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Without visual references, nonpilots exposed to coordinated flight turns underestimate the bank angle, because of discordant information of the roll-angular displacement from the otoliths, consistently signaling vertical position, versus the semicircular canals, enabling detection of the displacement. Pilots may also use their ability to perceive the G load and knowledge of the relation between load and angle to assess the bank angle. Our aim was to investigate whether the perception of bank angle can be improved by spatial orientation training in a centrifuge. Sixteen pilots/pilot students assessed their roll tilt, in complete darkness, during both real coordinated flight turns and gondola centrifugation, at roll tilts of 30° and 60°. The experiments were repeated after a 3-wk period, during which eight of the subjects performed nine training sessions in the centrifuge, comprising feedback on roll angle vs. G load, and on indicating requested angles. Before training, the subjects perceived in the aircraft and centrifuge, respectively: 37 (17)°, 38 (14)° during 60° turns and 19 (12)°, 20 (10)° during 30° turns. Training improved the perception of angle during the 60° [to 60 (7)°, 55 (10)°; P ≤ 0.04] but not the 30° [21 (10)°, 15 (9)°; P ≥ 0.30] turns; the improvement disappeared within 2 yr after training. Angle assessments did not change in the untrained group. The results suggest that it is possible to, in a centrifuge, train a pilot's ability to perceive large but not discrete-to-moderate roll-angular displacements. The transient training effect is attributable to improved capacity to perceive and translate G load into roll angle and/or to increased reliance on semicircular canal signals. NEW & NOTEWORTHY Spatial disorientation is a major problem in aviation. When performing coordinated flight turns without external visual cues (e.g., flying in clouds or darkness), the pilot underestimates the aircraft bank angle because the vestibular system provides unreliable information of roll tilt. The present study demonstrates that it is possible to, in a long-arm centrifuge, train a pilot's ability to perceive large but not discrete-to-moderate roll-angular displacements.

Current HLH-2004-based diagnostic criteria for familial hemophagocytic lymphohistiocytosis (FHL) are based on expert opinion. Here we performed a case-control study to test and possibly improve these clinical criteria. We also developed two complementary expert opinion-based diagnostic strategies for FHL in patients with signs/symptoms suggestive of HLH, based on genetic and cellular cytotoxicity assays. The cases (n=366) were children <16 years with verified familial and/or genetic FHL (n=341) or Griscelli syndrome type 2 (GS2) (n=25); 276 from the HLH-94/HLH-2004 databases and 90 from the Italian HLH Registry. All fulfilled the HLH-94/HLH-2004 patient inclusion criteria. Controls were 374 children with systemic-onset juvenile idiopathic arthritis (sJIA) and 329+361 children in two cohorts with febrile infections that could be confused with HLH and sepsis, respectively. To provide complete data sets, multiple imputations were performed. The optimal model, based on the number of diagnostic criteria fulfilled from 17 variables studied, reveled almost similar diagnostic thresholds as the existing criteria, with accuracy 99.1% (sensitivity 97.1%; specificity 99.5%). Notably, assessment of the original HLH-2004 criteria revealed accuracy 97.4% (sensitivity 99.0%; specificity 97.1%). Since cellular cytotoxicity assays here constitute a separate diagnostic strategy, HLH-2004 criteria without NK-cell function was also studied which showed accuracy 99.0% (sensitivity 96.2%; specificity 99.5%). Thus, we conclude that the HLH-2004 criteria (without NK-cell function) have significant validity in their current form when tested against severe infections or sJIA. It is important to exclude underlying malignancies and atypical infections. In addition, complementary cellular and genetic diagnostic guidelines can facilitate necessary confirmation of clinical diagnosis., (Copyright © 2024 American Society of Hematology.)

Intratumoral bacteria flexibly contribute to cellular and molecular tumor heterogeneity for supporting cancer recurrence through poorly understood mechanisms. Using spatial metabolomic profiling technologies and 16SrRNA sequencing, we herein report that right-sided colorectal tumors are predominantly populated with Colibactin-producing Escherichia coli (CoPEC) that are locally establishing a high-glycerophospholipid microenvironment with lowered immunogenicity. It coincided with a reduced infiltration of CD8 + T lymphocytes that produce the cytotoxic cytokines IFN-γ where invading bacteria have been geolocated. Mechanistically, the accumulation of lipid droplets in infected cancer cells relied on the production of colibactin as a measure to limit genotoxic stress to some extent. Such heightened phosphatidylcholine remodeling by the enzyme of the Land's cycle supplied CoPEC-infected cancer cells with sufficient energy for sustaining cell survival in response to chemotherapies. This accords with the lowered overall survival of colorectal patients at stage III-IV who were colonized by CoPEC when compared to patients at stage I-II. Accordingly, the sensitivity of CoPEC-infected cancer cells to chemotherapies was restored upon treatment with an acyl-CoA synthetase inhibitor. By contrast, such metabolic dysregulation leading to chemoresistance was not observed in human colon cancer cells that were infected with the mutant strain that did not produce colibactin (11G5 ∆ClbQ ). This work revealed that CoPEC locally supports an energy trade-off lipid overload within tumors for lowering tumor immunogenicity. This may pave the way for improving chemoresistance and subsequently outcome of CRC patients who are colonized by CoPEC.

