This cross-sectional study included 31 patients with COPD subjected to PFTs (including the N2SBW test) and a cardiopulmonary exercise test (CPET). Patients were also evaluated using the following questionnaires: the COPD assessment test (CAT), the 36-Item Short Form Health Survey (SF36) and St. George's Respiratory Questionnaire (SGRQ). Peak oxygen uptake (peak VO2) was negatively correlated with the phase III slope of the N2SBW (SIIIN2)  and positively correlated with forced expiratory volume in one second . Breathing reserve was negatively correlated with SIIIN2, closing volume/vital capacity, and residual volume (RV)  and positively correlated with FEV1, forced vital capacity (FVC) and FEV1/FVC . SIIIN2 and CAT were independently predictive of VO2 and breathing reserve at peak exercise. RV, FVC, and FEV1 were independently predictive of the SF36-physical component summary, SF36-mental component summary, and breathing reserve, respectively. The SGRQ did not present any independent variables that could explain the model. In stable COPD patients, inhomogeneity of ventilation explains a large degree of exercise intolerance assessed by CPETs and, to a lesser extent, poor quality of life.Pulmonary function tests (PFTs) traditionally used in clinical practice do not accurately predict exercise intolerance in patients with chronic obstructive pulmonary disease (COPD). The aim of this study was to assess whether the nitrogen single-breath washout (N Chronic obstructive pulmonary disease (COPD) is a major public health problem worldwide that affects health-related quality of life (HRQoL) of individuals and causes disability and high morbidity and mortality . The HRQ1) is a marker of airflow obstruction in the proximal airways, whereas airflow obstruction in COPD occurs primarily in the distal airways (2SBW) test because it is a simple, non-invasive tool and can detect heterogeneity in the ventilation distribution and small airway disease in cases in which traditional PFTs indicate normal values (2SBW (SIIIN2) and closing volume/vital capacity (CV/VC) indicate heterogeneity in the ventilation distribution and small airway disease, respectively  are valuable tools for the diagnosis and assessment of the severity of COPD and have many clinical applications, such as evaluating prognosis and response to therapy . Spirome airways ,5. In re airways . There hl values . Increasectively . Two recith COPD ,9.2) and a low breathing reserve have been identified as the main contributors that limit exercise (The cardiopulmonary exercise test (CPET) can detect abnormalities in the functional capacity of the respiratory and cardiovascular systems earlier than other tests . In patiexercise –13. Diffexercise ,12. In fexercise ,13.2SBW test explain exercise intolerance in stable COPD patients. Secondly, we sought to evaluate whether parameters of the N2SBW test explain poor quality of life of these patients.As the outcomes of traditional PFTs do not correlate well with CPET parameters, it is important to investigate other pulmonary function methods that are better associated with exercise intolerance in patients with COPD. Considering that ventilatory limitation aggravated by exercise is a major contributor to the reduced functional capacity in COPD patients, we hypothesized that heterogeneity in the ventilation distribution and small airway disease may contribute to better understand exercise intolerance in these patients . Thus, tBetween April 2015 and January 2017, we conducted a cross-sectional study involving 38 consecutive patients with COPD recruited at the Policlínica Newton Bethlem, Rio de Janeiro, Brazil. The exclusion criteria were age less than 40 years, smoking load of fewer than 10 pack-years, previous pleuropulmonary disease not related to COPD, use of supplemental oxygen therapy, previous thoracic surgery, respiratory exacerbations or infections in the past 4 weeks and any comorbid condition that might reduce exercise capacity. The project was approved by the Research Ethics Committee of the Centro Universitário Augusto Motta under CAAE No. 52885116.6.0000.5235 and complied with the Declaration of Helsinki. All subjects signed a consent form.The m-MRC scale is a subjective tool that assesses limitations in ADLs and has been validated for use in Portuguese language . The m-MThe CAT is a specific questionnaire used to measure the HRQoL of patients with COPD. This one-dimensional measure contains 8 items related to the impairment of health status. At the end of the test, the scores of all the responses are summed, and the clinical impact of COPD is evaluated according to the stratification of CAT scores. The total score ranges from 0 to 40, and higher scores indicate poorer health status .vs ≥2 not leading to hospital admission or ≥1 leading to hospital admission), patients were classified as follows: A ; B ; C , and D   and a mental component summary (MCS). The scores range from 0 to 100, with higher scores indicating better HRQoL .The SGRQ is a validated, well-known self-administered tool that measures symptoms, ADLs, and HRQoL of patients with chronic respiratory diseases, particularly COPD. It consists of 50 items divided into 3 domains: symptoms (8 items), activity (16 items) and impact (26 items). Each item has a derived weight, and lower values indicate better HRQoL .1 values after salbutamol use as follows: GOLD 1 ; GOLD 2 ; GOLD 3 , and GOLD 4   in the Hospital Universitário Pedro Ernesto of the Universidade do Estado do Rio de Janeiro, Brazil, following the standardization of the American Thoracic Society . The ref2SBW test with a 3000 HDpft  according to the recommendations of the American Thoracic Society/European Respiratory Society . Then, patients exhaled slowly at a flow rate of approximately 0.3–0.5 L/s until reaching the RV. The concentration of exhaled N2 was recorded by a device located at the airway opening. Two indices derived from this procedure were reported as a percentage of the predicted values: SIIIN2, which is the change in N2 concentration between 25 and 75% of the expiratory volume, and the CV/VC ratio, which is the percentage of the VC that is exhaled after the beginning of airway closure , carbon dioxide output (VCO2), minute ventilation (VE) and related variables were calculated breath-by-breath  coupled with a metabolic analyzer  in the Laboratório de Movimento Humano at the Centro Universitário Augusto Motta according to previous recommendations . We usedy-breath . Breathiy-breath . Heart ry-breath . The equy-breath .2, breathing reserve, CAT, SF36 PCS, SF 36 MCS, and SGRQ with demographic, clinical and resting lung function variables were analyzed using Pearson correlation coefficients. Due to the small number of patients for each item on the m-MRC scale, the patients were categorized into 2 groups according to the m-MRC scale (<2 or ≥2); this cut-off separates ‘low breathlessness' from ‘high breathlessness' . The associations between the variables peak VOessness' . The ass2SBW test) and possible confounders  that were independently related to performance during the CPET (peak VO2 and breathing reserve) and HRQoL . The data that were tested as independent variables in the forward stepwise regression analysis were as follows: forced vital capacity (FVC), FEV1, FEV1/FVC, forced expiratory flow during the middle half of the FVC (FEF25–75%), TLC, RV, RV/TLC, SIIIN2, and CV/VC. These models were adjusted for relevant confounders .Forward stepwise regression analysis was used to identify the resting lung function parameters . The overall performance measures of the regression models was evaluated using the coefficient of determination (R2), adjusted for the number of variables retained in the proposed model (cumulative R2).In addition, the forward stepwise regression analysis was used to identify the variables provided by spirometry and body plethysmography that were independently related to parameters of the Nvs predicted outcomes, along with regression lines showing the slope and intercept) and the limits of agreement (LoA) plot for each of the proposed models . Differences were considered significant for P values less than 0.05.Among the 38 patients evaluated for inclusion in this study, 7 were excluded for the following reasons: respiratory exacerbations in the month before recruitment (n=3), history of pleuropulmonary disease not associated with COPD (n=3), and use of home oxygen therapy (n=1). The average age was 67.5±9.9 years, and the average smoking load was 50.9±26.2 pack-years. All but 4 patients were treated with inhaled bronchodilators and/or inhaled corticosteroids. The demographic and clinical data, resting lung function parameters, and CPET data are shown in 2 was negatively correlated with SIIIN2  and positively correlated with FEV1 and FEF25-75% . Breathing reserve was negatively correlated with SIIIN2, CV/VC, RV and RV/TLC  and positively correlated with FEV1, FVC, FEV1/FVC and FEF25-75% . We further assessed the correlations between parameters of the N2SBW test with resting lung function variables and possible confounders. SIIIN2 was negatively correlated with FEV1, FVC, FEV1/FVC and FEF25-75%  and positively correlated with RV and RV/TLC . CV/VC was negatively correlated with FEV1, FVC, FEV1/FVC and FEF25-75%  and positively correlated with age, TLC, RV and RV/TLC . Changes in the demographic, clinical, lung function and CPET variables according to the m-MRC scale (class <2 vs class ≥2) were also evaluated; the results of this analysis indicated no significant difference in the variables between the patients divided into the 2 classes of the m-MRC scale.The univariate correlations between the demographic, clinical, lung function and CPET data are shown in 2SBW test) could independently predict performance during the CPET and the HRQoL in these patients. The results of the forward stepwise regression analysis for the prediction of the CPET and HRQoL variables are shown in N2 was an independent predictor of the CAT score, peak VO2 and breathing reserve. RV, FVC and FEV1 were independent predictors of SF36 PCS, SF 36 MCS and breathing reserve, respectively. The SGRQ could not be predicted by any independent variables in the models. We further assessed whether the resting lung function variables would demonstrate an independent role in predicting the parameters of the N2SBW test. FEV1 and RV/TLC were the only independent predictors for SIIIN2 and CV/VC, respectively  and the observed correlation for the main outcome (peak VO2) and SIIIN2 (r=-0.681). For an alpha of 0.05, the power was 99.3%, showing the adequacy of the studied sample size to get significant results.To provide a context for interpreting the null findings, a 2SBW test were associated to a lesser extent with the CPET parameters and HRQoL. In addition, other lung function variables measured by spirometry and body plethysmography were associated with performance during exercise and HRQoL of patients with COPD. To our knowledge, this study is the first to demonstrate that the parameters of the N2SBW test partially explain the exercise intolerance and poor quality of life in stable COPD patients.The