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Summerfield, Douglas T., Kirsten E. Coffman, Bryan J. Taylor, Amine N. Issa, and Bruce D. Johnson. Exhaled nitric oxide changes during acclimatization to high altitude: a descriptive study. High Alt Med Biol. 19:215-220, 2018.This study describes differences in the partial pressures of exhaled nitric oxide (PeNO) between subjects fully acclimatized (ACC) to 5300 m and those who have just arrived to high altitude.PeNO was determined in eight subjects newly exposed and nonacclimatized (non-ACC) to high altitude and compared with that in nine subjects who had ACC to high altitude for 1 month. In addition, systolic pulmonary artery pressure (sPAP) and arterial oxygen saturation (SaOPeNO levels on day 1 were significantly higher in the non-ACC versus ACC cohort (8.7 ± 3.5 vs. 3.9 ± 2.2 nmHg, p = 0.004). As the non-ACC group remained at altitude, PeNO levels fell and were not different when compared with those of the ACC group by day 9 (5.9 ± 2.4 vs. 3.9 ± 2.2 nmHg, p = 0.095). Higher sPAP was correlated with lower PeNO levels in all participants (R = -0.50, p = 0.043). PeNO levels were not correlated with SaOAs individuals acclimatized to high altitude, PeNO levels decreased. Even after acclimatization, PeNO levels continued to play a role in pulmonary vascular tone.

We aimed to assess lung fluid balance before and after gradual ascent to 5150m. Lung diffusion capacity for carbon monoxide (DLCO), alveolar-capillary membrane conductance (DmCO) and ultrasound lung comets (ULCs) were assessed in 12 healthy lowlanders at sea-level, and on Day 1, Day 5 and Day 9 after arrival at Mount Everest Base Camp (EBC). EBC was reached following an 8-day hike at progressively increasing altitudes starting at 2860m. DLCO was unchanged from sea-level to Day 1 at EBC, but increased on Day 5 (11±10%) and Day 9 (10±9%) vs. sea-level (P≤0.047). DmCO increased from sea-level to Day 1 (9±6%), Day 5 (12±8%), and Day 9 (17±11%) (all P≤0.001) at EBC. There was no change in ULCs from sea-level to Day 1, Day 5 and Day 9 at EBC. These data provide evidence that interstitial lung fluid remains stable or may even decrease relative to at sea-level following 8days of gradual exposure to high-altitude in healthy humans.

High-altitude ascent induces left (LV) and right (RV) ventricular adaptations secondary to hypoxia-related hemodynamic and myocardial alterations. Since cardiopulmonary decrements observed with aging (e.g., decreased LV compliance and increased pulmonary vascular resistance) may limit cardiac plasticity, this study examined myocardial adaptability throughout an 11 day sojourn to 5893 m in young and older-aged trekkers.Echocardiography was performed on 14 young (8 men; 32 ± 5 years) and 13 older-aged (8 men; 59 ± 5 years) subjects on non-trekking days (Day 0: 880 m; Day 3: 3100 m; Day 8: 4800 m; Day 12/post-climb: 880 m). RV systolic pressure (mmHg) was systematically higher in older-aged subjects (p 0.01) with similar progressive increases observed during ascent for young and older subjects, respectively (Day 0: 18 ± 1 vs 20 ± 2; Day 3: 25 ± 2 vs 29 ± 3; Day 8: 30 ± 2 vs 35 ± 2). Estimates of LV filling pressure (E/E') were systematically higher in older subjects (p 0.01) with similar progressive decreases observed during ascent for young and older-aged subjects, respectively (Day 0: 5.6 ± 0.3 vs 6.7 ± 0.5; Day 3: 5.1 ± 0.2 vs 6.1 ± 0.3; Day 8: 4.7 ± 0.3 vs 5.4 ± 0.3). Overall, RV end-diastolic and end-systolic area increased at altitude (p 0.01), while LV end-diastolic and end-systolic volume decreased (p 0.01). However, all RV and LV morphological measures were similar on Day 3 and Day 8 (p 0.05), and returned to baseline post-climb (p 0.05). Excluding mild LV dilatation in some older-aged trekkers on Day 8/Day 12 (p 0.01), altitude-induced morphological and functional adaptations were similar for all trekkers (p 0.05).Altitude-induced myocardial adaptations are chamber specific, secondary to RV and LV hemodynamic alterations. Despite progressive hemodynamic alterations during ascent, morphological and functional cardiac perturbations plateaued, suggesting rapid myocardial adaptation which was mostly comparable in young and older-aged individuals.

