Recurrent Pulmonary Embolism at High Altitude in a Mountaineer with Hereditary Thrombophilia.

Szymczak, Robert K., Magdalena Sawicka, and Malgorzata Jelitto. Recurrent pulmonary embolism at high altitude in a mountaineer with hereditary thrombophilia. High Alt Med Biol. 00:000-000, 2024.-It is speculated that high-altitude travel is an independent risk factor for thrombosis. Mountaineering-specific factors, such as hypoxia, cold, and immobilization, may interact with patient-specific risk factors and contribute to thrombus formation. We present the case of a mountaineer with hereditary thrombophilia who experienced recurrent pulmonary embolism during high-altitude expeditions.

Impact of lead position on tricuspid regurgitation, ventricular function, and heart failure exacerbation and mortality after cardiac implantable electronic device implantation. Preliminary results from the PACE-RVTR Registry.

BACKGROUND: The most frequent mechanism of lead-related tricuspid regurgitation (LRTR), which occurs in 7.2% to 44.7% of patients implanted with a cardiac implantable electronic device (CIED), is leaflet impingement or the restriction of its movement by a ventricular lead. It is unclear if the position of the lead tip - in the right ventricular apex (RVA) or other location (non-RVA) - has any influence on the development of LRTR. The study aimed to determine the impact of the CIED lead tip position on the development or progression of tricuspid regurgitation (TR) and its potential impact on heart failure exacerbation and mortality. METHODS: One hundred and two consecutive patients who received CIEDs between March 2020 and October 2021 were included in the prospective registry (PACE-RVTR). Patients were assigned to two groups depending on the lead position - the RVA group and the non-RVA group. All patients underwent echocardiographic evaluation before implantation and one year later. RESULTS: In terms of baseline clinical characteristics, the two groups did not differ. Before CIED implantation, patients in the non-RVA group had better left ventricular systolic function (P = 0.004). Pacemakers were implanted more often in the non-RVA group (P = 0.001) while implantable cardioverter-defibrillators in the RVA group (P = 0.008). Progression to severe or massive TR was more common in the non-RVA group (P = 0.005). CONCLUSION: Severe and massive TR occurred more often in patients with the non-RVA position of the lead. The right ventricular lead position did not impact heart failure progression or all-cause mortality at two-year follow-up.

The preliminary study suggests an association between NF-ĸB pathway activation and increased plasma 20S proteasome activity in intracranial aneurysm patients.

The significant role of increased activation of 20S proteasomes in the development of abdominal aortic aneurysms has been well-established in a mouse model. The available literature lacks similar studies concerning brain aneurysms. The aim of the study was to verify the hypothesis that patients with unruptured intracranial aneurysms (UIA) have increased 20S proteasome ChT-L activity compared to the control group of individuals without vascular lesions in the brain. In the next step, the relationship between the activity of 20S proteasomes ChT-L and precursor proteins from the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) family, namely NF-κB1 (p105), NF-κB2 (p100), NF-κB p65, and the inflammatory chemokine MCP-1, was examined. Patients with UIA had significantly higher 20S ChT-L proteasome activity compared to the control group. Patients with multiple aneurysms had significantly higher 20S proteasome ChT-L activity compared to those with single aneurysms. In patients with UIA, the activity of the 20S proteasome ChT-L negatively correlated with the concentration of NF-κB1 (p105) and NF-κB p65 precursor proteins and positively correlated with the concentration of the cerebrospinal fluid chemokine MCP-1. Our results may suggest that increased 20S proteasome ChT-L activity in UIA patients modulates inflammation in the cerebral arterial vessel via the MCP-1 chemokine as a result of activation of the canonical NF-κB pathway.

Proline Metabolism in WHO G4 Gliomas Is Altered as Compared to Unaffected Brain Tissue.