main finding of this study was that, in patients with COPD, a greater inhomogeneity in ventilation corresponded to a lower oxygen consumption and breathing reserve at peak exercise. The inhomogeneity of ventilation was also positively associated with poor HRQoL of these patients. Compared with the heterogeneity in ventilation, the changes in small airways measured by the NN2 (but not the CV/VC ratio) was the only independent predictor of peak VO2. Interestingly, Jones et al. (2 had a higher ventilatory inefficiency (higher ventilation/carbon dioxide output nadir) during the CPET. Therefore, we believe that increased SIIIN2 at rest indirectly indicates the ventilatory inefficiency detected during symptom-limited maximal exercise. Of note, our models were adjusted for relevant confounders . Furthermore, we used the predicted values for the lung function parameters, which adjust the absolute values for gender, age, weight and height . Breathing reserve depends on several factors that are responsible for ventilatory demand, including metabolic demand, body mass, dead space ventilation and neuroregulatory mechanisms  and that these abnormalities are associated with significant patient-centered outcomes, including shortness of breath and exercise intolerance (In our study, the strongest correlation was observed between SIIIchanisms . A low bchanisms  evaluateolerance ,28. Empholerance ,29.N2, our results indicate that changes in the CV/VC may not be a major contributor to CPET measurements in patients with COPD because CV/VC was not retained in any of the regression models that were developed. In the N2SBW test, an increased CV/VC reflects air trapping because of small airway closure, and therefore, it can potentially provide information about early abnormalities in the small airways in COPD (In contrast to the variations in SIII in COPD . Althoug in COPD .2 values that explained less than 50% of the variance (N2 alone explained 35% of the variability of the CAT scores. The clinical variables and traditional PFTs were not retained in the regression models in our study, likely because of the strong association between CAT and SIIIN2. In contrast to CAT, we were unable to build a regression model for the m-MRC scale. This result was expected because the CAT is a multidimensional scale that includes seven other items, not only shortness of breath, whereas the m-MRC scale is one-dimensional and assesses only dyspnea (Although COPD is primarily a lung disease, it also causes significant systemic effects that can lead to a decline in health status and HRQoL . A recenvariance . Conside dyspnea .In this study, the SF36 PCS was associated with various physiological parameters at rest. However, the strongest correlation was observed between the increase in RV and the decrease in SF36 PCS, and RV was the only physiological parameter that was included in the SF36 PCS regression model. Air trapping caused by the combined effect of peripheral airway disease and increased ventilatory demand imposes critical mechanical restrictions and worsens dyspnea, which, in turn, leads to the decline of HRQoL of patients with COPD . Interes2 and the SGRQ score. Similarly, other researchers reported that peak VO2 is a poor indicator of health status (Our findings were similar to those of Morishita-Katsu et al.  who evalh status ,39, suggh status .2SBW test assessments in randomized controlled trials. In this context, the N2SBW test may contribute to the categorization of patients and the evaluation of responses to various clinical and surgical therapies for COPD.Our study is characterized by the following limitations. First, this study included a small number of subjects from a single center and employed a cross-sectional design; therefore, the temporal effect on the stability of the response of each evaluated tool is unknown. Due to the multiple statistical tests performed, some of the findings may be a result of chance. Therefore, there is the possibility of type I error, i.e., accepting an alternative hypothesis when the results can be attributed to chance . Second,2SBW test measurements and CPET parameters in stable COPD patients. In these patients, inhomogeneity of ventilation explains much of the exercise intolerance assessed by the CPET and, to a lesser extent, the poor HRQoL. Compared with the N2SBW test, the variables measured by spirometry and body plethysmography more strongly influenced the HRQoL and, to a lesser degree, oxygen consumption in patients with COPD. The contribution of the N2SBW test to COPD studies should be further explored, as this test has the potential to be used as a complementary tool in clinical practice to assess these patients.In conclusion, there was a relationship between N


CHI3L1 proteins are involved in both innate and adaptive immune responses; however, to date, the correlation of these SNPs and their age of onset of bronchial asthma has not been demonstrated.Single nucleotide polymorphisms (SNPs) in To address the role of these genetic variations, 390 patients with well-controlled bronchial asthma and living in Japan were recruited, genotyped, and had a pulmonary function test performed on them in this study. To analyze the concentration levels of CHI3L1 protein, bronchial lavage fluids were examined.Forced expiratory volume in one second, %predicted (%FEV1), was significantly decreased in homozygotes of rs1214194 compared to heterozygotes and wild type. The age of onset of adult bronchial asthma was significantly younger in GG homozygotes of rs4950928 and AA homozygotes of rs1214194 than in the other two genotypes. The concentration of CHI3L1 protein in bronchial lavage fluid increased in both homozygotes of rs4950928 and rs1214194.CHI3L1 might predict an early onset of bronchial asthma and have the propensity to promote airway remodeling.Our study demonstrated that the homozygotes of rs4950928 and rs1214194 of Trial registration JMA-IIA00045 remodeling-ICS N-acetylglucosamine, is found in the walls of fungi; exoskeleton of crabs, shrimp, and insects; the microfilarial sheath of parasitic nematodes; and the lining of the digestive tracts of many insects [CHI3L1 have been associated with a risk of bronchial asthma, bronchial asthma severity, and pulmonary function in populations of European ancestry [CHI3L1 rs4950928 and rs1214194 genotypes were associated with lung function, the age of onset, and the airway expression of CHI3L1 protein in Japanese adult asthmatic patients.Bronchial asthma is a disorder of the conducting airways that leads to variable airflow obstructions in association with airway hyperresponsiveness and a local accumulation of inflammatory cells, particularly Th2-type lymphocytes, eosinophils, and mast cells . Allerge insects –8. Chiti insects –11. YKL- insects , 13. Ser insects , lung, b insects , and spu insects  have beeancestry . Althougancestry , the corAll study subjects were recruited from the Iwate Medical University Hospital. Patients aged ≥ 18 years were eligible if they had a diagnosis of asthma as defined by the American Thoracic Society criteria for ≥ 5 years and were using inhaled corticosteroid (ICS) at a stable dose for ≥ 1 year before screening. Well-controlled asthmatic patients who had no other medical disorders, who had smoked less than 10-pack-years, and who had not been exposed to environmental hazards were considered for the study to exclude concomitant COPD. Well-controlled asthma symptoms were defined as meeting none of the following criteria in the previous 4 weeks : (1) dayg for 10 min at 4 °C. The supernatant was decanted and stored at − 80 °C. Ten milliliters of BLF supernatant was concentrated to 1.0 mL (tenfold) by centrifugation using Centrifugal Filter Devices . CHI3L1 levels were measured in duplicate in BLF specimens using a commercially available ELISA kit for Human Chitinase 3-like 1 Immunoassay . The mean value of the 2 duplicates was used in the statistical analyses. Duplicate samples with coefficients of variation greater than 20% were reassayed.Asthmatic patients underwent fiberoptic bronchoscopic examinations during ICS treatment. Asthmatic bronchial lavage fluids (BLF) were obtained from (i) patients harboring CC (wild type) of rs4950928; (ii) patients harboring GG (homozygous) of rs4950928; (iii) patients harboring GG (wild type) of rs1214194; and (iv) patients harboring AA (homozygous) of rs1214194. Bronchial lavage was performed by inserting a flexible fiberoptic bronchoscope  under local anesthesia, as previously described [t-test. P values < 0.05 were considered significant.Statistical analyses were performed using JMP version 11 . All data were expressed as the mean ± standard error. Comparisons of the patients’ characteristics between the three groups were performed using one-way ANOVA. Post hoc multiple comparisons were performed using the Tukey–Kramer test for differences among all groups. Comparisons of the total and differential cell counts, and the concentration of CHI3L1 in BLF were performed using a Of 390 asthmatic patients screened, 381 of rs4950928 and 368 of rs1214194 were successfully genotyped (≥ 94%). We identified 270, 90, and 21 subjects that had CC wild type, CG heterozygotes, and GG homozygotes, respectively, for rs4950928 (Table We performed a bronchoscopy and collected BLF from the two groups to confirm whether GG and AA homozygotes of rs4950928 and rs1214194, respectively, expressed any increased CHI3L1 protein levels. Four patients who were genotyped as CC and 5 patients as GG of rs4950928 harboring wild type of rs1214194 and 6 patients who were genotyped as GG and 4 patients as AA of rs1214194 harboring wild type of rs4950928 were accepted for the BLF studies, which was performed following recommended safety procedures and was well tolerated in all subjects. There were no significant differences in total and differential cell counts between wild type and homozygous. In contrast, CHI3L1 levels in BLF were significantly increased in patients who were homozygous compared to wild type (Table CHI3L1 related to clinical characteristics in Japanese asthmatic patients. Several new findings have emerged from this study. First, we demonstrated that asthmatic patients with genetic variants of rs1214194 had a reduced %FEV1. Second, the age of onset of bronchial asthma was significantly younger in homozygotes of rs4950928 and rs1214194 than in other genotypes. When compared with restricted adult-onset asthma, the age of onset was significantly younger in homozygotes than in the wild type and heterozygotes genotypes. Third, CHI3L1 in BLF from CHI3L1 homozygotes of GG of rs4950928 and AA of rs1214194 increased compared to the wild type in asthmatic patients. Previous population studies of genetic variation in the CHI3L1 gene and bronchial asthma have shown an association with the promoter SNP rs4950928, intronic SNP rs1214194, and a decreased %FEV1 [STAT4 TT of rs925847 and IL13 AA of rs20541 are potential genomic biomarkers that predict lower pulmonary function. High-dose inhaled corticosteroid treatment increased the pulmonary function of patients homozygous for IL13AA of rs20541 but not of patients