Influence of Hyperoxic-Supplemented High-Intensity Interval Training on Hemotological and Muscle Mitochondrial Adaptations in Trained Cyclists.

Background: Hyperoxia (HYPER) increases O2 carrying capacity resulting in a higher O2 delivery to the working muscles during exercise. Several lines of evidence indicate that lactate metabolism, power output, and endurance are improved by HYPER compared to normoxia (NORM). Since HYPER enables a higher exercise power output compared to NORM and considering the O2 delivery limitation at exercise intensities near to maximum, we hypothesized that hyperoxic-supplemented high-intensity interval training (HIIT) would upregulate muscle mitochondrial oxidative capacity and enhance endurance cycling performance compared to training in normoxia. Methods: 23 trained cyclists, age 35.3 ± 6.4 years, body mass 75.2 ± 9.6 kg, height 179.8 ± 7.9 m, and VO2max 4.5 ± 0.7 L min-1 performed 6 weeks polarized and periodized endurance training on a cycle ergometer consisting of supervised HIIT sessions 3 days/week and additional low-intensity training 2 days/week. Participants were randomly assigned to either HYPER (FIO2 0.30; n = 12) or NORM (FIO2 0.21; n = 11) breathing condition during HIIT. Mitochondrial respiration in permeabilized fibers and isolated mitochondria together with maximal and submaximal VO2, hematological parameters, and self-paced endurance cycling performance were tested pre- and posttraining intervention. Results: Hyperoxic training led to a small, non-significant change in performance compared to normoxic training (HYPER 6.0 ± 3.7%, NORM 2.4 ± 5.0%; p = 0.073, ES = 0.32). This small, beneficial effect on the self-paced endurance cycling performance was not explained by the change in VO2max (HYPER 1.1 ± 3.8%, NORM 0.0 ± 3.7%; p = 0.55, ES = 0.08), blood volume and hemoglobin mass, mitochondrial oxidative phosphorylation capacity (permeabilized fibers: HYPER 27.3 ± 46.0%, NORM 16.5 ± 49.1%; p = 0.37, ES = 3.24 and in isolated mitochondria: HYPER 26.1 ± 80.1%, NORM 15.9 ± 73.3%; p = 0.66, ES = 0.51), or markers of mitochondrial content which were similar between groups post intervention. Conclusions: This study showed that 6 weeks hyperoxic-supplemented HIIT led to marginal gain in cycle performance in already trained cyclists without change in VO2max, blood volume, hemoglobin mass, mitochondrial oxidative phosphorylation capacity, or exercise efficiency. The underlying mechanisms for the potentially meaningful performance effects of hyperoxia training remain unexplained and may raise ethical questions for elite sport.

Craniomaxillofacial osteosarcoma - The role of surgical margins.

BACKGROUND: Osteosarcomas (OS) in the craniomaxillofacial (CMF) region are typically diagnosed at later age than long-bone OS, but they are reported to have better 5-year survival. Curative treatment warrants wide surgical resection, which is often not possible in the CMF region. The purpose of this article is to present a nationwide series of CMF in Finland to discuss the role of surgery. PATIENTS AND METHODS: All 21 CMF OS patients managed in Finland from 1992 to 2009 were included. The mean age was 40 years (range 15-72). Data on patient and tumor characteristics, treatment modalities, and survival were recorded. All patients had a minimum follow-up of 5 years or until death. RESULTS: OS was evenly represented in the mandible and maxillary bones, which together constituted 76% of all sites. Surgery with curative intent was carried out in 20 patients. Clear margins were achieved in only five cases. Eight (40%) of these 20 patients died due to OS, and their average survival time was 1.3 years. Seven (35%) out of the 20 patients received radiotherapy due to close/intralesional surgical margins, and four of them did not develop recurrences during the follow-up. CONCLUSIONS: The results suggest that postoperative radiotherapy may alter the prognosis in CMF OS, particularly in cases with close or intralesional margins. This may increase the survival rates achieved by prompt action in performing radical surgery.

