T1S were 68° and 19°, respectively, with similar diagnostic accuracy. CONCLUSION: This study demonstrated the clinical utility of the preoperative TIA for predicting the risk of postoperative kyphotic deformity after cervical laminoplasty. These findings suggest the importance of the preoperative assessment of thoracic inlet alignment in cervical spine surgery.

Breach of tolerance versus burden of bile acids: Resolving the conundrum in the immunopathogenesis and natural history of primary biliary cholangitis.

Primary biliary cholangitis (PBC) is a classic autoimmune disease due to the loss of tolerance to self-antigens. Bile acids (BA) reportedly play a major role in biliary inflammation and/or in the modulation of dysregulated immune responses in PBC. Several murine models have indicated that molecular mimicry plays a role in autoimmune cholangitis; however, they have all been limited by the relative failure to develop hepatic fibrosis. We hypothesized that species-specific differences in the BA composition between mice and humans were the primary reason for this limited pathology. Here, we aimed to study the impact of human-like hydrophobic BA composition on the development of autoimmune cholangitis and hepatic fibrosis. We took advantage of a unique construct, Cyp2c70/Cyp2a12 double knockout (DKO) mice, which have human-like BA composition, and immunized them with a well-defined mimic of the major mitochondrial autoantigen of PBC, namely 2-octynoic acid (2OA). 2OA-treated DKO mice were significantly exacerbated portal inflammation and bile duct damage with increased Th1 cytokines/chemokines at 8 weeks post-initial immunization. Most importantly, there was clear progression of hepatic fibrosis and increased expression of hepatic fibrosis-related genes. Interestingly, these mice demonstrated increased serum BA concentrations and decreased biliary BA concentrations; hepatic BA levels did not increase because of the upregulation of transporters responsible for the basolateral efflux of BA. Furthermore, cholangitis and hepatic fibrosis were more advanced at 24 weeks post-initial immunization. These results indicate that both the loss of tolerance and the effect of hydrophobic BA are essential for the progression of PBC.

Recurrent bilateral adrenal infarction with myelodysplastic/myeloproliferative neoplasm-unclassifiable (MDS/MPN-U): a case report.

BACKGROUND: Bilateral adrenal infarction is rare and only a small number of cases have been reported so far. Adrenal infarction is usually caused by thrombophilia or a hypercoagulable state, such as antiphospholipid antibody syndrome, pregnancy, and coronavirus disease 2019. However, adrenal infarction with myelodysplastic/myeloproliferative neoplasm (MDS/MPN) has not been reported. CASE PRESENTATION: An 81-year-old man with a sudden severe bilateral backache presented to our hospital. Contrast-enhanced computed tomography (CT) led to the diagnosis of bilateral adrenal infarction. Previously reported causes of adrenal infarction were all excluded and a diagnosis of MDS/MPN-unclassifiable (MDS/MPN-U) was reached, which was considered to be attributed to adrenal infarction. He developed a relapse of bilateral adrenal infarction, and aspirin administration was initiated. Partial primary adrenal insufficiency was suspected as the serum adrenocorticotropic hormone level was persistently high after the second bilateral adrenal infarction. CONCLUSION: This is the first case of bilateral adrenal infarction with MDS/MPN-U encountered. MDS/MPN has the clinical characteristics of MPN. It is reasonable to assume that MDS/MPN-U may have influenced bilateral adrenal infarction development, considering the absence of thrombosis history and a current comorbid hypercoagulable disease. This is also the first case of recurrent bilateral adrenal infarction. It is important to carefully investigate the underlying cause of adrenal infarction once adrenal infarction is diagnosed, as well as to assess adrenocortical function.

Toxic shock like syndrome caused by Streptococcus agalactiae bacteremia during treatment for multiple myeloma.

Toxic shock-like syndrome (TSLS) is a life-threatening hyperinflammatory complication caused by Streptococcus species infections. We reported the first case of TSLS caused by primary bacteremia of Streptococcus agalactiae during chemotherapy for multiple myeloma. A 74-year-old woman, who received combination chemotherapy of elotuzumab, pomalidomide, and dexamethasone for treatment-refractory multiple myeloma, was transported to our hospital under comatose and septic shock. Her blood culture detected Streptococcus agalactiae, and considering the progressive multiorgan failure, she was diagnosed with TSLS. Empiric antibiotic treatment with meropenem and respiratory and circulatory support were quickly initiated, resulting in an almost complete recovery of organ functions. It should be noted that with the advances of chemotherapy, the risk of infection is becoming more diverse.