Background: Gastric Mucosa Associated Lymphoid Tissue lymphoma (GML) development is triggered by Helicobacter pylori (H. pylori) infection. Little is known about the impact of H. pylori infection on gastric microbiota., Methods: The gastric microbiota was retrospectively investigated using 16S rRNA gene sequencing in 32 patients with untreated GML (10 H. pylori-positive and 22 H. pylori-negative), 23 with remitted and 18 refractory GML and 35 controls. Differences in microbial diversity, bacterial composition and taxonomic repartition were assessed., Results: There was no change in diversity and bacterial composition between GML and control patients taking into account H. pylori status. Differential taxa analysis identified specific changes associated with H. pylori-negative GML: the abundances of Actinobacillus, Lactobacillus and Chryseobacterium were increased while the abundances of Veillonella, Atopobium, Leptotrichia, Catonella, Filifactor and Escherichia&#95;Shigella were increased in control patients. In patients with remitted GML, the genera Haemophilus and Moraxella were significantly more abundant than in refractory patients, while Atopobium and Actinomyces were significantly more abundant in refractory patients., Conclusion: Detailed analysis of the gastric microbiota revealed significant changes in the bacterial composition of the gastric mucosa in patients with GML that may have a role in gastric lymphomagenesis but not any new pathobionts., Competing Interests: Declaration of Competing Interest Aurelien Amiot has received consulting fees from Abbvie, Tillotts pharma, Janssen, Hospira, Takeda, Fresenius Kabi, Pfizer and Gilead as well as lecture fees and travel accommodations from Abbvie, Janssen, Biocodex, Hospira, Ferring, Biogen, Tillotts pharma, Fresenius Kabi, Takeda and MSD., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Recently, an intestinal dysbiotic microbiota with enrichment in oral cavity bacteria has been described in colorectal cancer (CRC) patients. Here, we characterize and investigate one of these oral pathobionts, the Gram-positive anaerobic coccus Parvimonas micra . We identified two phylotypes (A and B) exhibiting different phenotypes and adhesion capabilities. We observed a strong association of phylotype A with CRC, with its higher abundance in feces and in tumoral tissue compared with the normal homologous colonic mucosa, which was associated with a distinct methylation status of patients. By developing an in vitro hypoxic co-culture system of human primary colonic cells with anaerobic bacteria, we show that P. micra phylotype A alters the DNA methylation profile promoters of key tumor-suppressor genes, oncogenes, and genes involved in epithelial-mesenchymal transition. In colonic mucosa of CRC patients carrying P. micra phylotype A, we found similar DNA methylation alterations, together with significant enrichment of differentially expressed genes in pathways involved in inflammation, cell adhesion, and regulation of actin cytoskeleton, providing evidence of P. micra's possible role in the carcinogenic process.

Background: During a simulated coordinated turn in a gondola centrifuge, experienced pilots show a substantial inter-individual variability in visual measures of perceived roll tilt. Because of the centrifuge's small radius, the pattern of stimuli to the semicircular canals during acceleration of the centrifuge differs in certain respects from that of an aircraft entering a turn., Objective: To explore whether these differences may be of significance for the pilot's roll- plane orientation and whether individual characteristics revealed in the centrifuge correspond to those during real flight., Method: 8 fixed-wing air-force pilots were tested in a centrifuge and a high-performance aircraft. The centrifuge was accelerated to 2 G (gondola inclination 60°) within 10 s. The duration at 2 G was 6 minutes. Similar profiles were created in the aircraft. The subjective visual horizontal (SVH) was measured using an adjustable luminous line in darkness. Each pilot was tested on three occasions: centrifuge (2 runs), aircraft (2 turns), centrifuge (2 runs). For each 2-G exposure, initial and final SVH values were established via curve fitting., Result: Despite a large inter-individual variability (±SD), group means were similar in the aircraft (initial: 43.0±20.6°; final: 22.5±14.8°) and centrifuge (initial: 40.6±17.0°; final: 20.5±16.0°). Further, individual peculiarities in response patterns were similar in the two conditions. For both the initial and final SVH tilt there was a high correlation between centrifuge and aircraft., Conclusion: The correspondence between conditions suggests that the centrifuge is an adequate means for demonstrating the fundamental motion pattern of coordinated flight and also for establishing the individual pilot's ability to perceive an aircraft's roll attitude.Findings are discussed in connection with vestibular learning and the possibility of underlying differences between pilots in the keenness for semicircular canal and somatosensory cues.

Purpose: Streptococcus gallolyticus subspecies gallolyticus ( SGG ) is an opportunistic pathogen causing invasive infections in the elderly often associated with colon neoplasia. The prevalence of SGG in the stools of patients with normal colonoscopy (control) was compared with patients with colorectal adenomas (CRA) or with carcinomas (CRC) from stages I to IV. The presence of the pk s island encoding colibactin as well as other CRC-associated bacteria such as toxicogenic Bacteroides fragilis , Fusobacterium nucleatum , and Parvimonas micra was also investigated., Patients and Methods: Fecal samples collected in France between 2011 and 2016 from patients with normal colonoscopy ( n = 25), adenoma ( n = 23), or colorectal cancer at different stages ( n = 81) were tested by PCR for the presence of SGG , B. fragilis , F. nucleatum , P. micra , and the pks island. Relative quantification of SGG , F. nucleatum , and P. micra in stools was performed by qPCR., Results: SGG prevalence was significantly increased in the CRC group. Our results also revealed i) a strong and significant increase of toxinogenic B. fragilis in patients with early-stage adenoma and of pks island at late-stage CRC and ii) increased levels of F. nucleatum and P. micra in the stools of CRC patients. Furthermore, the simultaneous detection of these five bacterial markers was only found in CRC patients., Conclusions: Our results indicate that the prevalence or relative levels of CRC-associated bacteria vary during CRC development. Among them, B. fragilis ( bft +) was singled out as the sole pathobiont detected at the early adenoma stage., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest, (Copyright © 2022 Périchon, Lichtl-Häfele, Bergsten, Delage, Trieu-Cuot, Sansonetti, Sobhani and Dramsi.)

