Dynamic Alteration in Cerebral Total Hemoglobin Concentration Measured Using Portable Near-infrared Spectroscopy in Orthostatic Hypotension and Intolerance

A portable near infrared spectroscopy (NIRS) system was used to evaluate alterations in cerebral total hemoglobin concentration (HbT) in individuals with orthostatic hypotension (OH) and orthostatic intolerance (OI) symptoms. We enrolled 238 healthy participants (mean age, 47.9 years) and assessed the presence of OH (orthostatic blood pressure (BP) drop of systolic BP ≥ 20 mmHg or diastolic BP ≥ 10 mmHg within 3 minutes of supine-to-stand) and OI symptoms using the OH questionnaire. The participants were categorized into three groups based on the presence of OH and OI symptoms: the classic OH (OH-BP) group, symptom alone (OH-Sx) group, and control group. Random case-control matching sets (age, sex, hypertension, and diabetes mellitus) were constructed consisting of 16 OH-BP and 69 OH-Sx-control sets. We measured the time-derivative of HbT change in the prefrontal cortex during the squat-to-stand maneuver. There were no differences in demographics, baseline BP, and heart rate among the matched sets. Among the NIRS parameters, the peak-time of maximum slope variation was significantly longer in the OH-Sx and OH-BP groups than in the matched control groups during transition to the standing position after squatting. Our results suggested that OH and OI symptoms are associated with dynamic alteration in cerebral HbT.

The Effect of Breathing Patterns Common to Competitive Swimming on Gas Exchange and Muscle Deoxygenation During Heavy-Intensity Fartlek Exercise

During competitive freestyle swimming, the change of direction requires a turn followed by ∼15 m of underwater kicking at various intensities that require a ∼5 s breath-hold (BH). Upon surfacing, breathing must be regulated, as head rotation is necessary to facilitate the breath while completing the length of the pool (∼25 s). This study compared the respiratory and muscle deoxygenation responses of regulated breathing vs. free breathing, during these 25–5 s cycles. It was hypothesized that with the addition of a BH and sprint during heavy-intensity (HVY) exercise, oxygen uptake (VO2) and oxygen saturation (SatO2) would decrease, and muscle deoxygenation ([HHb]) and total hemoglobin ([Hbtot]) would increase. Ten healthy male participants (24 ± 3 years) performed 4–6 min trials of HVY cycling in the following conditions: (1) continuous free breathing (CONLD); (2) continuous with 5 s BH every 25 s (CONLD-BH); (3) Fartlek (FLK), a 5 s sprint followed by 25 s of HVY; and (4) a combined Fartlek and BH (FLK-BH). Continuous collection of VO2 and SatO2, [Hbtot], and [HHb] via breath-by-breath gas analysis and near-infrared spectroscopy (normalized to baseline) was performed. Breathing frequency and tidal volumes were matched between CONLD and CONLD-BH and between FLK and FLK-BH. As a result, VO2 was unchanged between CONLD (2.12 ± 0.35 L/min) and CONLD-BH (2.15 ± 0.42 L/min; p = 0.116) and between FLK (2.24 ± 0.40 L/min) and FLK-BH (2.20 ± 0.45 L/min; p = 0.861). SatO2 was higher in CONLD (63 ± 1.9%) than CONLD-BH (59 ± 3.3%; p < 0.001), but was unchanged between FLK (61 ± 2.2%) and FLK-BH (62 ± 3.1%; p = 0.462). Δ[Hbtot] is higher in CONLD (3.3 ± 1.6 μM) than CONLD-BH (-2.5 ± 1.2 μM; Δ177%; p < 0.001), but was unchanged between FLK (2.0 ± 1.6 μM) and FLK-BH (0.82 ± 1.4 μM; p = 0.979). Δ[HHb] was higher in CONLD (7.3 ± 1.8μM) than CONLD-BH (7.0 ± 2.0μM; Δ4%; p = 0.011) and lower in FLK (6.7 ± 1.8μM) compared to FLK-BH (8.7 ± 2.4 μM; p < 0.001). It is suggested that the unchanged VO2 between CONLD and CONLD-BH was supported by increased deoxygenation as reflected by decreased Δ[Hbtot] and blunted Δ[HHb], via apneic-driven redistribution of blood flow away from working muscles, which was reflected by the decreased SatO2. However, the preserved VO2 during FLK-BH vs. FLK has been underpinned by an increase in [HHb].