Impact of the preoperative nutritional status on postoperative kyphosis in geriatric patients undergoing cervical laminoplasty.

PURPOSE: This study aimed to determine the association of preoperative malnutrition with an increased risk of cervical kyphosis after laminoplasty in geriatric patients with cervical spondylotic myelopathy (CSM). METHODS: Geriatric patients who underwent cervical laminoplasty were included. Malnutrition was defined as a geriatric nutritional risk index < 98 before surgery. The C2-7 angle and the global alignment parameters were analyzed on standing radiographs. The postoperative kyphosis was defined as a C2-7 angle < 0° during a 2-year follow-up. RESULTS: Ninety patients without preoperative kyphotic alignment were enrolled (mean age, 73.5 years old; 41.1% female). Twenty-one patients (23.3%) had malnutrition status (74.2 years old). Preoperatively, the global alignment parameters were comparable between the malnutrition and normal nutrition groups (SVA, 43.3 mm vs. 42.4 mm; T1S, 29.7° vs. 28.4°; TPA, 21.4° vs. 17.8°), with no significant difference in the C2-7 angle (15.1° vs. 15.2°). At 2 years postoperatively, the malnutrition group showed a significantly lower C2-7 angle than the normal nutrition group (9.3° vs. 15.8°, P = 0.03). Postoperative kyphosis was more prevalent in the malnutrition group (33.3% vs. 7.2%, P = 0.005). The preoperative nutritional status and C2-7 angle were independent predictors of postoperative kyphosis. The predictive C2-7 angles differed by preoperative nutritional status (malnutrition group, 11°; normal nutrition group, 7°). CONCLUSION: Among geriatric CSM patients, preoperative malnutrition was closely associated with the increased occurrence of cervical kyphosis after laminoplasty. Our results underscore the importance of preoperative nutritional assessment and management in geriatric populations undergoing cervical spine surgery, as malnutrition is a perioperative modifiable risk factor.

Retrotransposition disrupting EBP in a girl and her mother with X-linked dominant chondrodysplasia punctata.

X-linked dominant chondrodysplasia punctata (CDPX2) is a rare congenital disorder caused by pathogenic variants in EBP on Xp11.23. We encountered a girl and her mother with CDPX2-compatible phenotypes including punctiform calcification in the neonatal period of the girl, and asymmetric limb shortening and ichthyosis following the Blaschko lines in both subjects. Although Sanger direct sequencing failed to reveal a disease-causing variant in EBP, whole genome sequencing (WGS) followed by Manta analysis identified a ~ 4.5 kb insertion at EBP exon 2 of both subjects. The insertion was associated with the hallmarks of retrotransposition such as an antisense poly(A) tail, a target site duplication, and a consensus endonuclease cleavage site, and the inserted sequence harbored full-length SVA_F1 element with 5'- and 3'-transductions containing the Alu sequence. The results imply the relevance of retrotransposition to the human genetic diseases and the usefulness of WGS in the identification of retrotransposition.

Taurine supplementation enhances endurance capacity by delaying blood glucose decline during prolonged exercise in rats.

Taurine enhances physical performance; however, the underlying mechanism remains unclear. This study examined the effect of taurine on the overtime dynamics of blood glucose concentration (BGC) during endurance exercise in rats. Male F344 rats were subjected to transient treadmill exercise until exhaustion following 3 weeks of taurine supplementation or non-supplementation (TAU and CON groups). Every 10 min during exercise, BGC was measured in blood collected through cannulation of the jugular vein. Gluconeogenesis-, lipolysis-, and fatty acid oxidation-related factors in the plasma, liver, and skeletal muscles were also analyzed after 120-min run. Exercise time to exhaustion was significantly longer with taurine supplementation. BGC in the two groups significantly increased by 40 min and gradually and significantly decreased toward the respective exhaustion point. The decline in BGC from the peak at 40 min was significantly slower in the TAU group. The time when the once-increased BGC regressed to the 0-time level was significantly and positively correlated with exercise time until exhaustion. At the 120-min point, where the difference in BGC between the two groups was most significant, plasma free fatty acid concentration and acetyl-carnitine and N-acetyltaurine concentrations in skeletal muscle were significantly higher in the TAU group, whereas glycogen and glucogenic amino acid concentrations and G6Pase activity in the liver were not different between the two groups. Taurine supplementation enhances endurance capacity by delaying the decrease in BGC toward exhaustion through increases of lipolysis in adipose tissues and fatty acid oxidation in skeletal muscles during endurance exercise.