Background: Nerve compression disorders, such as carpal tunnel syndrome (CTS) and ulnar entrapment at the elbow (UNE), may be associated with apoptosis and neuroprotective mechanisms in the peripheral nerve that may be detected by biomarkers in the blood. The relationships between CTS and UNE and two biomarkers of apoptosis, i.e., caspase-3 and caspase-8, and the neuroprotective factor Heat Shock Protein 27 (HSP27) in plasma were examined in a population-based cohort., Method: The biomarkers caspase-3, caspase-8 and HSP27 were measured in plasma at inclusion of 4,284 study participants aged 46-68 years in the population-based Malmö Diet and Cancer study (MDCS). End-point retrieval was made from national registers concerning CTS and UNE. Independent t -test was used to examine the association between caspase-3, caspase-8 and HSP27 plasma levels and incidence of CTS and UNE. Cox proportional hazards regression was used to investigate if plasma levels of caspase-3, caspase-8 and HSP27 affected time to diagnosis of CTS or UNE., Results: During the mean follow-up time of 22 years, 189/4,284 (4%) participants were diagnosed with CTS and 42/4,284 (1%) were diagnosed with UNE. No associations were found between incident CTS or UNE and the biomarkers caspase-3, caspase-8 and HSP27 in plasma., Conclusion: The apoptotic biomarkers caspase-3 and caspase-8 and the neuroprotective factor HSP27 in plasma, factors conceivably related to a nerve injury, are not associated with the nerve compression disorders CTS and UNE in a general population., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Bergsten, Rydberg, Dahlin and Zimmerman.)

Colorectal carcinoma (CRC) is a common disease, the incidence of which is increasing according to Western lifestyle; it remains to have a poor prognosis. Western nutriments are presumed to induce mild inflammation within the colonic mucosa, resulting in the accumulation of DNA alterations in colonocytes through a multistage carcinogenesis process. This suggests that most CRCs are related to the environment. Of interest, fecal microbiota composition has been shown yielding a novel approach regarding how environment changes may impact health and disease. Here, we compare whole shotgun metagenomic gut microbiota of two monozygotic twin sisters, one of whom is suffering from an advance colorectal tumor with a profound disequilibrium of the composition of the gut microbiota due to the overexpression of virulent bacteria such as E. coli, Shigella, and Clostridium species in the colon cancer patient's feces contrasting with low levels of bacterial species such as Faecalibacterium and Akkermansia usually enriched in the healthy adults' microbial flora. The disequilibrium in microbiota of the CRC patient's feces as compared to her monozygotic twin sister is linked to inflammatory and immune cell infiltrates in the patient's colonic tissue. We speculate on the role of microbiota disequilibrium on the immune-tolerant cell infiltrate within CRCs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Sobhani, Bergsten, Charpy, Chamaillard and Mestivier.)

An increasing body of evidence highlights the role of fecal microbiota in various human diseases. However, more than two-thirds of fecal bacteria cannot be cultivated by routine laboratory techniques. Thus, physicians and scientists use DNA sequencing and statistical tools to identify associations between bacterial subgroup abundances and disease. However, discrepancies between studies weaken these results. In the present study, we focus on biases that might account for these discrepancies. First, three different DNA extraction methods (G'NOME, QIAGEN, and PROMEGA) were compared with regard to their efficiency, i.e., the quality and quantity of DNA recovered from feces of 10 healthy volunteers. Then, the impact of the DNA extraction method on the bacteria identification and quantification was evaluated using our published cohort of sample subjected to both 16S rRNA sequencing and whole metagenome sequencing (WMS). WMS taxonomical assignation employed the universal marker genes profiler mOTU-v2, which is considered the gold standard. The three standard pipelines for 16S RNA analysis (MALT and MEGAN6, QIIME1, and DADA2) were applied for comparison. Taken together, our results indicate that the G'NOME-based method was optimal in terms of quantity and quality of DNA extracts. 16S rRNA sequence-based identification of abundant bacteria genera showed acceptable congruence with WMS sequencing, with the DADA2 pipeline yielding the highest congruent levels. However, for low abundance genera (<0.5% of the total abundance) two pipelines and/or validation by quantitative polymerase chain reaction (qPCR) or WMS are required. Hence, 16S rRNA sequencing for bacteria identification and quantification in clinical and translational studies should be limited to diagnostic purposes in well-characterized and abundant genera. Additional techniques are warranted for low abundant genera, such as WMS, qPCR, or the use of two bio-informatics pipelines.

We report the largest prospective study thus far on hematopoietic stem cell transplantation (HSCT) in hemophagocytic lymphohistiocytosis (HLH), a life-threatening hyperinflammatory syndrome comprising familial/genetic HLH (FHL) and secondary HLH. Although all patients with HLH typically need intensive anti-inflammatory therapy, patients with FHL also need HSCT to be cured. In the international HLH-2004 study, 187 children aged <18 years fulfilling the study inclusion criteria (5 of 8 diagnostic criteria, affected sibling, or molecular diagnosis in FHL-causative genes) underwent 209 transplants (2004-2012), defined as indicated in patients with familial/genetic, relapsing, or severe/persistent disease. Five-year overall survival (OS) post-HSCT was 66% (95% confidence interval [CI], 59-72); event-free survival (EFS) was 60% (95% CI, 52-67). Five-year OS was 81% (95% CI, 65-90) for children with a complete response and 59% (95% CI, 48-69) for those with a partial response (hazard ratio [HR], 2.12; 95% CI, 1.06-4.27; P = .035). For children with verified FHL (family history/genetically verified, n = 134), 5-year OS was 71% (95% CI, 62-78) and EFS was 62% (95% CI, 54-70); 5-year OS for children without verified FHL (n = 53) was significantly lower (52%; 95% CI, 38-65) (P = .040; HR, 1.69; 95% CI, 1.03-2.77); they were also significantly older. Notably, 20 (38%) of 53 patients without verified FHL had natural killer cell activity reported as normal at diagnosis, after 2 months, or at HSCT, suggestive of secondary HLH; and in addition 14 (26%) of these 53 children had no evidence of biallelic mutations despite having 3 or 4 FHL genes analyzed (natural killer cell activity not analyzed after 2 months or at HSCT). We conclude that post-HSCT survival in FHL remains suboptimal, and that the FHL diagnosis should be carefully investigated before HSCT. Pretransplant complete remission is beneficial but not mandatory to achieve post-HSCT survival. This trial was registered at www.clinicaltrials.gov as #NCT00426101., (© 2020 by The American Society of Hematology.)