Proline metabolism has been identified as a significant player in several neoplasms, but knowledge of its role in gliomas is limited despite it providing a promising line of pursuit. Data on proline metabolism in the brain are somewhat historical. This study aims to investigate alterations of proline metabolism in gliomas of WHO grade 4 (GG4) in the context of the brain. A total of 20 pairs of samples were studied, consisting of excised tumor and unaffected brain tissue, obtained when partial brain resection was required to reach deep-seated lesions. Levels of proline oxidase/proline dehydrogenase (POX/PRODH), Δ1-pyrroline-5-carboxylate reductases (PYCR1/2/3), prolidase (PEPD), and metalloproteinases (MMP-2, MMP-9) were assessed, along with the concentration of proline and proline-related metabolites. In comparison to normal brain tissue, POX/PRODH expression in GG4 was found to be suppressed, while PYCR1 expression and activity of PEPD, MMP-2, and -9 were upregulated. The GG4 proline concentration was 358% higher. Hence, rewiring of the proline metabolism in GG4 was confirmed for the first time, with a low-POX/PRODH/high-PYCR profile. High PEPD and MMPs activity is in keeping with GG4-increased collagen turnover and local aggressiveness. Further studies on the mechanisms of the interplay between altered proline metabolism and the GG4 microenvironment are warranted.

Tricuspid Regurgitation (TR) after Implantation of a Cardiac Implantable Electronic Device (CIED)-One-Year Observation of Patients with or without Left Ventricular Dysfunction.

The frequency of tricuspid regurgitation (TR) progression after cardiac implantable electronic devices (CIEDs) implantation varies from 7.2% to 44.7%. TR is associated with increased mortality and hospitalizations due to heart failure (HF) decompensation. The aim of this study was to assess the rate of early TR progression after CIED implantation and the frequency of HF decompensation and mortality. The 101 patients, who received a CIED between March 2020 and October 2021, before the procedure were divided into two groups-one with left ventricle ejection fraction (LVEF) ≥ 40% (n = 60) and one with LVEF < 40% (n = 41). Lead-related tricuspid regurgitation (LRTR) was defined as an increase of TR by at least one grade. The follow-up period was similar between both groups and was on average 13 (12-16) months. In the whole study group, TR progression by one grade was 34.6% and by two or more grades 15.8%. The significant changes in the dynamic of TR degree were as follows before and after implantation: none/trivial TR in group 1 (61.7% vs. 28.3%, p = 0.01) and severe/massive TR in group 2 (0.0% vs. 14.6%, p = 0.03). The groups did not differ from each other in terms of survival from decompensation of HF (18.3% vs. 36.6%, p = 0.70) and survival from death (1.7% vs. 4.9%, p = 0.16). At the one-year follow-up, the baseline LVEF did not affect the survival rate from death or HF decompensation among patients with a progression of TR after CIED implantation. In this study, a progression by one grade was more common in group 1, but the occurrence of severe/massive TR after implantation was more specific for group 2.

Lead-related tricuspid regurgitation and ventricle dysfunction: Current management and future perspectives.

The implantation of cardiac implantable electronic devices (CIEDs) may result in or worsen previously existing tricuspid regurgitation (TR). The prevelence of lead-related tricuspid regurgitation (LRTR) in patients with CIEDs is between 7.2% and 44.7% when the degree of worsening TR is not reported, or from 9.8% and 38% when it is diagnosed as worsening of TR severity by at least 2 grades after a CIED has been implanted. It has been suggested that a CIED lead positioned over or pinning a leaflet may be the main cause of TR in this patient population. The septal and posterior leaflets of the tricuspid valve have been reported to be the most affected by CIED leads. Severe LRTR is related to the development of heart failure (HF) or worsening of previously existing dysfunction; it is also associated with elevated mortality. However, there are no definitive predictors of LRTR development or standardized methods of treatment. Some studies have suggested that imaging-guided lead placement can reduce the occurrence of LRTR. This review summarizes current knowledge concerning the development, evaluation, consequences, and management of LRTR.

Is depression the missing link between inflammatory mediators and cancer?