Neurotransmitters behind pain relief with transcranial magnetic stimulation - positron emission tomography evidence for release of endogenous opioids.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) at M1/S1 cortex has been shown to alleviate neuropathic pain. OBJECTIVES: To investigate the possible neurobiological correlates of cortical neurostimulation for the pain relief. METHODS: We studied the effects of M1/S1 rTMS on nociception, brain dopamine D2 and µ-opioid receptors using a randomized, sham-controlled, double-blinded crossover study design and 3D-positron emission tomography (PET). Ten healthy subjects underwent active and sham rTMS treatments to the right M1/S1 cortex with E-field navigated device. Dopamine D2 and µ-receptor availabilities were assessed with PET radiotracers [11 C]raclopride and [11 C]carfentanil after each rTMS treatment. Thermal quantitative sensory testing (QST), contact heat evoked potential (CHEP) and blink reflex (BR) recordings were performed between the PET scans. RESULTS: µ-Opioid receptor availability was lower after active than sham rTMS (P ≤ 0.0001) suggested release of endogenous opioids in the right ventral striatum, medial orbitofrontal, prefrontal and anterior cingulate cortices, and left insula, superior temporal gyrus, dorsolateral prefrontal cortex and precentral gyrus. There were no differences in striatal dopamine D2 receptor availability between active and sham rTMS, consistent with lack of long-lasting measurable dopamine release. Active rTMS potentiated the dopamine-regulated habituation of the BR compared to sham (P = 0.02). Thermal QST and CHEP remained unchanged after active rTMS. CONCLUSIONS: rTMS given to M1/S1 activates the endogenous opioid system in a wide brain network associated with processing of pain and other salient stimuli. Direct enhancement of top-down opioid-mediated inhibition may partly explain the clinical analgesic effects of rTMS. SIGNIFICANCE: Neurobiological correlates of rTMS for the pain relief are unclear. rTMS on M1/S1 with 11 C-carfentanyl-PET activates endogenous opioids. Thermal and heat pain thresholds remain unchanged. rTMS induces top-down opioid-mediated inhibition but not change the sensory discrimination of painful stimuli.

Neck muscle activity in skydivers during parachute opening shock.

This observational study investigated skydiver neck muscle activity during parachute opening shock (POS), as epidemiological data recently suggested neck pain in skydivers to be related to POS. Twenty experienced skydivers performed two terminal velocity skydives each. Surface electromyography quantified muscle activity bilaterally from the anterior neck, the upper and lower posterior neck, and the upper shoulders; and two triaxial accelerometers sampled deceleration. Muscle activity was normalized as the percentage of reference maximum voluntary electrical activity (% MVE); and temporal muscle activity onset was related to POS onset. Our results showed that neck muscle activity during POS reached mean magnitudes of 53-104% MVE, often exceeding reference activity in the lower posterior neck and upper shoulders. All investigated muscle areas' mean temporal onsets occurred <50 ms after POS onset (9-34 ms latencies), which is consistent with anticipatory motor control. The high muscle activity observed supports that the neck is under substantial strain during POS, while temporal muscle activation suggests anticipatory motor control to be a strategy used by skydivers to protect the cervical spine from POS. This study's findings contribute to understanding the high rates of POS-related neck pain, and further support the need for evaluation of neck pain preventative strategies.

A Pilot Study on the Influence of Facial Expression on Measurements in Three-Dimensional Digital Surfaces of the Face in Infants With Cleft Lip and Palate.

OBJECTIVE: Three-dimensional surface imaging is an increasingly popular modality for face measurements in infants with cleft lip and palate. Infants are noncompliant toward producing specific facial expressions, and selecting the appropriate moment of acquisition is challenging. The objective was to estimate amount and spatial distribution of deformation of the face due to facial expression in infants with cleft lip and palate and provide recommendations for an improved acquisition protocol, including a method of quality control in terms of obtaining images with true neutral expression. MATERIAL AND METHODS: Three-dimensional surface images of ten 4-month-old infants with unrepaired cleft lip and palate were obtained using a 3dMDface stereophotogrammetric system. For each subject, five surface images judged as representing a neutral expression were obtained during the same photo session. Mean and maximum deformations were calculated. A formalized review was performed, allowing the image exhibiting the "best" neutral expression to be selected, thus decreasing errors due to residual facial expression. RESULTS: Deformation due to facial expression generally increased from forehead to chin. The amount of deformation in three selected regions were determined: nose (mean, 1 mm; maximum = 3 mm); cleft region (mean, 2 mm; maximum = 5 mm); chin region (mean, 5 mm; maximum = 12 mm). Analysis indicated that introduction of a formalized review of images could reduce these errors by a factor of 2. CONCLUSIONS: The continuous change of facial expression in infants represents a substantial source of error; however, this may be reduced by incorporating a formalized review into the acquisition protocol.