Background and Objectives: This study aimed to investigate the possible association between exclusive breastfeeding duration during early infancy and susceptibility to allergy and influenza in adulthood. Furthermore, we also investigated the association of breastfeeding duration with DNA methylation at two sites in the promoter of the toll-like receptor-1 (TLR1) gene, as well as the association between DNA methylation of the toll-like receptor-1 (TLR1) gene and susceptibility to different diseases. Materials and Methods: Blood samples were collected from 100 adults and classified into two groups according to breastfeeding duration (

Aim The purpose of this study was to evaluate whether the open apex measurements of the lower teeth can be used for prediction of the pubertal growth spurt. Materials and methods The study group consisted of 150 males and 142 females ranging in age from 10 to 16 years. A total of 292 panoramic and 292 hand-wrist radiographs were obtained and analyzed. The skeletal maturity was determined according to the skeletal maturity indicators (SMIs) developed by Fishman. The open apices measurements of the left lower teeth were made according to the method described by Cameriere. Results The Spearman rank order correlation coefficient revealed a relationship between the skeletal maturity stages and the open apex measurements. These correlations ranged from 0.577 for the lower second premolar to 0.830 for the lower canine. The measurement of the left lower canine showed the highest correlation, so its relationship with the SMIs was further investigated. The measurements of 6.07 (or greater) indicated to SMI4, and 2.485 (or lesser) indicated to SMI7. Conclusion The skeletal maturity well related to the measurements of the open apices of the lower teeth. Lower canine open apex measurements could be used as an indicator of the SMI4 and SMI7. Clinical significance The measurements of the open apices of the left lower canines from panoramic radiographs may be clinically useful as an indicator of the beginning and the ending of the pubertal growth period. How to cite this article Issa YN, Burhan AS, Nawaya FR, Massouh LG. Assessment of the Pubertal Growth Period using the Open Apices of the Lower Teeth. J Contemp Dent Pract 2017;18(1):16-22.

Local control for Ewing sarcoma (ES) has improved in modern studies. However, it is unclear if these gains have also been achieved for pelvis tumors. The purpose of this study is to evaluate local control and survival in pelvis ES patients treated in the modern era.All pelvis ES patients diagnosed from 1990 to 2012 and seen at Mayo Clinic were identified. Factors relevant to survival and local control were analyzed.The cohort consisted of 48 patients. Fifty-two percent had metastatic disease at diagnosis. The 5-year overall survival and event-free survival was 73% and 65%, respectively, for localized disease. The 5-year cumulative incidence of local recurrence was 19%, with a 26% incidence for radiation, 13% for surgery, and 0% for surgery + radiation (P = 0.54). All local failures occurred in-field. Sacral involvement by tumor trended toward a higher incidence of local recurrence (hazard ratio 3.06, P = 0.09). Patients treated with definitive radiation doses ≥5,600 cGy had a lower incidence of local recurrence (17% vs. 28%, P = 0.61).Our study demonstrates excellent survival for localized tumors in the modern era. Anatomical localization within the pelvis likely correlates with outcomes. Local control remains problematic, especially for patients treated with definitive radiation. Though statistically not significant, surgery + radiation and definitive radiation dose ≥5,600 cGy were associated with the lowest incidence of local failure, suggesting treatment intensification may improve local control for pelvis ES.