homozygous for STAT4 TT of rs925847 [GLCCI1 rs37972 and rs37973 and the asthmatic treatment steps used with the Japanese population, showing an OR of 2.78 and 2.28, respectively, but not with pulmonary function [In this study, we investigated genetic variants of ed %FEV1 . Howeverrs925847 . Anotherfunction . We concCHI3L1 on the age of onset of bronchial asthma have not been addressed. To clarify this issue, we compared the ages of adult-onset bronchial asthma between the genotypes for SNPs in CHI3L1 in Japanese patients. It is generally considered that early-onset asthma included child-onset asthma and adult-onset asthma. However, based on the remaining possibility of the prevention of bronchial asthma development via an improvement of lifestyle habit, it should be distinguished from the perspective of preventive medicine. Genotyping of CHI3L1 could be considered significant if the development of bronchial asthma can be avoided in men who are found to have a genetic variation of CHI3L1, have a family history of bronchial asthma, and are notified early enough to be able to sufficiently adjust their lifestyle habits. Studies of this have added to our understanding of the importance of genetic variations by demonstrating that CHI3L1 rs4950928 and rs1214194 genotypes play a critical role in early-onset adult asthma. Bronchial asthma should be suspected in anyone with episodic wheezing, shortness of breath, and cough, especially if more than one of the symptoms is worse at night or is precipitated by an upper airway infection; however, these symptoms are relatively nonspecific in adult individuals. Using an examination of SNPs in CHIL3L1 might promote early detection and intervention in preventing airflow obstructions.YKL-40/CHI3L1 plays a role in the pathophysiology of bronchial asthma by modulating innate and adaptive immune responses. Surprisingly, to date, the effects of genetic variation in Increased levels of the YKL-40 protein have been found in patients with a broad spectrum of pathologies, including those with rheumatoid arthritis , obstrucCHI3L1 might be promising genomic biomarkers as predictors of progressing airway remodeling. Before the age of onset of bronchial asthma for patients who have these genetic variants, we need to consider the development of a preventative program that can be implemented before symptoms occur or worse.In conclusion, this study demonstrated that rs4950928 and rs1214194 homozygotes of


Background: One of the most commonly used auricular acupuncture points selected for different pain treatment regimens is Shenmen. This point on the ear has been recognized as having a wide number of applications, as found by scientific investigation. Methods: Within this crossover study, the ear acupoint Shenmen was stimulated with two different kinds of laser  in 22 healthy volunteers . Both green and yellow lasers were used for 15 min in the same volunteers in two different sessions. Results: The most prominent finding was that systolic blood pressure decreased significantly (p = 0.048) after yellow laser stimulation. Heart rate also decreased significantly (p < 0.001), whereas heart rate variability ratio low frequency (LF)/high frequency (HF) (p < 0.001) increased. The effects were significantly more pronounced in females than in males. In addition, the temperature was measured, and temperature increases were demonstrated at different locations on the ear using imaging methods. Conclusions: This study shows evidence of the effect of auricular laser acupuncture. However, a comparison with other publications was impossible because this is the first study using green and yellow laser stimulation on the ear. Laser acupuncture is a scientifically well-investigated method for the non-invasive stimulation of acupuncture points and has proven to be clinically effective in both patients with needle phobia and children ,2. LaserThe question “which wavelength should be used in laser acupuncture” is sometimes related to the question “how deep does light penetrate human tissue”. It is well known that red laser light has a deeper penetration depth than violet, blue, green, or yellow. Infrared light is not visible, but some authors have demonstrated that it penetrates human tissue at least as deep as visible red light. Within this study, we have used green (532 nm) and yellow (589 nm) laser light because for ear acupuncture we do not need a very high penetration depth .The original aim of the present randomized crossover study was to analyze for the first time the possible effects of a single-point laser ear acupuncture  with green and yellow lasers on physiological parameters of subjects. However, the gender-specific evaluation also brought very interesting results, although the original study design was not designed primarily for their analysis.2 and for the yellow laser it was calculated to be 13.8 kJ/cm2.The radiation of a green  and a yellow  laser  was coupled into an optical fiber and the so-called laser needle was attached to the distal end of the optical fiber . The dosAcupuncture with a green laser  has so far not found a broad field of application. There are a few indications to use the method as a supplement to red, near-infrared, and violet laser stimulation within the framework of acupuncture. The penetration depth of the green laser (532 nm) is 0.5–1 cm [The yellow laser is another option for laser acupuncture. Our research group is the first ever to study yellow light laser . The proA total of 22 volunteers with a mean age ± SD of 25.3 ± 4.1 years  were stimulated with both green and yellow lasers in two sessions each. The average stature of the subjects was 172.6 ± 7.9 cm, and the average body weight was 66.9 ± 14.0 kg. No person was under the influence of drugs. The non-invasive stimulation and registration of vital signals were approved by the local ethics committee and performed in accordance with the recommendations of the Helsinki Declaration of the World Medical Association. All subjects gave their written consent.The measurement procedure was divided into two sections: One 15 min green and one 15 min yellow laser acupuncture were performed on the subjects in randomized order. A computerized random number generator was used to produce a randomization schedule employing simple randomization by an independent researcher, who was not involved in the recruitment, intervention, assessment, or statistical analysis. Ten subjects were assigned to the green laser first  and 12 to the yellow laser first . There was a break of at least 30 min between the two stimulation modalities. The study was conducted in the laboratory of the TCM Research Center of the Medical University of Graz, and the participants lay relaxed on a patient couch during the entire examination see . The pro® AR12 system . This system is suitable for a monitoring period over 24 h. The sampling rate was 4096 Hz. Three Skintact Premier F-55 ECG electrodes  were attached to the thorax  were recorded with an HRV Medilogorax see a. The raorax see , and theorax see . The calm in the right middle cerebral artery were respectively registered after an initial resting period of 10 min immediately before the start of the measurements and after completion of the measurement scheme .The blood pressure (systolic BP sys and diastolic BP dia) and the mean blood flow velocity vIn addition, thermographic images of the ear  were taken at each of the measurement times A–F, and analyses of peripheral temperature-specific measurements at times A–E were performed .p < 0.05.The statistical analysis was carried out with the computer program SigmaPlot 13.0 . An analysis of variance (one-way repeated measure ANOVA) was used. In addition, post-hoc analyses  were carried out. The level of significance was set at p < 0.003) during and after yellow laser stimulation in sections d and e compared to baseline values a , there were no significant changes in all 22 subjects. However, the LF/HF ratio was also significantly altered in women for the yellow laser stimulation during and after laser irradiation .p = 0.048) of the systolic blood pressure (BP sys) after yellow laser stimulation, whereas the diastolic value (BP dia) showed no significant change. The results of blood pressure readings for both the green and yellow lasers of all 22 subjects are shown in The results of the blood pressure measurements were characterized by a significant decrease , Cavum Conchae (CC) and Control Point (CP)) after yellow laser stimulation, whereas the green laser showed partially significant temperature increases. An example of the measurements (No. 20) is demonstrated in m) in the middle cerebral artery showed no significant changes compared with baseline values .The findings of the blood flow velocity , which is usually included in the field of acupuncture research. Wherever possible (continuous monitoring of the ECG), the temporal aspects were included in the analyses . Unfortunately, no continuous non-invasive blood pressure measurement or continuous temperature imaging was available for the measurements, so not all parameters were always recorded at the same time compare . TherefoThe outlier data points in The autonomic nervous system is a key regulator of the cardiovascular system. The two divisions, the sympathetic and the parasympathetic systems, have co-regulatory effects on cardiac homeostasis. Neurovegetative modulation and dysfunction are also believed to affect various cardiac diseases. Recently, evidence has been provided suggesting gender differences in autonomic nervous system activity .In multiple previous studies, neurovegetative states were primarily assessed using heart rate variability, muscle sympathetic nerve activity, coronary blood flow velocity, and plasma biomarkers. As mentioned before, heart rate variability is a non-invasive measure, which can be analyzed in terms of low-frequency and high-frequency oscillations, which indicate the sympathetic and parasympathetic tone, respectively. These measures have been studied in females and males in states of rest and stress and in cardiac disease .Recent studies support the concept of a significant gender difference in neurovegetative activity. Further studies are necessary to elucidate specific differences and mechanisms, which could guide targeted therapies.The following conclusions can be drawn from this pilot study: gender-specific differences in the effects of laser acupuncture likely exist and need to be scientifically proven. The pilot study showed differences in female and male subjects after yellow laser stimulation in the ear. The differences were found primarily in the behavior of the heart rate and its variability. Interestingly, the yellow laser stimulation at the ear point Shenmen was able to lower the systolic blood pressure of the subjects. Although this was also the case with the green laser, significance was found exclusively with the yellow laser. One reason for this could be the higher energy dosage used with the yellow laser.In order to find explanatory models or mechanisms for the results, comprehensive studies—in animal and human medicine—are certainly necessary.