Role of two sequence motifs of mesencephalic astrocyte-derived neurotrophic factor in its survival-promoting activity.

Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a prosurvival protein that protects the cells when applied intracellularly in vitro or extracellularly in vivo. Its protective mechanisms are poorly known. Here we studied the role of two short sequence motifs within the carboxy-(C) terminal domain of MANF in its neuroprotective activity: the CKGC sequence (a CXXC motif) that could be involved in redox reactions, and the C-terminal RTDL sequence, an endoplasmic reticulum (ER) retention signal. We mutated these motifs and analyzed the antiapoptotic effect and intracellular localization of these mutants of MANF when overexpressed in cultured sympathetic or sensory neurons. As an in vivo model for studying the effect of these mutants after their extracellular application, we used the rat model of cerebral ischemia. Even though we found no evidence for oxidoreductase activity of MANF, the mutation of CXXC motif completely abolished its protective effect, showing that this motif is crucial for both MANF's intracellular and extracellular activity. The RTDL motif was not needed for the neuroprotective activity of MANF after its extracellular application in the stroke model in vivo. However, in vitro the deletion of RTDL motif inactivated MANF in the sympathetic neurons where the mutant protein localized to Golgi, but not in the sensory neurons where the mutant localized to the ER, showing that intracellular MANF protects these peripheral neurons in vitro only when localized to the ER.

Primary metastatic Ewing's family tumors: results of the Italian Sarcoma Group and Scandinavian Sarcoma Group ISG/SSG IV Study including myeloablative chemotherapy and total-lung irradiation.

BACKGROUND: The Italian Sarcoma Group and the Scandinavian Sarcoma Group designed a joint study to improve the prognosis for patients with Ewing's family tumors and synchronous metastatic disease limited to the lungs, or the pleura, or a single bone. PATIENTS AND METHODS: The study was opened in 1999 and closed to the enrollment in 2008. The program consisted of intensive five-drug combination chemotherapy, surgery and/or radiotherapy as local treatment, and consolidation treatment with high-dose busulfan/melphalan plus autologous stem cell rescue and total-lung irradiation. RESULTS: During the study period, 102 consecutive patients were enrolled. The median follow-up was 62 months (range 24-124). The 5-year event-free survival probability was 0.43 [standard deviation (SD) = 0.05] and the 5-year overall survival probability was 0.52 (SD = 0.052). Unfavorable prognostic factors emerging on multivariate analysis were a poor histological/radiological response at the site of the primary tumor [relative risk (RR) = 3.4], and incomplete radiological remission of lung metastases after primary chemotherapy (RR = 2.6). One toxic death and one secondary leukemia were recorded. CONCLUSIONS: This intensive approach is feasible and long-term survival is achievable in ∼50% of patients. New treatment approaches are warranted for patients responding poorly to primary chemotherapy.

Determination of residual antiplatelet activity of clopidogrel before neuraxial injections.

BACKGROUND: Guidelines recommend discontinuation of clopidogrel for 7 days before a neuraxial injection, while other directives suggest that 5 days might be adequate. We examined the time course of antiplatelet activity after clopidogrel discontinuation in patients undergoing epidural injections. METHODS: Thirteen patients were studied at baseline, 3, 5, and 7 days after discontinuation of clopidogrel. P(2)Y(12) determinations were performed using the VerifyNow(®) assay (Accumetrics, San Diego, CA, USA), and clot closure times with stimulation by collagen/epinephrine and collagen/adenosine diphosphate using the PFA-100(®) (Platelet Function Analyzer, Siemens Diagnostics, Deerfield, IL, USA). Repeated-measures ANOVA was used to evaluate P(2)Y(12) platelet reaction units, PFA-100 closure times, and per cent P(2)Y(12) inhibition values. Wilcoxon's signed-rank test was used to compare the frequencies of ≥30%, 11-29%, and ≤10% platelet inhibition between the baseline and subsequent sampling points after discontinuation of clopidogrel. RESULTS: On day 3 after clopidogrel discontinuation, two subjects had ≥30%, seven subjects had 11-29%, and four subjects had ≤10% platelet inhibition; the corresponding numbers were 0, 3, and 10 subjects on day 5 (P=0.04). There were no differences between the ≥30%, 11-29%, and <10% platelet inhibition groups between days 5 and 7 (0, 0, and 13 subjects, P=1.0). PFA-ADP closure times were normal throughout the study period except in one patient. CONCLUSIONS: These findings support the recommendation that discontinuation of clopidogrel for 5 days allows >70% of platelet function and might be adequate before a neuraxial injection is performed.