Effects of Different Seat Pressures and Rowing Cadences on Muscle Oxygenation and Physiological Parameter Responses

This study investigated the effects of rowing with different seat cushion and cadence conditions on oxyhemoglobin (O2Hb) and total hemoglobin (tHb) levels of the erector spinae (ES) as well as the effects on heart rate (HR) and ratings of perceived exertion (RPE). Thirty healthy adults completed tests under three unstable air seat cushion pressure levels (0, 80, and 140 mmHg) and three rowing cadences (slow: 18 bpm, medium: 30 bpm, and fast: 36 bpm) on a rowing machine, for a total of nine test conditions. During the exercise period, rowing on cushions set to 80 mmHg resulted in greater O2Hb and tHb changes than did rowing at 0 mmHg (p < 0.05). When rowing cadence increased, the O2Hb and tHb decreased during the exercise period, whereas HR and RPE increased (p < 0.05). During the recovery period, O2Hb and tHb on cushions set to 140 mmHg during slow rowing were higher than those at 0 mmHg during slow rowing and 140 mmHg during fast rowing (p < 0.05). Rowing on an appropriate pressure of seat cushion and using a slow cadence contribute to increasing muscle oxygenation of low back during exercise.

Ftx-6058 Induces Fetal Hemoglobin Production and Ameliorates Disease Pathology in Sickle Cell Mice

Sickle cell disease (SCD) is a genetic disorder of the red blood cells caused by a mutation in the HBB gene, which results in red blood cell sickling, hemolysis, vaso-occlusive crises (VOCs), and other complications. Increasing HbF has the potential to prevent or reduce disease-related pathophysiology, including the risk of recurring events such as hemolysis and VOCs. Individuals with SCD who also have hereditary persistence of fetal hemoglobin (HPFH) and exhibit HbF levels of 25 - 30% are often asymptomatic from their SCD, underscoring the protective effect of increased HbF in SCD. Preclinical results with FTX-6058 demonstrate robust target engagement and corresponding increases in HbF levels up to approximately 40% of total hemoglobin, demonstrating the potential to have a significant impact in people living with SCD. FTX-6058 is an investigational, potent, and selective oral small-molecule inhibitor of Embryonic Ectoderm Development (EED) that has been demonstrated to induce robust fetal hemoglobin (HbF) protein expression in cell and murine models of SCD. Here, we report the in vivo effects of EED modulation, and subsequent polycomb repressive complex 2 (PRC2) inhibition in the Townes mouse model of Sickle Cell Disease. Compared with untreated and hydroxyurea treated animals, FTX-6058 (QD, 5mg/kg) exhibits potent target engagement as evidenced by ~70% reduction in H3K27me3 levels, the key epigenetic mark catalyzed by PRC2. Consistent with the robust target engagement observed with FTX-6058, a 2 - 3 fold increase in F cells and HbF protein were observed after 13 and 21 days of FTX-6058 treatment, which was pharmacologically superior to the fetal hemoglobin induction observed with 100 mg/kg hydroxyurea (~25% relative increase in F cells and HbF protein). A linear correlation was also observed between F cells and HbF protein production with FTX-6058 treatment, further supporting the robust HbF induction observed. Consistent with SCD disease presentation, Townes model mice have high reticulocyte counts as a result of premature RBC destruction and hemolysis. Townes model mice treated for 21 days with FTX-6058 ameliorated hemolysis as evidenced by decreases in reticulocytes and increases in red blood cells and total hemoglobin levels. Furthermore, FTX-6058 demonstrated the ability to impact inflammatory drivers of disease as evidenced by decreases in neutrophils and white blood cells. FTX-6058 did not have effects on other hematopoietic lineages. FTX-6058 also impacted pathophysiologic symptoms (e.g., splenomegaly) associated with SCD, as evidenced by ~25% reduction in spleen weight. While some trends were detected, no statistically significant changes were observed in hematological parameters or pathophysiologic symptoms with hydroxyurea, the current standard of care in SCD. These results observed with hydroxyurea underscore the need for new, novel therapies in SCD and other hemoglobinopathies. Taken together, these studies further support the therapeutic rationale of PRC2 modulation in SCD. The fetal hemoglobin induction and effects on hematological parameters and pathophysiologic symptoms observed with FTX-6058 have the potential to translate to meaningful clinical benefits in SCD and other hemoglobinopathies. Disclosures Matson: Fulcrum Therapeutics, Inc.: Current Employment. Xie: Fulcrum Therapeutics, Inc.: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Roth: Fulcrum Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Stuart: Fulcrum Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Bruno: Fulcrum Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Efremov: Fulcrum Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Thompson: Fulcrum Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Silver: Fulcrum Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Moxham: Fulcrum Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company.