Patients with cancer are at greater risk of developing depression in comparison to the general population and this is associated with serious adverse effects, such as poorer quality of life, worse prognosis and higher mortality. Although the relationship between depression and cancer is now well established, a common underlying pathophysiological mechanism between the two conditions is yet to be elucidated. Existing theories of depression, based on monoamine neurotransmitter system dysfunction, are insufficient as explanations of the disorder. Recent advances have implicated neuroinflammatory mechanisms in the etiology of depression and it has been demonstrated that inflammation at a peripheral level may be mirrored centrally in astrocytes and microglia serving to promote chronic levels of inflammation in the brain. Three major routes to depression in cancer in which proinflammatory mediators are implicated, seem likely. Activation of the kynurenine pathway involving cytokines, increases tryptophan catabolism, resulting in diminished levels of serotonin which is widely acknowledged as being the hallmark of depression. It also results in neurotoxic effects on brain regions thought to be involved in the evolution of major depression. Proinflammatory mediators also play a crucial role in impairing regulatory glucocorticoid mediated feedback of the hypothalamic-pituitary-adrenal axis, which is activated by stress and considered to be involved in both depression and cancer. The third route is via the glutamatergic pathway, whereby glutamate excitotoxicity may lead to depression associated with cancer. A better understanding of the mechanisms underlying these dysregulated and other newly emerging pathways may provide a rationale for therapeutic targeting, serving to improve the care of cancer patients.

Proline Metabolism in Malignant Gliomas: A Systematic Literature Review.

BACKGROUND: Proline has attracted growing interest because of its diverse influence on tumor metabolism and the discovery of the regulatory mechanisms that appear to be involved. In contrast to general oncology, data on proline metabolism in central nervous system malignancies are limited. MATERIALS AND METHODS: We performed a systematic literature review of the MEDLINE and EMBASE databases according to PRISMA guidelines, searching for articles concerning proline metabolism in malignant glial tumors. From 815 search results, we identified 14 studies pertaining to this topic. RESULTS: The role of the proline cycle in maintaining redox balance in IDH-mutated gliomas has been convincingly demonstrated. Proline is involved in restoring levels of glutamate, the main glial excitatory neurotransmitter. Proline oxidase influences two major signaling pathways: p53 and NF- κB. In metabolomics studies, the metabolism of proline and its link to the urea cycle was found to be a prognostic factor for survival and a marker of malignancy. Data on the prolidase concentration in the serum of glioblastoma patients are contradictory. CONCLUSIONS: Despite a paucity of studies in the literature, the available data are interesting enough to encourage further research, especially in terms of extrapolating what we have learned of proline functions from other neoplasms to malignant gliomas.

Proline Dehydrogenase/Proline Oxidase (PRODH/POX) Is Involved in the Mechanism of Metformin-Induced Apoptosis in C32 Melanoma Cell Line.

The role of proline dehydrogenase/proline oxidase (PRODH/POX) in the mechanism of antineoplastic activity of metformin (MET) was studied in C32 melanoma cells. PRODH/POX is a mitochondrial enzyme-degrading proline that is implicated in the regulation of cancer cell survival/apoptosis. The enzyme is activated by AMP kinase (AMPK). It has been found that MET induced a significant decrease in cell viability and DNA biosynthesis accompanied by an increase in the expressions of AMPK and PRODH/POX in C32 cells. The mechanism for MET-dependent cytotoxicity on C32 cells was found at the level of PRODH/POX-induced ROS generation and activation of Caspase-3 and Caspase-9 expressions in these cells. The effects were not observed in MET-treated PRODH/POX knock-out C32 cells. Of interest is an MET-dependent increase in the concentration of proline, which is a substrate for PRODH/POX. This phenomenon is due to the MET-dependent inhibition of collagen biosynthesis, which is the main proline-utilizing process. It has been found that the underlying mechanism of anticancer activity of MET involves the activation of AMPK, PRODH/POX, increase in the cytoplasmic concentration of proline, inhibition of collagen biosynthesis, and stimulation of PRODH/POX-dependent ROS generation, which initiate the apoptosis of melanoma cells.

Transient and Recurrent Vision Loss in a High-Altitude Porter from Pakistan on a Polish Winter Karakoram Expedition.

Visual sensations appear in most migraine auras, but binocular blindness is uncommon. We described a case of multiple transient losses of vision in a man on a winter expedition to K2. His symptoms were later diagnosed as recurrent visual auras without pain. Sojourns at altitude can induce migraine attack; therefore, susceptible individuals should avoid factors that might provoke migraines at high altitude, such as improper acclimatization, dehydration and an inadequate sleep regime.