Expression of GATA-6 transcription factor in pleural malignant mesothelioma and metastatic pulmonary adenocarcinoma.

BACKGROUND: Malignant mesothelioma (MM) is a highly aggressive tumour with poor prognosis and limited response to therapy. New markers for the prediction of prognosis in MM and in pulmonary adenocarcinoma of the pleura are valuable. GATA-6 belongs to a six member zinc finger transcription factor family named after their recognition motif W-GATA-R. AIM: To clarify the distribution and possible function of GATA-6 transcription factor in MM and in pleural metastasis of lung adenocarcinomas. METHODS: 63 pleural MM and 36 pleural metastatic pulmonary adenocarcinomas were studied for GATA-6 expression by immunohistochemistry using tissue microarrays. Expression of GATA-6 was examined in relation to thyroid transcription factor-1 expression, survival, proliferation and apoptosis. RESULTS: Nuclear immunoreactivity for GATA-6 was stronger and more frequent in MM than in metastatic pleural adenocarcinoma. Prognosis was better in patients with GATA-6 expression when compared to those with no GATA-6 expression (p = 0.002); in the subgroup analysis the difference was significant in epithelial and sarcomatous mesothelioma. GATA-6 was not associated with spontaneous proliferation or apoptosis of the tumour cells in situ. CONCLUSION: Results suggest that GATA-6 plays a role in pleural malignancies, predicting longer survival in subgroups of MM.

Glossopharyngeal pistoning for lung insufflation in patients with cervical spinal cord injury.

STUDY DESIGN: A prospective cohort study. OBJECTIVES: To evaluate whether patients with cervical spinal cord injury (CSCI) are able to learn the technique of glossopharyngeal pistoning (breathing) for lung insufflation (GI) and if learned, to evaluate the effects of GI on pulmonary function and chest expansion after 8 weeks. SETTING: Karolinska University Hospital, Stockholm, Sweden. METHODS: Twenty-five patients with CSCI (21 men, four women) with a mean age of 46 years (21-70), from the Stockholm area, were used in this study. The participants performed 10 cycles of GI four times a week, for 8 weeks. Pulmonary function tests made before and after the GI training included vital capacity (VC), expiratory reserve volume (ERV), functional residual capacity (FRC; measured with nitrogen washout), residual volume (RV) and total lung capacity (TLC). Chest expansion was measured before and after training. RESULTS: Five of the twenty-five participants had difficulty in performing GI and were excluded in further analysis. Performing a GI maneuvre increased participants' VC on average by 0.88+/-0.5 l. After 8 weeks of training, the participants had significantly increased their VC 0.23 l, (P<0.001), ERV 0.16 l, (P<0.01), FRC 0.86 l, (P<0.001), RV 0.70 l, (P<0.001) and TLC 0.93 l, (P<0.001). Chest expansion increased at the level of the xiphoid process by 1.2 cm (P<0.001) and at the level of the fourth costae by 0.7 cm (P<0.001). CONCLUSIONS: After using GI for a period of 8 weeks, the participants with CSCI who could perform GI were able to improve pulmonary function and chest expansion.

Gene copy number analysis in malignant pleural mesothelioma using oligonucleotide array CGH.

Conventional cytogenetic analyses and comparative genomic hybridization have revealed a complex and even chaotic nature of chromosomal aberrations in pleural malignant mesothelioma (MM). We set out to describe the complex gene copy number changes and screen for novel genetic aberrations using a high-density oligonucleotide microarray platform for comparative genomic hybridization (aCGH) of a series of 26 well-characterized MM tumor samples. The number of copy number changes varied from zero to 40 per sample. Gene copy number losses predominated over gains, and the most frequent region of loss was 9p21.3 (17/26 cases), the locus of CDKN2A and CDKN2B, both known to be commonly lost in MM. The most recurrent minimal regions of losses were 1p31.1--> p13.2, 3p22.1-->p14.2, 6q22.1, 9p21.3, 13cen-->q14.12, 14q22.1-->qter, and 22qcen-->q12.3. Previously unreported gains included 9p13.3, 7p22.3-->p22.2, 12q13.3, and 17q21.32-->qter. The results suggest that gene copy number losses are a major mechanism of MM carcinogenesis and reveal a recurrent pattern of copy number changes in MM.