Circadian blood pressure rhythm is controlled by intracellular molecular clocks, which allow the body to prepare for anticipated stimuli, the morning blood pressure surge helping to meet the challenges of the day while the nocturnal blood pressure fall sets the system for a period of rest.These rhythms vary in hypertensive and non-hypertensive individuals .1 CardioThis early morning blood pressure surge has also been shown in epidemiological studies to result in a clustering of cardiovascular complications such as stroke,5Early morning blood pressure surges occur in both poorly controlled and well-controlled hypertensives; with poor blood pressure control being associated with uncontrolled morning blood pressure levels in 70% of patients in the ACAMPA study .6Few antihypertensives are sufficiently long acting to sustain adequate blood pressure lowering for the full 24 hours between once-daily doses, and indeed many are at their lowest efficacy during the risky early morning period. The angiotensin receptor blocker (ARB) telmisartan has the longest plasma half-life, highest lipophilicity, highest receptor binding affinity, and slowest dissociation of any ARB, making it particularly suitable for sustained 24-hour blood pressure control.An important measure of 24-hour blood pressure control is the smoothness index (SI), which is considered to be a better indicator of blood pressure homogeneity over time.7 The SI is calculated by using the average of hourly changes in blood pressure over 24 hours, divided by the standard deviation. SI values greater than one indicate a reliable and sustainable effect over 24 hours.A recent meta-analysis,The predictive value of telmisartan’s SI of 1.13 systolic blood pressure (SBP) and 0.97 diastolic blood pressure (DBP) and the provision of 24-hour protection is supported by the results of two major trials, the MICADO II studyIn the PRISMA I and II studies , in which patients with mild-to-moderate hypertension (95–109 mmHg seated DBP) were randomised to once-daily treatment with telmisartan 80 mg or ramipril 5 mg force-titrated to 10 mg, researchers found that the reductions in both SBP and DBP during the last six hours of the dosing interval were significantly greater with telmisartan 80 mg than with ramipril 10 mg (p < 0.0001). Similar findings were observed throughout the 24-hour dosing period.Prescribing antihypertensives such as telmisartan with a prolonged duration of action not only provides blood pressure lowering during the vulnerable early morning hours but also mitigates against the loss of blood pressure control if a dose is missed. In a pooled analysis of two studies comparing telmisartan 80 mg with valsartan 160 mg once daily during the 24 hours after a missed dose in patients with mild-to-moderate hypertension (MICADO I and II studies), telmisartan sustained blood pressure control after a missed dose significantly better than with valsartan , an effect that was particularly marked during the last six hours of the dosing interval (p < 0.0001).In conclusion, clinical studies have shown that telmisartan provides 24-hour blood pressure control superior to that of the ARBs, losartan and valsartan, the calcium-channel blocker, amlodipine, and the ACE inhibitor, ramipril. This agent is particularly effective during the last six hours of the dosing interval when other antihypertensives tend to have reduced effectiveness. Telmisartan is, therefore, a highly appropriate antihypertensive for sustained 24-hour blood pressure control, especially during the risky early morning hours.


Optimal treatment for established renal failure is living donor kidney transplantation. However this pathway exposes healthy individuals to significant reduction in nephron mass via major surgical procedure. Laparoscopic donor nephrectomy is now the most common method for live donor transplantation, reducing both donor post-operative pain and recovery time. However this procedure exposes kidneys to additional haemodynamic stresses. It has been suggested that donor hydration—particularly the use of preoperative intravenous fluids—may counteract these stresses, reducing subclinical acute kidney injury and ultimately improving long-term renal function. This may be important in both preservation of donor renal function and recipient graft longevity.A prospective single-centre single-blinded randomized controlled trial will be carried out to determine the effects of donor preoperative intravenous fluids. The primary outcome is donor subclinical acute kidney injury  on day 1 postoperatively. Secondary outcomes include intraoperative haemodynamics, recipient subclinical acute kidney injury, perioperative complications and donor sleep quality.Donors will be randomised into two groups: the intervention group will receive active pre-hydration consisting of three litres of intravenous Hartmann’s solution between midnight and 8 am before morning kidney donation, while the control group will not receive this. Both groups will receive unlimited oral fluids until midnight, as is routine. Plasma NGAL will be measured at pre-specified perioperative time points, intraoperative haemodynamic data will be collected using non-invasive cardiac output monitoring and clinical notes will be used to obtain demographic and clinical data. The researcher will be blinded to the donor fluid hydration status. Blinded statistical analysis will be performed on an intention-to-treat basis. A prospective power calculation estimates a required sample size of 86 patients.This study will provide important data, as there is currently little evidence about the use of donor preoperative fluids in laparoscopic nephrectomy. It is hoped that the results obtained will guide future clinical practice.ISRCTN10199225, 20 April 2015).This study has been approved by the West of Scotland Research Ethics Committee 3  and is registered with the International Standard Randomised Controlled Trial Number Register (reference no.  Chronic kidney disease (CKD) has an estimated prevalence of 8.5% in the UK adult population . A smallRenal transplantation is associated with increased life expectancy and quality of life compared to dialysis and so should be considered in all patients with ESRD , 8. HoweThe price of better recipient outcomes with living kidney donation is some associated additional donor risk . EarlierFirst carried out in 1995, laparoscopic nephrectomy is now widespread and has resulted in increasing live donor transplantation . DespiteThe effect of increased intra-abdominal pressure is well characterized in abdominal compartment syndrome—organ dysfunction secondary to intra-abdominal hypertension, defined as ≥12 mm Hg . PneumopThis may reflect the fact that the kidneys have a large reserve, with approximately 50% of renal parenchyma compromise needed to see changes in eGFR. Therefore, even if renal damage has taken place, it may not be detectable by these functional measures. There is a new and emerging concept of subclinical acute kidney injury—injury not detected by functional criteria, but through measurement of biomarkers associated with tubular necrosis .NGAL is a small 25 kDa protein of the lipocalin family, and was first identified by transcriptome analysis of the murine model, investigating the early induction of gene expression after renal ischaemia. Its expression was found to be upregulated in tubular cells after ischaemic injury . NGAL leIn an evaluation of 125 specimens from healthy individuals using the Alere Triage® CardioRenal Panel, it was found that the 95th percentile upper limit was 153 ng/mL. A study to determine the clinical utility of this compared the NGAL level of 494 plasma samples from patients in intensive care with the standard RIFLE criteria for acute kidney injury. AUC was 0.83 and a positive test threshold of 150 ng/mL yielded a sensitivity of 0.86 and specificity of 0.62 . It was There has been wide variation in reports of the diagnostic accuracy of NGAL, including variation in the specificities reported. This may be in part as a result of the different populations studied. NGAL is also produced by activated neutrophils and therefore may be raised in infection or inflammation , 25. Pla® NGAL Device, have demonstrated superior diagnostic accuracies. For example, 2-h plasma NGAL measurement of 120 children who underwent cardiopulmonary by-pass obtained AUC of 0.96 and the same AKI threshold of 150 ng/ml yielded a sensitivity 0.84 and specificity of 0.94 [Other studies, using the point of care Triage of 0.94 . Several of 0.94 . TherefoIn the living donor population, Yoon et al. demonstrated that perioperative plasma NGAL in living donors correlates with 6 month donor eGFR. This correlation was found to be strongest using plasma NGAL at 1 week post-operatively, but a correlation was found at all time points .Pilot data obtained at our study centre involving 20 donors indicate that hand-assisted laparoscopic nephrectomy is associated with significant subclinical acute kidney injury, defined as plasma NGAL >153 ng/ml, and that preoperative fluids may reduce the incidence of this. In a non-randomised pilot series, where fluids were administered as per surgeon preference, there was found to be an incidence of subclinical acute kidney injury of approximately 50% in patients receiving <1000 ml of intravenous fluids compared with a 20% incidence in those receiving >2500 ml of intravenous fluids. An inverse correlation between increase in NGAL and post donation eGFR at 6 weeks was also demonstrated .The risk of subclinical acute kidney injury has been demonstrated by Hasse et al. who analysed pooled data from ten prospective observational studies, involving over 2000 patients with cardiorenal syndrome type 1. Subclinical acute kidney injury detected by NGAL was found to increase the risk of adverse outcomes, such as need for renal replacement therapy, hospital mortality, and duration of hospital stay, even in the absence of a diagnostically significant increase in serum creatinine .Any decrease in subclinical acute kidney injury is therefore likely to be beneficial. In the long term, it may result in a small increase in GFR, which may be beneficial for the remaining donor function, and reduced haemodynamic stress on the donated kidney may potentially result in greater longevity of the allograft. Therefore optimisation of perioperative fluid management is likely to have a protective role.There is some controversy surrounding perioperative fluid administration, and optimal fluid balance. The risks of restrictive fluid administration include inadequate organ perfusion and post-operative nausea, whereas liberal fluid use may increase the risk of prolonged post-operative ileus, poor wound healing and the potential for fluid overload leading to heart failure , 34.There have been variable findings in this field, with some studies demonstrating benefit from liberal fluid administration –37, and Our donor study population is a very healthy one, and all perioperative complications will be closely monitored for and reported.Potential mechanisms behind attenuation of subclinical acute kidney injury using preoperative fluids are that optimal hydration results in increased renal venous and arteriolar filling, preventing collapse and congestion. Also, increased inferior vena cava pressure may prevent reduced venous return during pneumoperitoneum, maintaining cardiac output. These mechanisms may also reduce vasoconstriction caused by activation of the renin-angiotensin-aldosterone system .