Ligation under vision (LUV) is a simple method for the surgical treatment of haemorrhoids. In this study, we evaluated the results of our initial experience with the procedure in terms of postoperative pain, patients' final satisfaction and complications. We reviewed a group of patients who had undergone suture ligation of symptomatic haemorrhoids of grade II and III. This was performed with the haemorrhoids under direct vision and without the use of any ancillary instrumentation such as a Doppler sensor. All interventions were performed in the day-care surgical unit using general or regional anaesthesia. Surgical outcome and degree of postoperative pain were determined from outpatient clinic follow-up and individual phone interviews. A total of 32 patients (19 men and 13 women) with a mean age of 59 years had undergone LUV. There were 23 patients (72%) with grade II and 9 patients (28%) with grade III haemorrhoids. The indication for the surgery was bleeding in 19 patients (59%), prolapse in 6 (19%) and both in 7 (22%). A previous rubber band ligation had been carried out in 17 patients (53%). On average, the surgery took 22 min. All patients were discharged on the same day. Four %patients (12%) suffered only mild postoperative pain, 14 (44%) suffered from moderate pain and another 14 (44%) had severe pain. At follow-up (median 21 months, range 9-33 months), 28 %patients (87.5%) were completely asymptomatic at the time of the phone interview. The final result was assessed as excellent by 19 patients (60%), successful by 10 (31%), and unsuccessful by 3 (9%). All patients had complete functional recovery and there were no major surgical complications. Our data show that LUV of symptomatic haemorrhoids is a simple and safe procedure. It can be performed as effective isolated surgery for symptomatic haemorrhoids and as an additional procedure in the treatment of complex perianal pathology.

Purpose We determined whether well-acclimatized humans have a reserve to recruit pulmonary capillaries in response to exercise at high altitude. Methods At sea level, lung diffusing capacity for carbon monoxide (DLCO), alveolar-capillary membrane conductance (DmCO), and pulmonary capillary blood volume (Vc) were measured at rest before maximal oxygen consumption (\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\dot{V}{\text{O}}_{2\hbox{max} }$$\end{document}V˙O2max) was determined in seven adults. Then, DLCO, DmCO and Vc were measured pre- and post-exhaustive incremental exercise at 5150 m after ~40 days of acclimatization. Results Immediately after exercise at high altitude, there was an increase in group mean DmCO (14 ± 10 %, P = 0.040) with no pre- to post-exercise change in group mean DLCO (46.9 ± 5.8 vs. 50.6 ± 9.6 ml/min/mmHg, P = 0.213) or Vc (151 ± 28 vs. 158 ± 37 ml, P = 0.693). There was, however, a ~20 % increase in DLCO from pre- to post-exercise at high altitude (51.2 ± 0.2 vs. 61.1 ± 0.2 ml/min/mmHg) with a concomitant increase in DmCO (123 ± 2 vs. 156 ± 4 ml/min/mmHg) and Vc (157 ± 3 vs. 180 ± 8 ml) in 2 of the 7 participants. There was a significant positive relationship between the decrease in \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\dot{V}{\text{O}}_{2\hbox{max} }$$\end{document}V˙O2max from sea level to high altitude and the change in DLCO and lung diffusing capacity for nitric oxide (DLNO) from rest to end-exercise at high altitude. Conclusion These data suggest that recruitment of the pulmonary capillaries in response to exercise at high altitude is limited in most well-acclimatized humans but that any such a reserve may be associated with better exercise capacity.

INTRODUCTION Recent physiological incidents involving pilots of high performance fighter aircraft have raised the question of whether inadvertent, short bursts of significantly reduced oxygen could negatively impact real-time performance. This study evaluated normobaric, real-time performance in the setting of transient near-anoxia to inform future countermeasure development. METHODS The study was performed on 12 healthy subjects without significant medical history. Following collection of baseline data, real-time performance changes were evaluated during sequentially increasing periods of near-anoxic gas exposure (F(I)0(2) = 1%) using a computer-based performance assessment tool. Both room air and 100% oxygen were used as the prebreathe/recovery gases. Statistical analysis was performed on the results. RESULTS Under normobaric conditions, subjects inspiring up to five near-anoxic breaths showed no significant performance decrement in either accuracy or effective actions per minute. Mean accuracy up to five near-anoxic breaths was 0.67 (SD = 0.01) as compared to a baseline mean of 0.68 (SD = 0.02). Hyperoxia had a protective effect on subject physiological response to near anoxia. DISCUSSION These normobaric findings offer an assessment of real-time performance changes in the setting of transient, near-anoxic gas exposure. Overall, the results help inform the design of increasingly complex aircraft oxygen delivery systems in terms of how tightly such systems must match the sea-level gas equivalent with increasing altitude. This is particularly relevant as such systems are being called upon to ensure safe aircrew operations across an expanding operational flight envelope.