Sporadic colorectal cancer (CRC) is a result of complex interactions between the host and its environment. Environmental stressors act by causing host cell DNA alterations implicated in the onset of cancer. Here we investigate the stressor ability of CRC-associated gut dysbiosis as causal agent of host DNA alterations. The epigenetic nature of these alterations was investigated in humans and in mice. Germ-free mice receiving fecal samples from subjects with normal colonoscopy or from CRC patients were monitored for 7 or 14 wk. Aberrant crypt foci, luminal microbiota, and DNA alterations (colonic exome sequencing and methylation patterns) were monitored following human feces transfer. CRC-associated microbiota induced higher numbers of hypermethylated genes in murine colonic mucosa (vs. healthy controls' microbiota recipients). Several gene promoters including SFRP1,2,3, PENK, NPY, ALX4, SEPT9, and WIF1 promoters were found hypermethylated in CRC but not in normal tissues or effluents from fecal donors. In a pilot study ( n = 266), the blood methylation levels of 3 genes ( Wif1 , PENK , and NPY ) were shown closely associated with CRC dysbiosis. In a validation study ( n = 1,000), the cumulative methylation index (CMI) of these genes was significantly higher in CRCs than in controls. Further, CMI appeared as an independent risk factor for CRC diagnosis as shown by multivariate analysis that included fecal immunochemical blood test. Consequently, fecal bacterial species in individuals with higher CMI in blood were identified by whole metagenomic analysis. Thus, CRC-related dysbiosis induces methylation of host genes, and corresponding CMIs together with associated bacteria are potential biomarkers for CRC., Competing Interests: Competing interest statement: I.S. shares rights in 3 patents: EP B31120, EP2635705, and EP 2955232 A1 20151216 based on methods for diagnosing adenomas and/or colorectal cancer.

The gastrointestinal tract is abundantly colonized by microbes, yet the translocation of oral species to the intestine is considered a rare aberrant event, and a hallmark of disease. By studying salivary and fecal microbial strain populations of 310 species in 470 individuals from five countries, we found that transmission to, and subsequent colonization of, the large intestine by oral microbes is common and extensive among healthy individuals. We found evidence for a vast majority of oral species to be transferable, with increased levels of transmission in colorectal cancer and rheumatoid arthritis patients and, more generally, for species described as opportunistic pathogens. This establishes the oral cavity as an endogenous reservoir for gut microbial strains, and oral-fecal transmission as an important process that shapes the gastrointestinal microbiome in health and disease., Competing Interests: TS, MH, LC, SL, PC, AV, JW, OM, RA, EB, Cd, IS, AH, SS, GZ, PW, PB No competing interests declared, (© 2019, Schmidt et al.)

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome comprising familial/genetic HLH (FHL) and secondary HLH. In the HLH-94 study, with an estimated 5-year probability of survival (pSu) of 54% (95% confidence interval, 48%-60%), systemic therapy included etoposide, dexamethasone, and, from week 9, cyclosporine A (CSA). Hematopoietic stem cell transplantation (HSCT) was indicated in patients with familial/genetic, relapsing, or severe/persistent disease. In HLH-2004, CSA was instead administered upfront, aiming to reduce pre-HSCT mortality and morbidity. From 2004 to 2011, 369 children aged <18 years fulfilled HLH-2004 inclusion criteria (5 of 8 diagnostic criteria, affected siblings, and/or molecular diagnosis in FHL-causative genes). At median follow-up of 5.2 years, 230 of 369 patients (62%) were alive (5-year pSu, 61%; 56%-67%). Five-year pSu in children with (n = 168) and without (n = 201) family history/genetically verified FHL was 59% (52%-67%) and 64% (57%-71%), respectively (familial occurrence [n = 47], 58% [45%-75%]). Comparing with historical data (HLH-94), using HLH-94 inclusion criteria, pre-HSCT mortality was nonsignificantly reduced from 27% to 19% ( P = .064 adjusted for age and sex). Time from start of therapy to HSCT was shorter compared with HLH-94 ( P = 020 adjusted for age and sex) and reported neurological alterations at HSCT were 22% in HLH-94 and 17% in HLH-2004 (using HLH-94 inclusion criteria). Five-year pSu post-HSCT overall was 66% (verified FHL, 70% [63%-78%]). Additional analyses provided specific suggestions on potential pre-HSCT treatment improvements. HLH-2004 confirms that a majority of patients may be rescued by the etoposide/dexamethasone combination but intensification with CSA upfront, adding corticosteroids to intrathecal therapy, and reduced time to HSCT did not improve outcome significantly., (© 2017 by The American Society of Hematology.)

Background: Courtship behavior plays a critical role in attracting females and reproduction success. However, the effects of exposure to a ubiquitous contaminant di(2-ethylhexyl) phthalate (DEHP) on these behaviors and, in particular, on courtship vocalizations have not been examined., Objective: The effects of adult exposure to DEHP on courtship and mating behaviors and gonadotropic axis and neural mechanisms involved in DEHP-induced effects were analyzed in male mice., Methods: Adult C57BL/6J males were orally exposed to DEHP (0, 0.5, 5, and 50μg/kg/d) for 4 wk. Olfactory preference, ultrasonic vocalizations (USVs), partner preference and mating, as well as locomotor activity and motor coordination, were measured. The kisspeptin system and testosterone levels were analyzed. Proteomic and molecular studies were conducted on the hypothalamic preoptic nucleus, the key region involved in sexual motivation to vocalize and mate., Results: DEHP at 50μg/kg/d reduced the emission of USVs, whereas lower doses changed the ratio of syllable categories. This was associated with diminished sexual interest of female partners toward males exposed to 5 or 50μg/kg/d and increased latency to mate, despite normal olfactory preference. The kisspeptin system and circulating testosterone levels were unaffected. In DEHP-exposed males, proteomic analysis of the preoptic nucleus identified differentially expressed proteins connected to the androgen receptor (AR). Indeed, exposure to 5 or 50μg/kg/d of DEHP induced selective AR downregulation in this nucleus and upstream chemosensory regions. The involvement of AR changes in the observed alterations was further supported by the reduced emission of courtship vocalizations in males with disrupted neural AR expression., Conclusions: These data demonstrate the critical role of neural AR in courtship vocalizations and raises the possibility that the vulnerability of this signaling pathway to exposure to endocrine disrupters may be detrimental for courtship communication and mating in several species. https://doi.org/10.1289/EHP1443.