Etiology of specific molecular alterations in human malignancies.

Cancer results from multiple genomic changes that affect DNA and its gene expression. The DNA sequences may be gained, lost or amplified, or translocated into different parts of the genome to form a fusion gene with oncogenic properties. The occurrence of specific chromosomal aberrations may be restricted to only one cancer type and it may be considered a primary carcinogenic event. Furthermore, the aberration profiles may be used to cluster tumors with similar origins. A variety of techniques exist for the detection of specific chromosomal and gene expression changes. However, the etiology of these molecular alterations remains unclear. Here we discuss the roles of Helicobacter pylori and asbestos burden as carcinogens that cause gastric cancer, mesothelioma and lung cancer.

Resistive respiratory muscle training improves and maintains endurance swimming performance in divers.

Respiratory work is increased during exercise under water and may lead to respiratory muscle fatigue, which in turn can compromise swimming endurance. Previous studies have shown that respiratory muscle training, conducted five days per week for four weeks, improved both respiratory and fin swimming endurance. This training (RRMT-5) consisted of intermittent vital capacity breaths (twice/minute) against spring loaded breathing valves imposing static and resistive loads generating average inspiratory pressures of approximately 40 cmH2O and expiratory pressures of approximately 47 cmH2O. The purpose of the present study (n = 20) was to determine if RRMT 3 days per week (RRMT-3) would give similar improvements, and if continuing RRMT 2 days per week (RRMT-M) would maintain the benefits of RRMT-3 in fit SCUBA divers. Pulmonary function, maximal inspiratory (P(insp)) and expiratory pressures (P(exp)), respiratory endurance (RET), and surface and underwater (4 fsw) fin swimming endurance were determined prior to and after RRMT, and monthly for 3 months. Pulmonary function did not significantly improve after either RRMT-3 or RMMT-5; while P(insp) (20 and 15%) and P(exp) (25 and 11%), RET (73 and 217%), surface (50 and 33%) and underwater (88 and 66%) swim times improved. VO2, VE and breathing frequency decreased during the underwater endurance swims after both RRMT-3 and RRMT-5. During RRMT-M P(insp) and P(exp) and RET and swimming times were maintained at post RRMT-3 levels. RRMT 3 or 5 days per week can be recommended to divers to improve both respiratory and fin swimming endurance, effects which can be maintained with RRMT twice weekly.

Cardiovascular aspects of glossopharyngeal insufflation and exsufflation.

Breath-hold divers use glossopharyngeal breathing to inhale above total lung capacity (glossopharyngeal insufflation, GI) or exhale below residual volume (glossopharyngeal exsufflation, GE). In these maneuvers, air is moved using glossopharyngeal rather than respiratory muscle activity. Four competitive divers performed several GI and GE maneuvers in sitting or standing position, while cardiovascular parameters were measured with a photoplethysmographic method; echocardiography was also performed during GE. During GI, the divers showed a 48% drop in mean arterial pressure (MAP) to 50 mmHg, with a 88% decrease in pulse pressure (PP), while heart rate (HR) increased by 36% to 103 beats/min and cardiac output (CO) dropped by 79% to 1.3 l/min. The increase in intrathoracic pressure during GI, measured in separate experiments, is probably responsible for these hemodynamic changes, by impeding venous return into the chest. Associated with the drop in MAP during GI were various neurological signs and symptoms, including dizziness, tunnel vision, involuntary twitching of facial muscles and one brief episode of loss of consciousness. During GE, initially MAP and PP increased by 36% and 61%, to 149 and 95 mmHg respectively; later HR decreased by 37% to 45 beats/min and CO dropped by 37% to 4.3 l/min. The early cardiovascular changes of GE may be related to a decrease in intrathoracic pressure, enhancing venous return, as shown by a 6 to 15% increase in end-diastolic diameter; later changes are similar to the responses to apnea at low lung volumes. Because of their hemodynamic effects, these breathing maneuvers should be performed with caution, particularly in the case of GI.

Loss of motor control and/or loss of consciousness during breath-hold competitions.