Introduction Targeting receptor tyrosine kinases (RTKs) with kinase inhibitors is a clinically validated anti-cancer approach. However, blocking one signaling pathway is often not sufficient to cause tumor regression and the effectiveness of individual inhibitors is often short-lived. As alterations in fibroblast growth factor receptor (FGFR) activity have been implicated in breast cancer, we examined in breast cancer models with autocrine FGFR activity the impact of targeting FGFRs in vivo with a selective kinase inhibitor in combination with an inhibitor of PI3K/mTOR or with a pan-ErbB inhibitor. Methods Using 4T1 or 67NR models of basal-like breast cancer, tumor growth was measured in mice treated with an FGFR inhibitor (dovitinib/TKI258), a PI3K/mTOR inhibitor (NVP-BEZ235) or a pan-ErbB inhibitor (AEE788) individually or in combination. To uncover mechanisms underlying inhibitor action, signaling pathway activity was examined in tumor lysates and transcriptome analysis carried out to identify pathways upregulated by FGFR inhibition. Anti-phosphotyrosine receptor antibody arrays (P-Tyr RTK) were also used to screen 4T1 tumors. Results The combination of dovitinib + NVP-BEZ235 causes tumor stasis and strong down-regulation of the FRS2/Erk and PI3K/Akt/mTOR signaling pathways. P-Tyr RTK arrays identified high levels of P-EGFR and P-ErbB2 in 4T1 tumors. Testing AEE788 in the tumor models revealed that the combination of dovitinib + AEE788 resulted in blockade of the PI3K/Akt/mTOR pathway, prolonged tumor stasis and in the 4T1 model, a significant decrease in lung metastasis. The results show that in vivo these breast cancer models become dependent upon co-activation of FGFR and ErbB receptors for PI3K pathway activity. Conclusions The work presented here shows that in the breast cancer models examined, the combination of dovitinib + NVP-BEZ235 or dovitinib + AEE788 results in strong inhibition of tumor growth and a block in metastatic spread. Only these combinations strongly down-regulate the FGFR/FRS2/Erk and PI3K/Akt/mTOR signaling pathways. The resultant decrease in mitosis and increase in apoptosis was consistently stronger in the dovitinib + AEE788 treatment-group, suggesting that targeting ErbB receptors has broader downstream effects compared to targeting only PI3K/mTOR. Considering that sub-classes of human breast tumors co-express ErbB receptors and FGFRs, these results have implications for targeted therapy.

Gangliogliomas comprise less than 1% of all brain tumors and occur most often in children. Therefore, there are a limited number of patients and data involving the use or role of adjuvant therapy after subtotal resections (STRs) of gangliogliomas. The objective of this study was to examine and review the Mayo Clinic experience of 88 patients with gangliogliomas, their follow-up, risk of recurrence, and the role of radiation therapy after STR or only biopsy.Eighty-eight patients with gangliogliomas diagnosed between 1970 and 2007 were reviewed. Data on clinical outcomes and therapy received were analyzed. The Kaplan-Meier method was used to estimate progression-free survival (PFS) and overall survival.The median age at diagnosis was 19 years. The median potential follow-up as of June 2008 was 142 months (range 9-416 months). Fifteen-year overall survival was 94%, median PFS was 5.6 years, with a 10-year PFS rate of 37%. Progression-free survival was dramatically affected by extent of initial resection (p0.0001).This single-institution retrospective series of patients with gangliogliomas is unique given its large cohort size with a long follow-up duration, and confirms the excellent long-term survival rate in this group. The study also shows the importance of resection extent on likelihood of recurrence. Patients with gangliogliomas who undergo STR or biopsy alone have poor PFS. Radiation therapy may delay time to progression in patients with unresectable disease.