Objectives: The present study assessed full-shift trunk and upper arm postural exposure amplitudes, frequencies, and durations among Swedish airport baggage handlers and aimed to determine whether exposures differ between workers at the ramp (loading and unloading aircraft) and baggage sorting areas., Methods: Trunk and upper arm postures were measured using inclinometers during three full work shifts on each of 27 male baggage handlers working at a large Swedish airport. Sixteen of the baggage handlers worked on the ramp and 11 in the sorting area. Variables summarizing postures and movements were calculated, and mean values and variance components between subjects and within subject (between days) were estimated using restricted maximum likelihood algorithms in a one-way random effect model., Results: In total, data from 79 full shifts (651h) were collected with a mean recording time of 495min per shift (range 319-632). On average, baggage handlers worked with the right and left arm elevated >60° for 6.4% and 6.3% of the total workday, respectively. The 90th percentile trunk forward projection (FP) was 34.1°, and the 50th percentile trunk movement velocity was 8° s(-1). For most trunk (FP) and upper arm exposure variables, between-subject variability was considerable, suggesting that the flight baggage handlers were not a homogeneously exposed group. A notable between-days variability pointed to the contents of the job differing on different days. Peak exposures (>90°) were higher for ramp workers than for sorting area workers (trunk 0.6% ramp versus 0.3% sorting; right arm 1.3% ramp versus 0.7% sorting)., Conclusions: Trunk and upper arm postures and movements among flight baggage handlers measured by inclinometry were similar to those found in other jobs comprising manual material handling, known to be associated with increased risks for musculoskeletal disorders. The results showed that full-shift trunk (FP) and, to some extent, peak arm exposures were higher for ramp workers compared with sorting workers., (© The Author 2016. Published by Oxford University Press on behalf of the British Occupational Hygiene Society.)

Background: One disorienting movement pattern, common during flight, is the entering of a coordinated turn. While the otoliths persistently sense upright head position, the change in roll attitude constitutes a semicircular canal stimulus. This sensory conflict also arises during acceleration in a swing-out gondola centrifuge. From a vestibular viewpoint there are, however, certain differences between the two stimulus situations; the aim of the present study was to elucidate whether these differences are reflected in the perceived roll attitude., Methods: Eight nonpilots were tested in a centrifuge (four runs) and during flight (two turns). The subjective visual horizontal (SVH) was measured using an adjustable luminous line in darkness. The centrifuge was accelerated from stationary to 1.56 G (roll 50°) within 7 s; the duration of the G plateau was 5 min. With the aircraft, turns with approximately 1.4 G (45°) were entered within 15 s and lasted for 5 min. Tilt perception (TP) was defined as the ratio of SVH/real roll tilt; initial and final values were calculated for each centrifugation/turn., Results: In both systems there was a sensation of tilt that declined with time. The initial TP was (mean ± SD): 0.40 ± 0.27 (centrifuge) and 0.37 ± 0.30 (flight). The final TP was 0.20 ± 0.26 and 0.17 ± 0.19, respectively. Both initial and final TP correlated between the two conditions., Conclusion: The physical roll tilt is under-estimated to a similar degree in the centrifuge and aircraft. Also the correspondence at the individual level suggests that the vestibular dilemma of coordinated flight can be recreated in a lifelike manner using a gondola centrifuge.

Background: During hovering with a helicopter, an involuntary change in attitude (during brownout) results in reduced lifting force and a horizontal acceleration component. This movement pattern is difficult to perceive via the otolith organs. If the angular displacement occurs rapidly, it will, however, activate the semicircular canals. The major aim of this study was to establish to what extent pitch-plane angular displacements can be perceived based on canal information when there is no tilt stimulus to the otoliths., Methods: In a helicopter, 9 nonpilots (N) and 8 helicopter pilots (P) underwent 5-6 pitch-forward displacements (magnitude 14-33°, angular velocity 2-7° · s -1 ). In a swing-out gondola centrifuge, 9 N and 3 P were exposed to a similar canal-otolith conflict (acceleration, seated centripetally) with four displacements of 25° and two of 60°. The visually perceived eye level (VPEL) was continuously recorded using an adjustable luminous dot in darkness. For each helicopter dive and centrifuge run the gain was calculated as the ratio (VPEL deflection)/(displacement of helicopter or gondola)., Results: In the helicopter there was no difference between N (0.28 ± 0.13) and P (0.36 ± 0.22). In the centrifuge the gains were 0.34 ± 0.18° (25° displacements) and 0.30 ± 0.16° (60° displacements). Values obtained in the helicopter did not differ significantly from those in the centrifuge. There was a correlation between data obtained during the 25° and 60° displacements in the centrifuge., Conclusion: There was a pronounced underestimation of pitch angular displacements in a helicopter. The interindividual variability was considerable. Gains for perceived displacement were similar in helicopter and centrifuge. Tribukait A, Bergsten E, Eiken O. Pitch-plane angular displacement perception during helicopter flight and gondola centrifugation. Aerosp Med Hum Perform. 2016; 87(10):852-861.