+131 mmol/L, K+ 5 mmol/L, HCO3− 29 mmol/L, Cl− 111 mmol/L and Ca2 2 mmol/L [We have chosen to use Hartmann’s solution (compound sodium lactate) preoperatively. This contains the following electrolyte concentrations: Na2 mmol/L . Althoug2 mmol/L .There have been few studies of donor perioperative fluids in laparoscopic nephrectomy. Intraoperative fluid restriction was associated with a lower urine output, but no difference in post-operative serum creatinine levels or complications . This maAs discussed, existing studies used functional criteria, such as serum creatinine, which detect only damage extensive enough to cause immediate functional changes, and any subtle effects present may be masked by the overwhelming effect of nephrectomy and subsequent compensatory renal hypertrophy (CRH). There is therefore currently a lack of evidence about preoperative fluids in laparoscopic nephrectomy, and significant variation in clinical practice. This study aims to address this.This study hypothesis is that the use of preoperative intravenous Hartmann’s solution will result in a decrease in donor subclinical acute kidney injury, defined as plasma NGAL >153 ng/ml.The primary aim of this study is to determine whether preoperative intravenous fluids result in a decrease in donor subclinical acute kidney injury. The secondary aims include investigating the effects of fluids on various donor and recipient clinical and biochemical outcomes, listed below.This study proposes that donors will be randomised to one of two groups: one group will receive active pre-hydration with three litres of intravenous Hartmann’s solution between midnight and 8 am before morning donation with unlimited oral fluid as desired, while the other group will receive just unlimited oral fluids until midnight.The primary outcome will be the incidence of donor acute kidney injury (as defined by plasma NGAL >153 ng/ml) on day 1 post-operatively.Day 1 change in donor plasma NGAL from baselineDonor renal function (serum creatinine and eGFR) day 1–4, week 6 and 1 year, as is standard procedureDonor BNP changesRecipient change in plasma NGAL from baselineRecipient serum creatinine and eGFR at 6 weeks and 1 yearDelayed graft function (DGF)—defined as use of dialysis in the first week postoperatively1 year graft and patient survival in recipientDonor intraoperative haemodynamics, including blood pressure, heart rate, stroke volume index, cardiac index and systemic vascular resistance index (collected from non-invasive cardiac output monitor).NGAL levels in blood obtained from renal vein during retrieval and implantation surgeryDonor and recipient perioperative mortalityDonor perioperative fluid balanceDonor fluid boluses and response to fluid challenge.Donor and recipient perioperative complications Donor sleep quality, assessed using the Richards–Campbell Sleep Questionnaire Adult patients aged >18 years of age. undergoing live donor hand-assisted laparoscopic nephrectomy eligible to participateConsent to participate givenEnglish-speaking or appropriate translation facilities to allow for consent to be validLaparoscopic nephrectomy taking place at the study siteTransplant taking place between dates of the trial.Patients undergoing open nephrectomyPatient unable or unwilling to consentBased on the observational pilot data discussed above, which demonstrated a 50% incidence of day 1 subclinical acute kidney injury in patients receiving <1000 ml of intravenous fluids and a 20% incidence of acute kidney injury (AKI) in patients receiving >2500 ml of intravenous fluids, we anticipate that 39 patients would be required in each arm to detect a similar magnitude of difference with 80% power and a significance level of 0.05. Allowing for 10% attrition, we intend to recruit a total of 86 patients.Patients who fit the stated inclusion and exclusion criteria will be identified at the time of allocation of a date for surgery. The recruitment process will involve approaching potential participants prior to surgery, and obtaining written consent upon hospital admission Fig. .Fig. 1PaA computer-generated 1:1 allocation sequence will be created by an independent operator who is not directly involved with the study. Allocation concealment will be achieved using sequentially numbered sealed opaque envelopes. Allocation to treatment arms will be performed by a member of the research team on the day prior to surgery, after the patient has provided valid written consent.This sort of intervention means that blinding of patients and clinicians is not feasible. Therefore a single-blind approach is being used, where the researcher will be blinded to the fluid hydration status of the patient at the time of data collection.The evening prior to surgery (day-1), between midnight and 8 am, patients in the intervention group will receive three litres of IV Hartmann’s solution. Patients in this group will also be admitted on the evening prior to surgery (day −1) but will not be given intravenous fluids. Both will receive unrestricted oral fluids in line with the European Society of Anaesthesiology perioperative fasting guidelines and will be encouraged to drink freely. It will be ensured that both groups have ready and equal access to unrestricted oral fluids, and any oral and intravenous fluid intake will be recorded via routine fluid charts.All patients will be admitted on the afternoon prior to surgery as is routine practice and receive entirely standard care in all ways other than the different pre-surgical fluid regimes indicated in this protocol.™ bioimpedance system  will be used—a novel and totally non-invasive monitor which employs impedance cardiography to measure cardiac output. It does so by measuring electrical signals produced by changes in the volume and velocity of the blood in the thoracic aorta. This NICCOMO system is complemented by another device—the CNAP™ Monitor 500 . The CNAP Monitor employs the volume-clamp method of Penaz to measure non-invasive arterial blood pressure continuously via two small inflatable cuffs applied to the fingers of one hand. The cardiac output monitor will be attached to the patient shortly after the induction of anaesthesia and will remain in situ throughout the surgical procedure. It will be removed at the end of the operation before the patient is transferred to the recovery room. The anaesthetist will be blinded to the results of the cardiac output monitor.All patients will receive standard anaesthetic care and monitoring. Additionally, in order to obtain key haemodynamic measurements, such as cardiac index (CI), systemic vascular resistance index (SVRI) and stroke volume index (SVI) measurements, the use of a non-invasive cardiac output monitor will be required. The NICCOMOThe cardiovascular response to a single 500 ml fluid challenge will be assessed following the induction to anaesthesia. Cardiovascular parameters with be recorded, then a “stat” 500 ml fluid challenge will be administered and cardiovascular parameters recorded again. Again, the anaesthetist will be blinded to the results of this challenge.Additionally a single 5 ml sample of venous blood will be obtained from the donor renal vein immediately after retrieval and immediately after implantation to assess the immediate impact on biomarkers of AKI.After surgery, patients will be taken to the recovery room and monitored according to standard hospital policy before return to the transplant ward for post-operative care.Patients will receive their normal medications prior to surgery unless otherwise directed by the anaesthetist.Every effort will be made to retain patients in the trial and to minimise withdrawals. Patients with capacity to consent may request to be withdrawn from this study at any time. If the patient develops a severe or life-threatening condition and loses capacity, continued consent will be presumed unless it is deemed that continuation of the trial will result in an adverse outcome for the patient. This is because follow-up of patients who have complications is particularly important for this trial, as it is examining the effect that preoperative intravenous fluid has on these.In patients who do withdraw from the study, reasons for withdrawal will be documented. All data accumulated up to the time of withdrawal will be retained and included in subsequent statistical analyses.The study will be conducted solely within the West of Scotland Renal Transplant Unit. Follow-up will be undertaken in out-patient clinics throughout NHS Greater Glasgow and Clyde by the Renal Transplantation Team.Data will be obtained from the ward observation and fluid charts, anaesthetic record, recovery room observation chart, laboratory and bedside blood test results, intraoperative data collection and clinical review in the post-operative period. To avoid any bias, the outcome assessor will be blinded to the fluid hydration that the patient received. The data that will be collected includes demographic data, patient details, perioperative details and primary and secondary outcome data Table .Table 1DData will be entered on a patient-by-patient basis into a computerised password-protected database on a computer within the Department of Renal Transplantation by an investigator blinded to the study group allocation. Patients will be identified by their study number only. After data analysis has been performed, it will be combined with the randomisation code and the nature of each patient’s perioperative fluid regimen will be revealed. This will be performed in accordance with the Data Protection Act. A case report file will be created for each patient. These will be archived in a locked facility and kept for a period of 3 years.Descriptive statistics will be used to describe continuous variables. Results for continuous variables will be reported as mean (+/− standard deviation) or median (interquartile range). The primary outcome, proportion of patients in each group with subclinical acute kidney injury, will be compared using a chi-square test and 95% confidence intervals for the difference in proportions.t-test. If data are found to not be Normally distributed, a Mann Whitney U-test will be used. Analysis will be performed on an intention-to-treat basis.If the data for continuous variables follow a Normal distribution, the variables will be compared using a Student’s Study reporting will be in accordance with the CONSORT guidelines.As there is currently relatively little data about preoperative fluid use in laparoscopic donor nephrectomy, it is hoped that this study will provide important clinical information. Prior to this study, trials looking at preoperative fluids have shown a beneficial effect on intraoperative haemodynamics. In this study, plasma NGAL will be used to determine whether this effect translates to a reduction in subclinical acute kidney injury, which may be of benefit for both the donor and the recipient.In terms of the volume of intravenous fluid administration, Mertens zur Borg et al. based the volume of fluid administered on ideal body weight . Though It is hoped that, whatever the findings of the study, the results will be of real clinical relevance. If preoperative intravenous fluids are found to be of benefit, then this could lead to their widespread use in clinical practice. If, however, no difference is found between the groups, then live donors may not need be admitted to hospital until the morning of the surgery which would mean greater patient convenience and reduced costs.