Successful treatment of pneumonia caused by multidrug-resistant Pseudomonas aeruginosa after allogeneic hematopoietic stem cell transplantation with colistin and amikacin inhalation therapy.

Pseudomonas aeruginosa is a Gram-negative bacillus that often causes severe infections during immunosuppression in patients with hematologic malignancies. P. aeruginosa can easily acquire drug resistance, and often develops into multidrug-resistant P. aeruginosa (MDRP). Although many antibiotics are used in combination to treat MDRP infections, colistin and amikacin are less likely to be transferred to the lungs, and inhalation therapy may be used. Herein, we report a Case of pneumonia caused by MDRP after allogeneic hematopoietic stem cell transplantation (HSCT) treated with inhaled colistin and amikacin. This 61-year-old female patient was diagnosed with myelodysplastic syndromes and underwent allogeneic HSCT from an 8/8 HLA-matched unrelated donor after reduced-intensity conditioning. On the day of the stem cell infusion, the patient's sputum culture was found to be positive for MDRP. The patient subsequently developed bacteremia, pneumonia, and lung abscess caused by MDRP, and we administered multidrug antibiotic therapy including colistin and amikacin inhalation therapy. The patient's blood cultures were subsequently turned negative, and the lung abscess disappeared. To our knowledge, this is the first case of MDRP pneumonia after HSCT in which colistin and amikacin inhalation therapy was effective.

High D-index during mobilization predicts poor mobilization of CD34+ cells after anti-lymphoma salvage chemotherapy.

BACKGROUND: Performing stem cell collection after mobilization chemotherapy was a well-balanced strategy between anti-tumor effect and efficient collection of CD34+ cells, but deep and prolonged nadir exposed patients to risk of febrile neutropenia. Febrile neutropenia was known to be associated with lower yields of CD34+ cells, but quantitative data referring to association between yields of CD34+ cells and severity of neutropenia was lacking. We hypothesized that D-index, which was developed for quantitative evaluation of severity of neutropenia especially in the field of hematologic malignancies, could predict yields of CD34+ cells. METHODS: We performed a single center, retrospective analysis of patients with relapsed or refractory aggressive lymphoma who were mobilized with ESHAP or modified ESHAP. We evaluated the association between yields of CD34+ cells at first apheresis and D-index. RESULTS: Thirty-six patients were included, and we demonstrated that yields of CD34+ cells from patients with higher D-index were significantly lower than those from patients with lower D-index. Multivariate linear regression analysis and logistic regression analysis also demonstrated the significant predictive power of D-index. Further, D-index was significantly correlated to platelet count before starting mobilization chemotherapy. Platelet count was known to predict yields of CD34+ cells, and combination of platelet count and D-index could identify patients with lowest CD34+ yields. CONCLUSION: D-index could predict yields of CD34+ cells and it seemed that its predictive power was not less than that of platelet count. Prospective studies including more heterogeneous patients were needed to validate our study.

Impaired Bile Acid Synthesis in a Taurine-Deficient Cat Model.

Deficiency of the functional amino acid-like compound taurine induced in cats by taurine-depleted food was previously shown to significantly decrease the levels of taurine-conjugated bile acids (BAs) and significantly increase the levels of unconjugated BAs, with a significant decrease in total BA concentration in the bile. Because the ratios of primary BAs (cholic acid [CA] and chenodeoxycholic acids [CDCA]) have also been shown to be altered in the bile, taurine has been suggested to play an important role in BA synthesis in the liver. The present study showed that in the liver of taurine-deficient cats, CYP7A1 protein expression and its metabolites (7α-hydroxycholesterol and α-hydroxy-4-cholesten-3-one) were significantly increased and, therefore, the ratio of the CA product in this pathway was decreased. On the other hand, the expression of the mitochondrial CYP27A1 protein and its metabolite 27-hydroxycholesterol (27HC) were significantly decreased in the taurine-deficient liver. Thus, a significantly decreased ratio of CDCA, which is the main product of 27HC, was found. The decreased activity of the CDCA-producing pathway might be related to mitochondrial dysfunction induced by taurine deficiency. In addition, a significant decrease in cholesterol levels in the liver was induced by a decrease in intestinal cholesterol absorption because of decreased hepatic-intestinal circulation of taurine-conjugated BAs. The results of this study showed that taurine deficiency alters both the quality and quantity of BAs through inactivity of the mitochondrial CDCA production pathway caused by impaired mitochondrial function and inhibited the absorption of cholesterol in the intestine.