Since the first official world championships in breath-hold diving (1996), a sport has developed where the athletes compete in various disciplines of breath-hold diving. One of the rules is that the diver should surface from a dive without showing any signs of hypoxia. Depending on the severity of hypoxia, a diver may suffer disqualifying signs such as loss of consciousness (LOC) or loss of motor control (LMC), the latter including signs such as confusion, affected postural control, spasms or speech problems. Data was collected from the results of the major international competitions following AIDA guidelines (Association International pour le Dévelopment de l'Apnée) in 1998, 2001-2004. The data was analyzed for frequency of LOC and LMC during constant weight diving and during static apnea. In constant weight diving, the diver swims down (and up) as deeply as possible along a vertically suspended rope (current record 105 m). In static apnea, the diver strives for maximum duration, floating motionless face down in a pool (current record 8.58 min). A total of 601 static apnea (SA) performances and 596 constant weight dives were judged in the six competitions. On average, 10 % of SA, and 11 % of CW performances were disqualified due to signs of hypoxia. For the competitions in 2002-2004, a distinction was made in the rules between LOC and LMC; of a total number of 355 SA performances, 1.1 % resulted in LOC, while 9.6 % resulted in LMC. For CW, the number was 344 with 6.1 % LOC and 6.1 % LMC. Despite the relatively high incidence of dramatic signs, it is noteworthy that there have been no reports of fatal accidents or permanent injuries from any of the above-mentioned competitions. This descriptive paper shows a relatively high incidence of disqualifications due to signs of hypoxia in breath-hold competitions 1998-2004.

The heart rate of breath-hold divers during static apnea: effects of competitive stress.

Breath-hold divers compete with regard to depth, time and/or distance. The present observations were carried out on athletes performing static apnea where they perform one breath-hold for as long a duration as possible with the body and face immersed in water. Heart rate was measured on eight competitors participating in the Swedish Championship in static apnea 2001, both during the competition and during a separate training session using the Polar NV system. The duration of apneas during the competition ranged from 3 minutes 27 seconds to 5 minutes 33 seconds. The divers exhibited significantly faster heart rates prior to and during the first 90 seconds of apnea in connection with competition, than during training. One subject experienced a loss of motor control during the competition. We suggest that mental stress in humans, caused here by a competitive situation, leads to an increase in the heart rate during apnea.

Time components of circulatory transport from the lungs to a peripheral artery in humans.

Blood gas changes occurring in the lung undergo delay and damping on their way to a peripheral artery sampling site. Knowledge of the time components of circulatory transfer is important for the understanding of respiratory control and cardiovascular reflexes in response to blood gas transients. Providing steady state with regard to VA/Q distribution, cardiac output and peripheral blood flow, the relationship between the time courses of small end-tidal and peripheral PO2 changes is determined by the transfer function of the interposed vascular segment. This transfer function, expressed as delay time TD and mean transit time (MTT), was measured in six well-trained subjects, allowing the calculation of arterial time-courses from end-tidal to the reverse. They were studied at rest and during four different dynamic leg exercise intensities in the supine posture. TD and MTT amounted to 15.8 +/- 1.7 (mean +/- SEM) and 18.3 +/- 2.1 s at rest and were shortened to 7.7 +/- 0.6 and 11.5 +/- 1.8 s during exercise at 170 W. The shortening of TD and MTT did not appear to be simply an inverse function of cardiac output, suggesting that the shortening occurs in the central circulatory segment but not in the arm segment.

Effects of IKK inhibitor PS1145 on NF-kappaB function, proliferation, apoptosis and invasion activity in prostate carcinoma cells.

A key antiapoptotic transcription factor, nuclear factor kappa-B (NF-kappaB), is known to be critically important for tumor cell growth, angiogenesis and development of metastatic lesions. We and others showed previously that NF-kappaB transcription factor was constitutively activated in androgen-independent prostate carcinoma (PC) cell lines due to the upregulated activity of inhibitor of NF-kappaB kinases (IKK). In this work, using luciferase assay, electrophoretic mobility shift assay and Northern blot analysis of expression of endogenous kappaB-responsive genes, we demonstrate that a novel highly specific small-molecule IKK inhibitor, PS1145, efficiently inhibited both basal and induced NF-kappaB activity in PC cells. We found that PS1145 induced caspase 3/7-dependent apoptosis in PC cells and significantly sensitized PC cells to apoptosis induced by tumor necrosis factor alpha. We also showed that PS1145 inhibited PC cell proliferation. Effects of PS1145 on proliferation and apoptosis correlated with inhibition of interleukin (IL)-6, cyclin D1, D2, inhibitor of apoptosis (IAP)-1 and IAP-2 gene expression and decreased IL-6 protein level. In addition, we found that incubation with PS1145 inhibited the invasion activity of highly invasive PC3-S cells in invasion chamber assay in a dose-dependent manner. Overall, this study provides the framework for development of a novel therapeutic approach targeting NF-kappaB transcription factor to treat advanced PC.