To evaluate macular pigment optical density (MPOD) and to identify its determinants in a sample of Brazilian individuals.This was a cross-sectional study. One hundred three healthy individuals had both eyes photographed using a Visucam 500 digital fundus camera  in combination with the MPOD module. Four variables were obtained: maximum MPOD, mean MPOD, MPOD volume, and MPOD area. Demographic data and information on lifestyle habits were also collected.Mean MPOD was 0.14 density unit ± 0.05. MPOD was not influenced by gender, smoking history, or refractive error. MPOD was significantly higher among black individuals than among white and biracial individuals. There was a positive but low correlation between MPOD and age.This study found MPOD values to be similar to those found in European samples but lower than other studies performed on Asian and Australian samples. This is the first data regarding MPOD in a South American Population. Macular pigment is composed of chemical substances known as xanthophylls, which include three isomers: lutein, zeaxanthin, and meso-zeaxanthin . The macMacular pigments work as an optic filter for wavelengths below 550 nm and also have antioxidant properties. It is believed that they are a protective factor for diseases caused by oxidative stress, such as age-related macular degeneration .The quantitative study of macular pigment and its distribution is possible through macular pigment optical density (MPOD). The methods for MPOD measurement can be divided into subjective and objective approaches. Subjective methods include heterochromatic flicker photometry (HFP) and motion photometry. Objective methods include reflectometry, autofluorescence, and Raman scattering .MPOD can also be objectively evaluated using the Visucam 500 digital fundus camera , which measures the reflectance of a blue light close to the macular pigment’s area of maximum absorption. This method produces a graph that shows the three-dimensional distribution of macular pigment and evaluates four variables: maximum MPOD, mean MPOD, MPOD volume, and MPOD area –10.It is believed that different populations have different macular pigment distributions . Other vThere is no literature on an average MPOD value for healthy individuals in a Brazilian sample. This information is essential, since it will serve as a point of reference for future studies of macular pigments and macular degeneration in this population.The purpose of this study was to determine the mean MPOD value in a sample of the Brazilian population and to evaluate the influence of sex, age, ethnicity, smoking history and refractive status on MPOD values in this sample.This study was approved by the Ethics Committee of the School of Medicine of the Federal University of Goiás and obeys the Declaration of Helsinki.A cross-sectional study was performed. One hundred fifty healthy subjects between the ages of 18 and 76 were selected from the Panamerican Institute for Eyesight (Instituto Panamericano da Visão), in the city of Goiânia, Goiás State, Brazil. All subjects were informed of the study and signed an informed consent form.All subjects received a complete ophthalmologic exam, including visual acuity testing, testing to determine refractive error, biomicroscopy, fundoscopy, and tonometry. Subjects with a positive spherical equivalent above 0.25 D were considered hyperopic; those with a negative spherical equivalent were considered myopic, and those with a spherical equivalent between 0.00 and + 0.25 D were classified as emmetropic. Demographic data was collected on sex, age, and ethnicity, the latter of which was self-reported according to the classification used by the Brazilian Institute of Geography and Statistics (IBGE), which offers the categories of white, black, biracial, and indigenous . Data on2. The value of MPOD area corresponds to the area where pigment is detected and is given in degrees2 [All subjects had both eyes dilated using tropicamide 0.5 mg/mL and, after 30 min, both eyes were photographed using the Visucam 500 system  combined with the MPOD module. MPOD was calculated at 7 degrees of eccentricity, at which point the highest concentration of xanthophyll was reached. All images were collected by the same technician, under the same light conditions, with the same flash intensity and after mydriasis. The MPOD analysis provided information on maximum MPOD, mean MPOD, MPOD volume, and MPOD area, as well as a colored map and a three-dimensional pigment distribution profile. Maximum and mean MPOD were measured in density units (d.u.). The value of MPOD volume corresponds to the sum of the optical density values at all points and is given in d.u. degreesdegrees2 .The software Statistical Package for Social Science (SPSS) for Windows (version 21.0) was used for data analysis.The category variables are provided in a table with absolute values (f) and percentages (%) The continuous variables are presented as a mean ± SD and with a confidence interval of 95%.Wilcoxon test for paired data was used to check for the presence of a significant difference between the MPOD variables  measured in the right and left eye.Mann–Whitney test for independent data was used to check for the existence of a significant difference between the four MPOD variables  when correlated with sex, ethnicity, and tobacco use. Mann–Whitney test was also employed to determine whether there was a significant difference in the MPOD variables  when correlated with refractive error .Linear regression analysis was used to determine whether there were any correlations between the MPOD variables and age.p < 0.05.All tests employed a 95% confidence interval and defined significance as For sample calculations, Table Two hundred six eyes of 103 subjects were analyzed.The distribution of the subjects according to sex, ethnicity, and history of tobacco use is shown in Table The mean value of the four MPOD variables  are shown in Table The mean values for the MPOD variables  were correlated with ethnicity, and the comparisons are found in Tables 2 = 0.37996, p < 0.001). The linear regression of age and maximum MPOD is shown in Fig. 2 = 0.2455, p < 0.001). There was no correlation between the other MPOD variables and age.The linear regression of age and mean MPOD is shown in Fig. There was no statistically significant difference in the comparisons between the four MPOD variables  and sex. There was also no statistically significant difference between smokers and non-smokers.There were no statistically significant differences in MPOD values when the results for myopic, emmetropic, and hyperopic subjects were compared. There was also no statistically significant difference between the MPOD values obtained when the results for left eyes and right eyes were compared.It is believed that different populations have different distributions of macular pigments . StudiesThis study did not find significant differences in the MPOD values between men and women. In fact, most studies found no correlations between MPOD values and sexes , 16, 20,In this study, all MPOD variables  were found to be significantly higher in black subjects than in biracial and white individuals. Studies show that white individuals have lower central MPOD values than non-whites, including Southern Asian , 22, 23 History of tobacco consumption does not seem to influence MPOD values , 16, 17.Few studies have evaluated the influence of refractive error on MPOD and have not found a significant difference between myopic, emmetropic, and hyperopic individuals . This stNo significant differences were found in MPOD values obtained from right eyes versus left eyes. This is in line with findings described in the literature –30. In fThis study found a low but positive correlation between mean and maximum MPOD and age. Other MPOD variables (area and volume) were not correlated with age. There is no consensus in literature regarding the influence of age on MPOD values. Berendschot et al.  found anThis study presents some limitations. The subjects’ diets were not evaluated, and the amount of serum xanthophylls was not measured. These factors could affect MPOD , 12. DesMean MPOD was 0.14 density unit ± 0.05. MPOD was not influenced by gender, smoking history, or refractive error. MPOD was significantly higher among black individuals than among white and biracial individuals. There was a positive but low correlation between mean and maximum MPOD and age.This is the first data regarding MPOD in a South American Population and establishes reference values for future studies.