Urinary Beta-2-Microglobulin and Late Nephrotoxicity in Childhood Cancer Survivors.

The objectives of this study were to evaluate urinary beta-2-microglobulin (ß2M) levels in long-term childhood cancer survivors and to establish its association with anticancer drug-induced nephrotoxicity. The study consisted of 165 childhood cancer survivors (CCS) who were in continuous complete remission. We reported that CCS had a significantly higher level of ß2M (p < 0.001) and ß2M/Cr. ratio (p < 0.05) than healthy peers. Among all participants, 24 (14.5%) had decreased eGFR (<90 mL/min/1.73 m2). A significant positive correlation between ß2M/Cr. ratio and body mass index (coef. 14.48, p = 0.046) was found. Furthermore, higher levels of urinary ß2M were detected among CCS with a longer follow-up time (over 5 years) after treatment. Subjects with decreased eGFR showed statistically higher urinary ß2M levels (20.06 ± 21.56 ng/mL vs. 8.55 ± 3.65 ng/mL, p = 0.007) compared with the healthy peers. Twelve survivors (7.2%) presented hyperfiltration and they had higher urinary ß2M levels than CCS with normal glomerular filtration (46.33 ± 93.11 vs. 8.55 ± 3.65 ng/mL, p = 0.029). This study did not reveal an association between potential treatment-related risk factors such as chemotherapy, surgery, radiotherapy, and the urinary ß2M level. The relationship between treatment with abdominal radiotherapy and reduced eGFR was confirmed (p < 0.05). We demonstrated that urinary beta-2-microglobulin may play a role in the subtle kidney injury in childhood cancer survivors; however, the treatment-related factors affecting the ß2M level remain unknown. Further prospective studies with a longer follow-up time are needed to confirm the utility of urinary ß2M and its role as a non-invasive biomarker of renal dysfunction.

Prolonged Sojourn at Very High Altitude Decreases Sea-Level Anaerobic Performance, Anaerobic Threshold, and Fat Mass.

Background: The influence of high altitude on an organism's physiology depends on the length and the level of hypoxic exposure it experiences. This study aimed to determine the effect of a prolonged sojourn at very high altitudes (above 3,500m) on subsequent sea-level physical performance, body weight, body composition, and hematological parameters. Materials and Methods: Ten alpinists, nine males and one female, with a mean age of 27±4years, participated in the study. All had been on mountaineering expeditions to 7,000m peaks, where they spent 30±1days above 3,500m with their average sojourn at 4,900±60m. Their aerobic and anaerobic performance, body weight, body composition, and hematological parameters were examined at an altitude of 100m within 7days before the expeditions and 7days after they descended below 3,500m. Results: We found a significant (p<0.01) decrease in maximal anaerobic power (MAPWAnT) from 9.9±1.3 to 9.2±1.3W·kg-1, total anaerobic work from 248.1±23.8 to 228.1±20.1J·kg-1, anaerobic threshold from 39.3±8.0 to 27.8±5.6 mlO2·kg-1·min-1, body fat mass from 14.0±3.1 to 11.5±3.3%, and a significant increase (p<0.05) in maximal tidal volume from 3.2 [3.0-3.2] to 3.5 [3.3-3.9] L after their sojourn at very high attitude. We found no significant changes in maximal aerobic power, maximal oxygen uptake, body weight, fat-free mass, total body water, hemoglobin, and hematocrit. Conclusion: A month-long exposure to very high altitude led to impaired sea-level anaerobic performance and anaerobic threshold, increased maximal tidal volume, and depleted body fat mass, but had no effect on maximal aerobic power, maximal oxygen uptake, or hemoglobin and hematocrit levels.

Death Zone Weather Extremes Mountaineers Have Experienced in Successful Ascents.