Rapid quantification of tissue perfusion properties with a two-stage look-up table: a simulation study

Tissue perfusion properties reveal crucial information pertinent to clinical diagnosis and treatment. Multispectral spatial frequency domain imaging (SFDI) is an emerging imaging technique that has been widely used to quantify tissue perfusion properties. However, slow processing speed limits its usefulness in real-time imaging applications. In this study, we present a two-stage look-up table (LUT) approach that accurately and rapidly quantifies optical (absorption and reduced scattering maps) and perfusion (total hemoglobin and oxygen saturation maps) properties using stage-1 and stage-2 LUTs, respectively, based on reflectance images at 660nm and 850nm. The two-stage LUT can be implemented on both CPU and GPU computing platforms. Quantifying tissue perfusion properties using the simulated diffuse reflectance images, we achieved a quantification speed of 266, 174, and 74 frames per second for three image sizes 512x512, 1024x1024, and 2048x2048 pixels, respectively. Quantification of tissue perfusion properties was highly accurate with only 3.5% and 2.5% error for total hemoglobin and oxygen saturation quantification, respectively. The two-stage LUT has the potential to be adopted in existing SFDI applications to enable real-time imaging capability of tissue hemodynamics.

Association of Clinical and Hematological variables with the disease severity in Indian Sickle cell anemia patients

Sickle cell anemia (SCA) is the most common genetic disorder that is caused due to mutation of the β globin gene. Although SCA is a monogenic disorder, the clinical presentation varies greatly among patients. The present study was designed to be a cross sectional study, aimed at analysing the SCA severity and its association with different clinical, biochemical and hematological variables in SCA patients of Indian origin. About 190 random homozygous SCA patients confirmed by hemoglobin electrophoresis were used in the study. Routine biochemical laboratory (liver function test and Renal function test) and hematologic tests (Total hemoglobin, fetal hemoglobin, hematocrit, MCV and MCH) were done. Values pertaining to complete blood count (CBC), Hb-HPLC and clinical investigations were collected from patient’s records. The mean age of patients with severe disease was significantly lesser than the moderate and mild disease patients. The body mass index (BMI) was also significantly lower in severe disease patients compared to the moderate and mild disease. The patients with severe disease had low levels of red blood cells, total hemoglobin (tHb) and fetal hemoglobin (HbF) compared to the other groups. There is no significant difference in the kidney and liver function among various degrees of disease severity. In summary, this study demonstrates that the tHb and HbF and total leucocyte count (TLC) are major prognostic factors for several clinical complications in SCA. Baseline measurement of these important variables is paramount in predicting important aspects of clinical course and improves the quality lives of these children.