This is the first known study examining renal function following stereotactic body radiotherapy (SBRT) for pancreatic head adenocarcinoma.Thirty-eight borderline-resectable/unresectable patients, part of an ongoing prospective trial, underwent 3 cycles of gemcitabine/5-fluorouracil followed by SBRT (5 daily fractions of 5/6/7/8 Gy) and concurrent nelfinavir. Thereafter, in resectable cases, surgery was performed within 4–8 weeks. The last available pre-SBRT creatinine was recorded, along with the highest post-SBRT value. Glomerular filtration rate (GFR) was calculated by the commonly-utilized Modification of Diet in Renal Disease formula. GFR decline was defined as the post-SBRT nadir GFR minus the pre-SBRT GFR. Correlations with the V5–V30, and mean/maximum kidney doses was performed. Statistics included Pearson correlation, Mann-Whitney, and Fisher’s exact tests.3. Median dosimetric values were as follows: V5 (209 cm3), V10 (103 cm3), V15 (9 cm3), V20 (0 cm3), V25 (0 cm3); and mean (6.7 Gy) & maximum kidney dose (18.3 Gy). Median GFR change was −23  mL/min/1.73 cm2. Of all dosimetric parameters, only V5 was significantly associated with changes in GFR . In patients with V5 < 210 cm3, median GFR change was −11.8 mL/min/1.73 cm2, as compared with −37.1 mL/min/1.73 cm2 change in those with V5 ≥ 210 cm3 (p = 0.02). A GFR change < −23 mL/min/1.73 cm2 was observed in 6/20 (30%) patients with V5 < 210 cm3, versus 15/18 (83%) of those with V5 ≥ 210 cm3. Patients with V5 ≥ 210 cm3 were over ten times as likely to have GFR change < −23 mL/min/1.73 cm2 (p = 0.003). Using linear regression, GFR change ≈ −0.1748 × V5(cm3) + 8.63.The median total kidney volume was 355 cm3 was associated with a post-SBRT GFR decline of >23 mL/min/1.73 cm2. If V5 is kept <210 cm3, median GFR decline was only 11.8 mL/min/1.73 cm2. Further validation is needed to ascertain definite dose-volume parameters and examine late renal decline.In the first known analysis of renal function after pancreatic SBRT, evaluating patients on a prospective study, V5 ≥ 210 cm The recent popularity of neoadjuvant stereotactic body radiotherapy (SBRT) for pancreatic cancer has created a necessity to better define dose-volume parameters in order to ensure the safety of nearby organs-at-risk (OARs) . AlthougThis study was a retrospective secondary analysis of an ongoing prospective study of chemotherapy followed by SBRT and concurrent nelfinavir, a human immunodeficiency virus protease inhibitor harboring tumoricidal and radiosensitizing effects, observed in both preclinical studies , phase IBlood chemistries were obtained weekly during chemotherapy, and immediately prior to SBRT. Treatment course is also described elsewhere , 14, but−1.154 × age−0.203 × 0.742 × 1.210(if African-American). GFR change was calculated as the post-SBRT nadir GFR minus pre-SBRT GFR; negative values indicated a decline, positive values a rise. Though creatinine can indeed fluctuate in any patient, we deliberately analyzed based on the nadir GFR for this study, for multiple reasons. First, follow-up in the prospective trial was well-controlled in terms of post-SBRT/surgical medication changes, adjuvant therapies, and other items potentially influencing kidney function. Second, the methods were based on those in nephrologic literature, wherein the concept of peak creatinine/nadir GFR continues to gain popularity in follow-up for conditions having poor prognoses and/or frequent creatinine fluctuations [Retrospectively, the last available pre-SBRT serum creatinine value (mg/dL) was recorded, along with post-SBRT values for the duration of patients’ follow-up/survival. For each creatinine value, the Modification of Diet in Renal Disease (MDRD) formula was used to calculate the corresponding glomerular filtration rate (GFR): 175 × Cr3 of kidney receiving ≥5Gy)–V30, as well as mean and maximum kidney dose. Statistics were performed using SAS v.9.3 . These included the Mann-Whitney & Fisher’s exact tests as non-parametric tests of comparing mean/maximum values and proportions, respectively, of several parameters analyzed herein. In order to associate GFR decline with dose-volume parameters, Pearson correlation was utilized; linear regression provided a numerical comparison between both variables.Dosimetric parameters analyzed for this study included V5 .Of 40 consecutively/prospectively-enrolled patients, two were excluded for not having available pre/post-SBRT creatinine values. Characteristics of the 38-patient study population is shown in Table Of the 26 patients who experienced a nadir GFR within 3 months, four patients experienced Common Toxicity Criteria for Adverse Events (CTCAE) grade 1 toxicity (creatinine 1.5–2 times above baseline), grade 2 (2–3 times above baseline) in one patient, and grade 3 (creatinine over three times baseline and/or over 4 mg/dL) in two patients . In the 12 patients whose GFR nadir occurred more chronically (after 3 months), six patients were categorized as grade 1 renal toxicity, five patients grade 2, and one patient grade 3. No patient required dialysis. At last follow-up however, five patients persisted with grade 1 renal toxicity and the remainder had no CTCAE-defined toxicities. Regarding post-nadir trends, by last follow-up, creatinine was stable (within 20% of baseline –24) in 13 respectively. Median values of kidney mean and maximum doses were 6.7 and 18.3 Gy, respectively. Though V10–V30, age, gender, baseline GFR, tumor resection, and postoperative chemotherapy did not correlate with GFR decline , V5 correlated significantly  values for V5, V10, V15, V20, and V25 were 209 (52–320), 103 (0–242), 9 (0–110), 0 (0–22), and 0 (0–5) cm2 was observed in 6/20 (30%) patients with V5 < 210 cm3, versus 15/18 (83%) of those with V5 ≥ 210 cm3. Moreover, in patients with V5 < 210 cm3, median GFR change was −11.8 mL/min/1.73 cm2, as compared with −37.1 mL/min/1.73 cm2 change in those with V5 ≥ 210 cm3 (p = 0.02). Patients with V5 ≥ 210 cm3 were vastly more likely to have GFR change < −23 mL/min/1.73 cm2 (p = 0.003).A GFR change < −23 mL/min/1.73 cmIn summary, these data relate kidney V5 to renal GFR decline after pancreas SBRT. By retrospectively analyzing data obtained as part of a prospective trial, we provide the first known association between kidney doses in pancreatic SBRT and renal dysfunction. It should be mentioned that these data are applicable to pancreatic SBRT and not necessarily to SBRT for other intra-abdominal areas. Nevertheless, our results underscore the need to control low-dose spillage to the renal system.There are salient reflections from these data. It is most likely that V5, but not other higher-dose parameters, correlated most with the renal endpoints herein, because of the higher amount of low-dose spillage to the kidneys with SBRT, which notably depends also on treatment technique. This is consistent with comparatively fewer differences between patients in V10 and higher values, whereas V5 was most liable to be different between patients. This is a prime reason our data may not apply to primary renal neoplasms, which are associated with higher renal doses from closer anatomic proximity, as opposed to the largely lower kidney doses delivered during pancreas SBRT. However, it does not rule out the fact that both high-dose as well as low-dose areas could impact kidney function. Nevertheless, a message of our results is that pancreas SBRT is not likely to deliver high renal doses, thus decreasing the likelihood that high-dose areas would find to correlate with renal decline.Our data will next be compared to existing literature. Currently, only one other study has published data on observed kidney doses, but without correlation to renal function; this study also used an uncommon, and therefore potentially less generalizable, single-fraction SBRT technique . This st2  was utilized as a comparative “standard”, high-quality data have demonstrated its value. In patients with similar baseline creatinine, a drop in 35 mL/min/1.73 cm2 is associated with increased all-cause and cardiovascular mortality [2 are considered “clinically noteworthy” endpoints. Additionally, it has been recommended to grade kidney injury using GFR changes, and a change of 23 mL/min/1.73 cm2 roughly corresponds with a one-level upstaging of chronic kidney disease (CKD) [n = 10), none of which displayed outliers in renal measurements for the study period. Furthermore, it was not feasible to control for every potential medication that may have effects on the kidney. Additionally, our contouring of both kidneys as one structure, instead of proportional/spared volume or other parameters, is consistent with other sources [Regarding strengths and weaknesses of these data, this investigation is part of a prospective trial and the associated standardization of treatment, thus avoiding potential bias associated with retrospective data analysis. It should be mentioned, however, that this endpoint was planned to be analyzed but not specifically listed as a pre-specified endpoint of the trial. Moreover, confirmation of our methods from the nephrology perspective is noteworthy. Chiefly, though creatinine can indeed fluctuate in various individuals, as mentioned before, there were multiple reasons for deliberately measuring peak creatinine/nadir GFR  including being an increasingly-utilized option in patients with poor prognosis , 21. Addortality . Hence,  sources . HoweverIn summary, the value of kidney V5 in clinically-evident renal function decline must be validated in an independent cohort (and in non-SBRT cases), as these data are hypothesis-generating. Additionally, though this study measured a GFR nadir and did not seek to examine a prolonged time course of post-SBRT GFR decline, this can indeed occur after SBRT ; unfortu3 was associated with a post-SBRT GFR decline of >23 mL/min/1.73 cm2. If V5 is kept <210 cm3, median GFR decline was only 11.8 mL/min/1.73 cm2. Further verification of these data is needed to better ascertain dose-volume relationships with GFR, and examine late renal decline.In the first known analysis of renal function after pancreatic SBRT, evaluating patients on a prospective study, total kidney V5 ≥ 210 cm