Alveolar gas composition before and after maximal breath-holds in competitive divers.

The urge to breathe, as stimulated by hypercapnia, is generally considered to cause a breath-hold diver to end the breath-hold, and pre-breath hold hyperventilation has been suggested to cause hypoxic loss of consciousness (LOC) due to the reduced urge to breathe. Competitors hyperventilate before "Static Apnea", yet only 10% surface with symptoms of hypoxia such as loss of motor control (LMC) or LOC. We hypothesized that the extensive hyperventilation would prevent hypercapnia even during prolonged breath-holding and we also recorded breaking-point end-tidal PO2 in humans. Nine breath-hold divers performed breath-holds of maximal duration according to their chosen "Static Apnea" procedure. They floated face down in a swimming pool (28 degrees C). The only non-standard procedure was that they exhaled into a sampling tube for end-expiratory air, before starting the breath-hold and before resuming breathing. Breath-hold duration was 284 +/- 25 (SD) seconds. End-tidal PCO2 was 18.9 +/- 2.0 mmHg before apnea and 38.3 +/- 4.7 mmHg at apnea termination. End-tidal PO2 was 131.7 +/- 2.7 mmHg before apnea and 26.9 +/- 7.5 mmHg at apnea termination. Two of the subjects showed LMC after exhaling into the sampling tube; their end-tidal PAO2 values were 19.6 and 21.0 mmHg, respectively. End-tidal CO2 was normocapnic or hypocapnic at the termination of breath-holds. These data suggest that the athletes rely primarily on the hypoxic stimuli, probably in interaction with CO2 stimuli to determine when to end breath-holds. The severity of hypoxia close to LOC was similar to that reported for acute hypobaric hypoxia in humans.

Effects of respiratory muscle training on respiratory CO2 sensitivity in SCUBA divers.

Typically, ventilation is tightly matched to CO2 production. However, in some cases CO2 is retained (SCUBA diving). One factor behind hypoventilation in divers may be low respiratory CO2 sensitivity. If this is due to inadequate respiratory muscle performance it might be remedied by respiratory muscle training (RMT). We retrospectively investigated respiratory CO2 sensitivity prior to and after RMT in several groups of SCUBA divers. CO2 sensitivity (slope of expired ventilation as a function of inspired PCO2) was measured with a rebreathing technique in 35 subjects with diving experience. RMT consisted of either isocapnic hyperventilation or intermittent vital capacity breaths (twice/minute) against spring loaded breathing valves imposing static and resistive loads generating average inspiratory pressures of approximately 40 cmH2O and expiratory pressures of approximately 47 cmH2O; RMT was performed 30 min/day, 3 or 5 days/week for 4 weeks. Based on pre-RMT CO2 sensitivity the subjects were divided into three groups: low sensitivity: < 2 l/min/mmHg PCO2, normal: 2-4 l/min/mmHg, and high sensitivity: > 4 l/min/mmHg of inspired PCO2. The normal group had a Pre-RMT CO2 sensitivity of 2.88 +/- 0.60 and a post RMT sensitivity of 2.51 +/- 0.88 l/min/mmHg (Mean +/- SD, n = 19, p = n.s). Response in low sensitivity subjects increased from 1.41 +/- 0.32 to 2.27 +/- 0.53 (n = 10, p = 0.002,) while in the high sensitivity group it decreased from 5.41 +/- 1.25 to 2.90 +/- 0.32 l/min/mmHg (n = 6, p = 0.003). These preliminary findings showed that 46% of the subjects had abnormal sensitivity, and suggest that RMT may normalize it in hypo- and hyper-ventilating divers. If the present results are verified, RMT may be an effective means of enhancing safety in CO2 retaining divers.