Background: During a simulated coordinated turn in a gondola centrifuge, the perceived roll-tilt, quantified as the subjective visual horizontal (SVH), may differ tenfold between individuals. One aim of this study was to discern whether this variability reflects real individual characteristics or is due to noise or day-to-day variation. We also wanted to establish whether there are any habituation or learning effects of the centrifuge test., Methods: In nine nonpilots (NP) and nine student pilots (SP), with a flight experience of 150 h, the SVH was measured using an adjustable luminous line in darkness. At two test occasions (T1, T2) (interval 5-14 d) subjects underwent two runs (R1, R2; acceleration to 2 G in 10 s, gondola inclination 60 degrees, 5 min at 2 G, deceleration to 1 g in 10 s, interval between runs 5 min) in a centrifuge (r = 9.1 m). Initial and final SVH was determined for each individual run., Results: Acceleration of the centrifuge induced a tilt of the SVH. At T1 R1, this SVH tilt was, in NP, initially 24 +/- 18 degrees and finally 8 +/- 10 degrees. The corresponding values for SP were 28 +/- 18 degrees and 31 +/- 33 degrees. The SVH tilt was slightly larger at R2 than at R1. There was no difference between T1 and T2. Reliability coefficients ranged between 0.86 and 0.98 for NP and between 0.78 and 0.99 for SP., Conclusion: The large interindividual variability combined with a very high reproducibility suggests the existence of persistent individual characteristics in the perception of complex vestibular stimuli. Habituation or learning effects of gondola centrifugation appears to be small.

Background: G protection afforded by the abdominal bladder of a pneumatic anti-G suit is usually attributed to counteraction of G-induced caudad displacement of the heart and pooling of blood in the abdominal veins. The study examined whether the abdominal bladder might provide G protection also via other mechanisms., Methods: Each subject was exposed to +Gz loads while sitting relaxed, wearing a full-coverage anti-G suit modified to permit separate pressurization of the abdominal and leg bladders. In two experimental series (N = 8, N = 14), subjects were breathing at positive airway pressure (PPB); in a third series, five subjects were breathing at atmospheric airway pressure. Intrathoracic pressures were estimated by use of esophageal catheters., Results: During PPB at high G loads, intrathoracic pressure was higher with than without the pressurized abdominal bladder. In 7 of the 14 subjects, basilar intrathoracic pressure exceeded airway pressure during PPB when the abdominal bladder was pressurized. The mean arterial pressure response at high G loads was higher in this subset of subjects (55 +/- 23 mmHg) than in the subjects in whom airway pressure exceeded intrathoracic pressure (41 +/- 27 mmHg). Without PPB at increased G load, the intrathoracic pressure gradient was higher with than without the pressurized abdominal bladder., Discussion: During PPB, the abdominal bladder acts as an airway counterpressure, thereby facilitating pressure transmission from the airways to the thorax and hence improving G protection. It also appears that in several individuals, pressure may be transmitted from the abdominal bladder to the thorax and heart.

Germ-line mutations in the tumour suppressor proteins BRCA1 and BRCA2 predispose to breast and ovarian cancer. We have recently identified a Greenlandic Inuit BRCA1 nucleotide 234T>G/c.115T>G (p.Cys39Gly) founder mutation, which at that time was the only disease-causing BRCA1/BRCA2 mutation identified in this population. Here, we describe the identification of a novel disease-causing BRCA1 nucleotide 4803delCC/c.4684delCC mutation in a Greenlandic Inuit with ovarian cancer. The mutation introduces a frameshift and a premature stop at codon 1572. We have also identified a BRCA1 nucleotide 249T>A/c.130T>A (p.Cys44Ser) mutation in another Greenlandic individual with ovarian cancer. This patient share a 1-2 Mb genomic fragment, containing the BRCA1 gene, with four Danish families harbouring the same mutation, suggesting that the 249T>A/c.130T>A (p.Cys44Ser) mutation originates from a Danish ancestor. We conclude that screening of Greenlandic Inuits with high risk of breast or ovarian cancer should include sequencing of the entire BRCA1 gene.

Germ-line mutations in the tumour suppressor proteins BRCA1 and BRCA2 predispose to breast and ovarian cancer. We examined 32 breast and/or ovarian cancer patients from Greenland for mutations in BRCA1 and BRCA2. Whereas no mutations were identified in 19 families, 13 families exhibited a BRCA1 exon 3 nucleotide 234 T > G mutation, which has not previously been reported in the breast cancer information core (BIC) database. The mutation changes a conserved cysteine 39 to a glycine in the Zn(2+) site II of the RING domain, which is essential for BRCA1 ubiquitin ligase activity. Eight of the families had members with ovarian cancer, suggesting that the RING domain may be an ovarian cancer hotspot. By SNP array analysis, we find that all 13 families share a 4.5 Mb genomic fragment containing the BRCA1 gene, showing that the mutation originates from a founder. Finally, analysis of 1152 Inuit, representing almost ~2% of the total Greenlandic Inuit population, showed that the frequency of the mutation was 1.0%. We conclude that the BRCA1 nucleotide 234 T > G is a common Greenlandic Inuit founder mutation. The relative high frequency in the general population, together with the ease of screening and possibility to reduce mortality in gene carriers, may warrant screening of the Greenlandic Inuit population. Provided screening is efficient, about 5% of breast- and 13% of ovarian cancers, respectively, may be prevented.