The use of near-infrared spectroscopy for the evaluation of a 4-week rehabilitation program in patients with COPD

Background Near-infrared spectroscopy (NIRS) technology can evaluate muscle metabolism and oxygenation. NIRS-based oximeters can measure skeletal muscle oxygen delivery and utilization during static and dynamic work non-invasively. Our goal was to assess the value and usability of NIRS technology in chronic obstructive pulmonary disease (COPD) rehabilitation program. Methods Forty patients with COPD participated in a 4-week inpatient rehabilitation program that included breathing exercises and personalized cycle/treadmill training adjusted to the functional capacity, physical activity and comorbidities of the patients. A NIRS muscle oxygen monitor was used to measure tissue oxygenation and hemoglobin levels. Total hemoglobin index, average muscle oxygenation, minimal and maximal muscle oxygenation were recorded before and after the rehabilitation program. Results Rehabilitation resulted improvement in 6 min walking distance (6MWD:335.3 ± 110. vs. 398.3 ± 126.2 m; P < 0.01), maximal inspiratory pressure (MIP: 57.7 ± 22.7 vs. 63.6 ± 18.0 cmH2O; P < 0.01), chest wall expansion (CWE: 2.84 ± 1.26 vs, 4.00 ± 1.76 cm; P < 0.01), breath hold time (BHT: 25.8 ± 10.6 vs. 29.2 ± 11.6 s; P < 0.01) and grip strength (GS: 24.9 ± 11.9 vs. 27.0 ± 11.4 kg; P < 0.01). Quality of life improvement was monitored by COPD Assessment Test (CAT: 17.00 ± 8.49 vs. 11.89 ± 7.3, P < 0.05). Total hemoglobin index (tHb: 12.8 ± 1.3% vs. 12.8 ± 1.4), average muscle oxygenation (SmO2: 67.5 ± 14.4% vs. 65.2 ± 20.4%) showed a tendency for improvement. Maximal muscle oxygenation decreased (SmO2 max: 98.0 ± 20.5% vs. 90.1 ± 14.3%; P < 0.01). Minimal muscle oxygenation increased (SmO2 min: 42.6 ± 12.6% vs. 54.8 ± 14.3%; P < 0.01). Conclusions NIRS results showed that muscle oxygenation and microcirculation can be described as a high-risk factor in COPD patients. The 4-week rehabilitation improves functional parameters, quality of life and tissue oxygenation levels in COPD patients.

A functional cerebral endothelium is necessary to protect against cognitive decline

A vascular insult occurring early in disease onset may initiate cognitive decline leading to dementia, while pharmacological and lifestyle interventions can prevent this progression. Mice with a selective, tamoxifen-inducible deletion of NF-κB essential modulator (Nemo) in brain endothelial cells were studied as a model of vascular cognitive impairment. Groups included NemoFl controls and three NemobeKO groups: One untreated, and two treated with simvastatin or exercise. Social preference and nesting were impaired in NemobeKO mice and were not countered by treatments. Cerebrovascular function was compromised in NemobeKO groups regardless of treatment, with decreased changes in sensory-evoked cerebral blood flow and total hemoglobin levels, and impaired endothelium-dependent vasodilation. NemobeKO mice had increased string vessel pathology, blood-brain barrier disruption, neuroinflammation, and reduced cortical somatostatin-containing interneurons. These alterations were reversed when endothelial function was recovered. Findings strongly suggest that damage to the cerebral endothelium can trigger pathologies associated with dementia and its functional integrity should be an effective target in future therapeutic efforts.

fNIRS Monitoring of Infant Prefrontal Cortex During Crawling and an Executive Functioning Task

Functional near-infrared spectroscopy (fNIRS)is a brain-imaging technology used to reveal brain activity by measuring blood oxygenation. Using fNIRS we measured activity in the left prefrontal lobe of 8–14 month-old infants as they crawled or were pushed in a stroller and as they were given a passive attention task or an active executive function (EF) task. For each task, we measured peak total hemoglobin concentration and peak Oxy relative to baseline. Results revealed differences in peak Oxy levels for crawling vs. strolling and between the EF and passive cognitive tasks, with total hemoglobin greater for the EF task than the passive attention task. These results support the theoretical view that both active locomotion and EF engage the prefrontal cortex (PFC) during early development.