BACKGROUND: Few data are available on mountaineers' survival prospects in extreme weather above 8000 m (the Death Zone). We aimed to assess Death Zone weather extremes experienced in climbing-season ascents of Everest and K2, all winter ascents of 8000 m peaks (8K) in the Himalayas and Karakoram, environmental records of human survival, and weather extremes experienced with and without oxygen support. MATERIALS AND METHODS: We analyzed 528 ascents of 8K peaks: 423 non-winter ascents without supplemental oxygen (Everest-210, K2-213), 76 ascents in winter without oxygen, and 29 in winter with oxygen. We assessed environmental conditions using the ERA5 dataset (1978-2021): barometric pressure (BP), temperature (Temp), wind speed (Wind), wind chill equivalent temperature (WCT), and facial frostbite time (FFT). RESULTS: The most extreme conditions that climbers have experienced with and without supplemental oxygen were: BP 320 hPa (winter Everest) vs. 329 hPa (non-winter Everest); Temp -41°C (winter Everest) vs. -45°C (winter Nanga Parbat); Wind 46 m⋅s-1 (winter Everest) vs. 48 m⋅s-1 (winter Kangchenjunga). The most extreme combined conditions of BP ≤ 333 hPa, Temp ≤ -30°C, Wind ≥ 25 m⋅s-1, WCT ≤ -54°C and FFT ≤ 3 min were encountered in 14 ascents of Everest, two without oxygen (late autumn and winter) and 12 oxygen-supported in winter. The average extreme conditions experienced in ascents with and without oxygen were: BP 326 ± 3 hPa (winter Everest) vs. 335 ± 2 hPa (non-winter Everest); Temp -40 ± 0°C (winter K2) vs. -38 ± 5°C (winter low Karakoram 8K peaks); Wind 36 ± 7 m⋅s-1 (winter Everest) vs. 41 ± 9 m⋅s-1 (winter high Himalayan 8K peaks). CONCLUSIONS: 1.The most extreme combined environmental BP, Temp and Wind were experienced in winter and off-season ascents of Everest.2.Mountaineers using supplemental oxygen endured more extreme conditions than climbers without oxygen.3.Climbing-season weather extremes in the Death Zone were more severe on Everest than on K2.4.Extreme wind speed characterized winter ascents of Himalayan peaks, but severely low temperatures marked winter climbs in Karakoram.

Comparison of Environmental Conditions on Summits of Mount Everest and K2 in Climbing and Midwinter Seasons.

(1) Background: Today's elite alpinists target K2 and Everest in midwinter. This study aimed to asses and compare weather at the summits of both peaks in the climbing season (Everest, May; K2, July) and the midwinter season (January and February). (2) Methods: We assessed environmental conditions using the ERA5 dataset (1979-2019). Analyses examined barometric pressure (BP), temperature (Temp), wind speed (Wind), perceived altitude (Alt), maximal oxygen uptake (VO2max), vertical climbing speed (Speed), wind chill equivalent temperature (WCT), and facial frostbite time (FFT). (3) Results: Most climbing-season parameters were found to be more severe (p < 0.05) on Everest than on K2: BP (333 ± 1 vs. 347 ± 1 hPa), Alt (8925 ± 20 vs. 8640 ± 20 m), VO2max (16.2 ± 0.1 vs. 17.8 ± 0.1 ml·kg-1·min-1), Speed (190 ± 2 vs. 223 ± 2 m·h-1), Temp (-26 ± 1 vs. -21 ± 1°C), WCT (-45 ± 2 vs. -37 ± 2 °C), and FFT (6 ± 1 vs. 11 ± 2 min). Wind was found to be similar (16 ± 3 vs. 15 ± 3 m·s-1). Most midwinter parameters were found to be worse (p < 0.05) on Everest vs. K2: BP (324 ± 2 vs. 326 ± 2 hPa), Alt (9134 ± 40 vs. 9095 ± 48 m), VO2max (15.1 ± 0.2 vs. 15.3 ± 0.3 ml·kg-1·min-1), Speed (165 ± 5 vs. 170 ± 6 m·h-1), Wind (41 ± 6 vs. 27 ± 4 m·s-1), and FFT (<1 min vs. 1 min). Everest's Temp of -36 ± 2 °C and WCT -66 ± 3 °C were found to be less extreme than K2's Temp of -45 ± 1 °C and WCT -76 ± 2 °C. (4) Conclusions: Everest presents more extreme conditions in the climbing and midwinter seasons than K2. K2's 8° higher latitude makes its midwinter BP similar and Temp lower than Everest's. K2's midwinter conditions are more severe than Everest's in the climbing season.