Background: Positive pressure breathing (PPB) is commonly used in modern fighter aircraft as part of the anti-G ensemble. PPB is combined with a chest counterpressure bladder which is pressurized to the same magnitude as the breathing mask (balanced PPB). The chest counterpressure is expected to reduce the expiratory work of breathing, reduce the risk for lung rupture, and increase G tolerance. In a previous study we did not find any effect from chest counterpressure on G tolerance or G endurance. The aim of this study was to investigate the effects of chest counterpressure on the work of breathing and the risk for lung rupture., Methods: Eight male test subjects were exposed to 20-s periods of PPB at +1.0, 5.0, 6.0, 7.0, and 8.0 Gz. Each Gz level was accomplished twice, with and without pressurization of the chest bladder. Inspiratory and expiratory flows were measured and esophageal pressures were measured in the lower and upper third of the thorax. Subsequently, work and power of breathing and apical transpulmonary pressure were estimated., Results: The apical transpulmonary pressure was slightly larger without than with chest counterpressure at 1.0 Gz, while chest counterpressure did not affect apical transpulmonary pressure at increased Gz load. Nor did the chest counterpressure affect work or power of breathing at any Gz load., Conclusion: Inflation of the chest bladder does not seem to have any effects on work or power of breathing or risk for lung rupture during PPB at high Gz loads.

Background: In aviation, vestibular-induced spatial disorientation is a significant cause of accidents. Recreating flight-like vestibular stimuli in simulators might be a means for training pilots to respond adequately in disorienting situations. Due to the physical constraints of land-based simulators, the question arises whether a given illusion may be created in different ways. For instance, is it possible to induce sensations of tilt by rotary stimuli? The present study concerns the relationship between sensations of rotation and tilt during complex vestibular stimulation., Methods: The visual sensation of roll rotation was quantified by means of a velocity-matching procedure. In a large gondola centrifuge eight subjects underwent four runs (2 G, 2 min) with different heading positions (forward, backward, centripetally, and centrifugally). The inclination of the gondola persistently corresponded with the vector sum of the Earth gravity force and the centrifugal force (60 degrees at 2 G). Thus, the semicircular canal stimulus in roll was combined in different ways with stimuli in yaw and pitch, as well as with an increasing or decreasing G vector., Results: The magnitude of the responses was only dependent on the roll component of the stimulus. The gain, defined as the ratio between the response and the roll stimulus, was 7-10%. The responses decayed with a time constant ranging from 4 to 5.5 s., Conclusion: The visual sensation of roll rotation reflects the roll plane canal velocity stimulus independently of other stimulus components. This is in contrast to earlier findings on the sensation of changes in position (roll tilt).

Introduction: G protection in the 39 Gripen aircraft is provided by a full coverage anti-G suit, a pressure-breathing system, and anti-G straining maneuvers (AGSM). The purpose was to study (1) the interaction of pressure breathing and AGSM while wearing an anti-G suit; and (2) the G-protective properties of the anti-G suit alone and in combination with the pressure-breathing system., Methods: During rapid onset rate G-time profiles (< or =9 G), 10 subjects were investigated in 5 conditions: (I) sitting relaxed, without any G-protective garment; (II) sitting relaxed and wearing an anti-G suit; (III) sitting relaxed, wearing an anti-G suit, and pressure breathing; IV) wearing an anti-G suit and performing AGSM; and V) wearing an anti-G suit, pressure breathing, and performing AGSM. In supplementary experiments (n=9), the share of the anti-G suit protection afforded by the abdominal bladder was investigated., Results: G tolerance was 3.4 Gz (range: 2.8-4.3) in condition I, > or = 6.5 Gz (4.5-9.0) in II, > or = 8.0 Gz (6.5-9.0) in III, > or = 8.9 Gz (8.5-9.0) in IV and > or = 9.0 Gz (8.5-9.0) in V. In the supplementary experiments, the anti-G suit afforded a 2.8-G protection, a third of which was contributed by the abdominal bladder. In the relaxed state, pressure applied to the airways was transmitted undistorted to the intrathoracic space. During AGSM, intrathoracic pressure rose to 10-14 kPa, regardless of whether AGSM was performed with or without pressure breathing., Discussion and Conclusions: The anti-G suit and the pressure breathing system provide G protection of > or = 4.6 G, of which the anti-G suit contributes about 3.0 G. The C-protective properties of the anti-G suit and those of pressure breathing appears to be additive, whereas the G protection afforded by pressure breathing does not add to that provided by AGSM.

Background: In agile fighter aircraft positive pressure breathing is commonly used as part of the anti-G ensemble. To optimize G protection and prevent over-distention of the lungs, increased airway pressure is balanced by applying a counterpressure to the chest. The aim was to investigate the efficacy of chest counterpressure., Methods: Three series of experiments were performed using the anti-G ensemble of the 39 Gripen aircraft (AGE-39) and exposing the subjects to 20-s G time profiles; in the first (n = 12) up to +8.0 Gz, in the second (n = 9) up to + 9.0 Gz, and also to simulated aerial combat maneuvers (SACM). Central and peripheral vision, arterial and airway pressures, pressure in the lower portion of the esophagus, and chest wall distension were measured. In the third series, six subjects were exposed to up to +7.0 Gz and esophageal pressure was measured in the upper thorax. In all series, two conditions were compared: with and without pressurized chest bladder., Results: During the 20-s profiles arterial and esophageal pressures, chest wall distension, and visual impairment were similar with and without pressurized chest bladder. Upper esophageal pressure was slightly higher by 10-24% with than without chest bladder (p = 0.03). During SACM, time to exhaustion and the level of perceived exertion were similar with and without pressurized chest bladder., Summary: The results suggest that the chest counterpressure can be removed from the AGE-39 without diminishing G tolerance or G endurance or significantly increasing the risk of lung parenchyma disruption.