Blood Taurine Dynamics in Captive Lions: Relationship with Feed and Bile Acid Composition.

Taurine is an essential nutrient for felines including lions. Various severe symptoms induced by taurine deficiency have been reported for domestic and captive felines. Particularly for captive lions in zoos, little information related to taurine requirements is available. Therefore, this study evaluated the relationship between blood taurine concentration and taurine content in prey feed given at zoos, as well as the composition, types, and conjugation properties of bile acids (BAs) in blood collected repeatedly from four lions housed at three zoos. Blood taurine concentrations in four lions were within the normal range, although individual differences and variations were found. Taurine was abundant in feed supplied at the zoos. A positive correlation between blood taurine concentration and feed amount was observed in lions housed at the same zoo. Approximately 70-80% of the total BA pool was cholic acid, with 50-70% being taurine-conjugated. Individual differences and variations were found. No correlation was found between blood taurine concentration and the compositions of BAs in the blood. Results showed that supply of taurine was sufficient for all lions fed the prey feed. Future studies must be conducted to clarify influences on individual differences, as well as individual variations in blood taurine concentration and blood BA composition.

Reduction of cycles of bendamustine plus rituximab therapy in the cases with good response for indolent B-cell lymphomas.

Bendamusutine plus rituximab (BR) regimen is one of the standard regimens for indolent B-cell lymphomas, yet the possibility of reduction of cycles of BR therapy without compromising therapeutic effects is not still uncovered. We retrospectively surveyed 57 cases including 40 follicular lymphoma cases who underwent BR regimen in our institute. The overall response (OR) rate and complete response (CR) rate were 86.0% (95% confidential interval (CI), 74.2-93.7) and 54.4% (40.7-67.6), respectively. Five-year overall survival (OS) and 5-years progression-free survival (PFS) were 76.8% and 45.7%, respectively. We then grouped the patients by the number of administered cycles of BR regimen. PFS was significantly longer in 41 cases of the later cessation group (cycle 4-6) than in 16 cases of the earlier cessation group (cycle 1-3) (p = 0.012, 5-years PFS; 46.8% vs. 35.2%, respectively), and both of OR and CR rate of the former was better than the latter (OR rate; 95.1% vs. 62.5%, p < 0.01, CR rate; 61.4% vs. 31.3%, p = 0.04). Interestingly PFS of twenty-one (36.8%) cases receiving just 4 cycles was longer than that of 20 cases who received five or 6 cycles (p < 0.01, 5-years PFS; 71.8% vs. 23.2%, respectively). Focusing on the group of four cycles, the 12 case with CR revealed longer PFS than seven cases with partial response (PR), and median PFS was not reached in CR cases and 16.9 months in the PR cases (p < 0.01). These results suggest that four cycles at least should be administered if possible, and the outcome of the patients who discontinued BR after four cycles was not inferior to that of the cases who received five or six cycles. In conclusion, discontinuation after four cycles may be permissible in some cases with complete response to BR regimen.

Identification of colorectal neoplasia by using serum bile acid profile.

BACKGROUND: Colonoscopy is the gold standard for detecting earlier stages of CRC, although screening of patients is difficult because of invasiveness, low compliance and procedural health risks. Therefore, the need for new screening methods for CRC is rising. Previous studies have demonstrated the diagnostic ability of serum BAs; however, the results have been inconsistent. In this study, we conducted a comprehensive analysis of serum BAs from patients with CRC and verified their diagnostic ability to detect CRC. METHODS: A total of 56 CRC patients (n = 14 each of stages I-IV), 59 patients with colonic adenoma and 60 healthy controls were included. Age and sex were matched for each group. Serum BA compositions were measured by LC-MS/MS and serum concentration of 30 types of BAs were analysed by discriminant analysis with multidimensional scaling method. RESULTS: Free CA, 3epi-DCA&CDCA, 3-dehydro CA, GCA and TCA were extracted as principal component (PC) 1 and free 3-dehydroDCA as PC 2 by canonical discriminant function coefficients. The verification of discriminability using cross-validation method revealed that the correct classification rate was 66.3% for original data and 52.6% for cross-validation data. CONCLUSIONS: A combined analysis using comprehensive serum BA concentration can be an efficient method for screening CRC.