Gravito-inertial load in the head-to-foot direction (Gz) and compression of the lower body half by an anti-G suit (AGS) are both known to influence ventilation distribution in the lungs. To study the interaction of Gz and AGS and to asses the separate contributions from lower limbs and abdominal compressions to large and small-scale ventilation inhomogeneities nine males performed SF6/He vital capacity (VC) single-breath washouts at 1, 2, and 3 Gz in a centrifuge, with abdominal and/or lower limbs compressions. SF6/He and (SF6-He) phase III slopes were used for determination of overall and small-scale ventilation inhomogeneity. Closing volume and phase IV height were used as measures of large-scale inhomogeneity. VC decreased marginally with G-load but markedly with lower limbs compression. Small-scale ventilation inhomogeneity increased slightly with G-load, but substantially with AGS pressurization. Small-scale ventilation inhomogeneity increased with AGS pressurization. Large-scale inhomogeneity increased markedly with G-load. Translocation of blood to the lungs might be the key determinant for changes in small-scale ventilation inhomogeneity when pressurizing an AGS.

This study assessed the effects of increased gravity in the head-to-foot direction (+G(z)) and anti-G suit (AGS) pressurization on functional residual capacity (FRC), the volume of trapped gas (V(TG)), and ventilation distribution by using inert- gas washout. Normalized phase III slope (Sn(III)) analysis was used to determine the effects on inter- and intraregional ventilation inhomogeneity. Twelve men performed multiple-breath washouts of SF(6) and He in a human centrifuge at +1 to +3 G(z) wearing an AGS pressurized to 0, 6, or 12 kPa. Hypergravity produced moderately increased FRC, V(TG), and overall and inter- and intraregional inhomogeneities. In normogravity, AGS pressurization resulted in reduced FRC and increased V(TG), overall, and inter- and intraregional inhomogeneities. Inflation of the AGS to 12 kPa at +3 G(z) reduced FRC markedly and caused marked gas trapping and intraregional inhomogeneity, whereas interregional inhomogeneity decreased. In conclusion, increased +G(z) impairs ventilation distribution not only between widely separated lung regions, but also within small lung units. Pressurizing an AGS in hypergravity causes extensive gas trapping accompanied by reduced interregional inhomogeneity and, apparently, results in greater intraregional inhomogeneity.

The influences of body posture and tidal volume (VT) on inter- and intraregional ventilation inhomogeneity were assessed by normalized phase III slope (Sn(III)) analysis of multiple-breath washout recordings of SF(6) and He in 11 healthy men. Washouts with target VT of 750, 1,000, and 1,250 ml were performed standing and supine. A linear-fit method was used to establish the contributions of convection-dependent (interregional) (cdi) and diffusion-convection interaction-dependent (intraregional) inhomogeneity (dcdi). Overall inhomogeneity was defined as the sum of cdi and dcdi. The difference in first-breath Sn(III) for SF(6) vs. He, the (SF(6) - He)Sn(III), served as an index of intra-acinar inhomogeneity. Multiple-regression analysis revealed greater cdi supine vs. standing (P < 0.001) but no significant effects of posture on dcdi or overall inhomogeneity. Larger VT were associated with greater cdi (P < 0.001), particularly when supine, but reduced dcdi (P < 0.001), overall inhomogeneity (P < 0.001), and (SF(6) - He)Sn(III) (P = 0.031). In conclusion, during resting breathing overall and intraregional ventilation inhomogeneities remain unchanged when the supine posture is assumed and improve with larger VT, but supine posture and larger breaths result in greater interregional inhomogeneities.

Background: Platelet-derived growth factor (PDGF), which is a major mitogen for vascular smooth muscle cells and has been implicated in the pathogenesis of arteriosclerosis, is composed of dimers of PDGF-A and PDGF-B polypeptide chains, encoded by different genes. Here, we have analyzed the chromosomal localization, structure, and expression of 2 newly identified human genes of the PDGF family, called PDGFC and PDGFD., Methods and Results: We used fluorescence in situ hybridization to locate PDGFC and PDGFD in chromosomes 4q32 and 11q22.3 to 23.2, respectively. Exon structures of PDGFC and PDGFD were determined by sequencing from genomic DNA clones. The coding region of PDGFC consists of 6 and PDGFD of 7 exons, of which the last 2 encode the C-terminal PDGF cystine knot growth factor homology domain. An N-terminal CUB domain is encoded by exons 2 and 3 of both genes, and a region of proteolytic cleavage involved in releasing and activating the growth factor domain is located in exon 4 in PDGFC and exon 5 in PDGFD. PDGF-C was expressed predominantly in smooth muscle cells and PDGF-D in fibroblastic adventitial cells, and both genes were active in cultured endothelial cells and in a variety of tumor cell lines. Both PDGF-C and PDGF-D also stimulated human coronary artery smooth muscle cells., Conclusions: PDGFC and PDGFD have similar genomic structures, which resemble those of the PDGFA and PDGFB genes. Their expression in the arterial wall and cultured vascular cells suggests that they can transduce proliferation/migration signals to pericytes and smooth muscle cells.

The term 'platelet-derived growth factor' (PDGF) refers to a family of disulphide-bonded dimeric isoforms that are important for growth, survival and function in several types of connective tissue cell. So far, three different PDGF chains have been identified - the classical PDGF-A and PDGF-B and the recently identified PDGF-C. PDGF isoforms (PDGF-AA, AB, BB and CC) exert their cellular effects by differential binding to two receptor tyrosine kinases. The PDGF alpha-receptor (PDGFR-alpha) binds to all three PDGF chains, whereas the beta-receptor (PDGFR-beta) binds only to PDGF-B. Gene-targeting studies using mice have shown that the genes for PDGF-A and PDGF-B, as well as the two PDGFR genes, are essential for normal development. Furthermore, overexpression of PDGFs is linked to different pathological conditions, including malignancies, atherosclerosis and fibroproliferative diseases. Here we have identify and characterize a fourth member of the PDGF family, PDGF-D. PDGF-D has a two-domain structure similar to PDGF-C and is secreted as a disulphide-linked homodimer, PDGF-DD. Upon limited proteolysis, PDGF-DD is activated and becomes a specific agonistic ligand for PDGFR-beta. PDGF-DD is the first known PDGFR-beta-specific ligand, and its unique receptor specificity indicates that it may be important for development and pathophysiology in several organs.