Severe cellulitis caused by Achromobacter xylosoxidans after allogeneic hematopoietic stem cell transplantation.

Achromobacter xylosoxidans (A. xylosoxidans) is an aerobic gram-negative bacillus and often isolated from aquatic environments. It is supposed to cause infections in patients with malignancy or immunodeficiency. It causes various healthcare-associated infections, but cellulitis is rare. Herein, we report the first case of sever cellulitis by A. xylosoxidans after allogeneic hematopoietic stem cell transplantation (HSCT). A 49-year-old man underwent allogeneic HSCT from 8/8 HLA-matched unrelated donor with myeloablative conditioning for relapsed acute myeloid leukemia. He developed skin chronic graft versus host disease 11 months after HSCT. During the prolonged treatment with prednisolone and cyclosporine, he developed cellulitis on his left leg and admitted to our hospital. Blood and exudate culture revealed A. xylosoxidans. Although empirical therapy with cefepime was ineffective, his symptoms were dramatically improved after administration of meropenem. To our knowledge, this is the first case of A. xylosoxidans cellulitis after allogeneic HSCT. A. xylosoxidans should be considered as a possible cause of cellulitis in post-allogeneic HSCT patients on prolonged immunosuppressive therapy.

Clinical features and early post-operative complications of isolated C2 odontoid fractures: a retrospective analysis using a national inpatient database in Japan.

PURPOSE: To examine the clinical features and post-treatment complications in patients with isolated C2 odontoid fractures. METHODS: We extracted data for all patients who were admitted with C2 odontoid fractures from the Japanese Diagnosis Procedure Combination database between July 2010 and March 2017. We then compared the post-treatment complications during hospitalization according to treatment types: conservative treatment (with or without use of halo-vest) and surgery (anterior or posterior spinal fixation). RESULTS: A total of 3167 patients (1533 men, 1634 women; mean age, 70 years) with isolated C2 odontoid fractures were identified, including 1124 patients (35%) aged ≥ 80 years. Among the total patients, 2476 (78%) received conservative treatment (with halo-vest, 728; without halo-vest, 1748). The remaining 691 patients (22%) underwent surgery (anterior surgery, 129; posterior surgery, 556; combined surgery, 6). There were no differences between the conservative treatment and surgery groups in baseline characteristics and preexisting comorbid conditions except for age (71 vs. 69 years, p = 0.042). In-hospital death occurred in 136 patients (4.3%). There was no significant difference in in-hospital mortality between the two groups (overall, conservative treatment 4.6% vs. surgery 3.0%, p = 0.066; age ≥ 80 years, conservative treatment 7.2% vs. surgery 5.4%, p = 0.34). Use of halo-vest was not associated with increased mortality (with halo-vest 3.7% vs. without halo-vest 5.0%, p = 0.15). CONCLUSION: The great majority of isolated odontoid fractures occurred in elderly patients. Conservative treatment and surgery had similarly low in-hospital mortality. Use of halo-vest was not associated with an increase in mortality.

FGFR1-mediated protocadherin-15 loading mediates cargo specificity during intraflagellar transport in inner ear hair-cell kinocilia.

The mechanosensory hair cells of the inner ear are required for hearing and balance and have a distinctive apical structure, the hair bundle, that converts mechanical stimuli into electrical signals. This structure comprises a single cilium, the kinocilium, lying adjacent to an ensemble of actin-based projections known as stereocilia. Hair bundle polarity depends on kinociliary protocadherin-15 (Pcdh15) localization. Protocadherin-15 is found only in hair-cell kinocilia, and is not localized to the primary cilia of adjacent supporting cells. Thus, Pcdh15 must be specifically targeted and trafficked into the hair-cell kinocilium. Here we show that kinocilial Pcdh15 trafficking relies on cell type-specific coupling to the generic intraflagellar transport (IFT) transport mechanism. We uncover a role for fibroblast growth factor receptor 1 (FGFR1) in loading Pcdh15 onto kinociliary transport particles in hair cells. We find that on activation, FGFR1 binds and phosphorylates Pcdh15. Moreover, we find a previously uncharacterized role for clathrin in coupling this kinocilia-specific cargo with the anterograde IFT-B complex through the adaptor, DAB2. Our results identify a modified ciliary transport pathway used for Pcdh15 transport into the cilium of the inner ear hair cell and coordinated by FGFR1 activity.