Diabetic ketoacidosis (DKA) in patients receiving tacrolimus as part of their immunosuppressive regimen is a rarely reported adverse event. We report a patient with autosomal dominant polycystic kidney disease (ADPKD) and no known history of diabetes mellitus who presented with DKA, 3 months after kidney transplantation. For 2 decades now, kidney allograft survival has been shortening despite an obvious decrease in acute allograft rejection. The possibility of a single agent capable of both outcomes is being considered. Tacrolimus, the most potent calcineurin inhibitor, may be the reason for both. Its popularity is clearly a consequence of the excellent short term outcome. However, as second kidney transplant becomes the norm because of the reduced allograft survival, alternative immunosuppressive regimens ought to be considered.New-onset diabetes mellitus after transplantation (NODAT) is now a well-established adverse effect of calcineurin inhibitors, mostly tacrolimus. NODAT has been reported to occur in 32% of patients after solid organ transplantation and may be the most important contributing factor for decreased long-term allograft survival . ImmunosThe case presented here describes an accelerated development of tacrolimus-induced DKA 3 months after kidney transplantation. To our knowledge, only 14 cases of tacrolimus-induced DKA have been reported.2. Laboratory work-up revealed hyperglycemia, high anion gap metabolic acidosis, significant ketosis with a beta-hydroxybutyrate level of 4.45 mmol/l (reference range 0.02–0.27 mmol/l), ketonuria, and normal lactate levels. Glycated hemoglobin (A1C) was 9.8% compared to 4.8%, 30 days after transplant. Tacrolimus trough level was 13.9 ng/ml. Glutamic acid decarboxylase (GAD-65) autoantibodies were negative. Infectious etiology for hyperglycemia was ruled out.A 44-year-old Caucasian male, with no past medical history of diabetes mellitus, was admitted to the hospital with DKA, three months after receiving a deceased-donor kidney transplant for end stage renal disease (ESRD) secondary to ADPKD. The posttransplant course was unremarkable. Patient's immunosuppressive regimen included tacrolimus 1.5 mg BID, mycophenolate sodium 720 mg BID, and low dose prednisone of 5 mg daily. Patient presented to the emergency department with nausea, polyuria, and abdominal pain. He did not have family history of diabetes mellitus. Physical exam was unremarkable except for mild overweight, body mass index of 27 kg/mThe patient received intravenous fluids and a bolus of intravenous insulin followed by continuous insulin infusion which was gradually switched to subcutaneous insulin. Daily insulin requirements were approximately 40 units. He was educated about his new diagnosis and discharged on diabetic diet and subcutaneous insulin therapy. Upon follow-up, tacrolimus dose was adjusted to a lower therapeutic index. Insulin requirements markedly decreased and patient was able to be taken off insulin 9 months after. Glycated hemoglobin (A1C) checked at 9 months was 5.2%.Many of the risk factors that predispose nontransplant patients to diabetes mellitus have been identified as risk factors for NODAT. Some risk factors are unique to the transplant population. Immunosuppressive agents that contribute to NODAT include glucocorticoids, calcineurin inhibitors, and mTOR inhibitors. Both cyclosporine and tacrolimus increase the risk of NODAT. Tacrolimus is more diabetogenic than cyclosporine , 4. OtheIn a study using data from the United States Renal Data System (USRDS), 21,489 patients were enrolled, of whom 4,105 developed NODAT by 3 years after transplant. Diabetes complications developed in 58.3% of patients. DKA developed in 8.1% of patients with NODAT . In mostIncluding our case, there are 15 cases of tacrolimus associated DKA presentation in organ transplant patients reported in the literature –18. Summ2 as in our case.Higher body mass index (BMI) has been associated with increased risk for NODAT . HoweverFemale gender, African American ethnicity, recipients of deceased donor kidney transplant, younger age (33–44 versus >55 years), and recent transplant patients had significantly higher risk of DKA after kidney transplantation .Maintenance immunosuppressive therapy is essential to prevent rejection in renal transplant recipients. Calcineurin inhibitors play an integral role in immunosuppressive regimens, with tacrolimus being the preferred agent over cyclosporine, as several studies showed lower incidence of acute rejections with its use , 20. In Transplant patients on tacrolimus as part of their immunosuppressive regimen had increased risk of DKA compared to cyclosporine based immunosuppressive regimens , 19. BotDecreased insulin requirement after DKA is suggestive of transient pancreatic damage by toxic levels of tacrolimus which is usually dose dependent and appears reversible . Both taImportantly, DKA in renal transplant patients has been associated with increased mortality .Tacrolimus remains the preferred immunosuppressive agent after kidney transplantation given lower incidence of acute rejections and better patients' tolerance. However, tacrolimus's contribution to new-onset diabetes ketoacidosis, as a consequence of pancreatic islet beta cell toxicity, adds to the accumulating evidence of reduced allograft survival observed since its introduction as the immunosuppressant of choice. Despite rarity of reported cases of posttransplant tacrolimus-induced DKA, it seems possible that the decrease in allograft survival observed in the last two decades is just the consequence of tacrolimus-induced diabetes and its complications. The successful decrease in acute allograft rejection provided by tacrolimus has likely confounded this observation. The development of diabetes mellitus with ketoacidosis in patients on therapeutic tacrolimus levels, with no risk factors for diabetes, highlights the need for alternative immunosuppressive agents that will not compromise patients' allografts long-term survival at the expense of inducing a devastating chronic disease. This case study highlights the importance of regular monitoring of fasting blood glucose in transplant patients on tacrolimus based regimen for early detection of NODAT in order to prevent life-threatening complications. It is also another call for attention on the toxic effects of this potent calcineurin inhibitor.


A pressure difference between the intraocular and intracranial compartments at the site of the lamina cribrosa has been hypothesized to have a pathophysiological role in several optic nerve head diseases. This paper reviews the current literature on the translamina cribrosa pressure difference (TLCPD), the associated pressure gradient, and its potential pathophysiological role, as well as the methodology to assess TLCPD.For normal-tension glaucoma (NTG), initial studies indicated low intracranial pressure (ICP) while recent findings indicate that a reduced ICP is not mandatory.Data from studies on the elevated TLCPD as a pathophysiological factor of NTG are equivocal. From the identification of potential postural effects on the cerebrospinal fluid (CSF) communication between the intracranial and retrolaminar space, we hypothesize that the missing link could be a dysfunction of an occlusion mechanism of the optic nerve sheath around the optic nerve. In upright posture, this could cause an elevated TLCPD even with normal ICP and we suggest that this should be investigated as a pathophysiological component in NTG patients. The importance of an imbalance between intracranial pressure (ICP) and intraocular pressure (IOP) in the pathophysiology of several diseases involving the eye and the brain has received increased attention in recent years , 2•, 3. The idea of detrimental pressure difference, between the eye and the brain as part of glaucoma pathophysiology, is not new. It was first described as a possible contributing cause of glaucoma in the 1970s , 6. ReceIn this review, we aim to summarize what is known from publications about the translamina cribrosa pressure difference (TLCPD) and the related pressure gradient effect over the lamina cribrosa (LC), and its potential as a pathophysiologic component in optic nerve head (ONH) diseases.Gradient effects from differences between ICP and IOP are found at the ONH, specifically at the LC. The LC is a trabecular structure of several layers and pores of different sizes through which the optic nerve fiber bundles pass, and it is a continuation of the inner layer of the posterior sclera. IOP is the pressure within the intraocular compartment anteriorly of LC. Posteriorly, the optic nerve (ON) is surrounded by the three layers of meninges: dura mater, arachnoid mater, and pia mater. The cerebrospinal fluid (CSF) filled subarachnoid space ends within a blind pouch behind the LC •, 10, 11Volkov  suggesteThe basic hypothesis has been that increased TLCPD is detrimental to the axons of the optic nerve via a mechanical insult and/or through a disturbed axoplasmic transport, which then causes edema. A change in either IOP or ICP may affect the homeostasis of the ONH. The imbalance can be due to increased ICP, e.g., in SANS and idiopathic intracranial hypertension (IIH), or to elevated IOP as in the case of glaucoma. It is, however, important to remember that there are large individual differences in the biomechanical properties of the LC that determine how susceptible the axons are to this stress , 12. ThiIn the last decade, it has also been postulated that possible low ICP in normal-tension glaucoma (NTG) patients might contribute to NTG pathophysiology through increased TLCPD . Morgan It has been shown that ICP decreases with age , 18. WosAn interesting new concept is the postulated presence of a perivascular transport system for waste clearance in the eye and the brain, i.e., the “glymphatic system” which is another means to move extracellular fluid –25. A reMeasurement of the LC with high enough resolution to estimate its thickness with acceptable accuracy is difficult in human in vivo studies. Furthermore, direct measurement of the retrolaminar pressure in humans is not possible due to practical and ethical considerations. Thus, the evaluation of gradient effects and their potential detrimental effect on the ONH is challenging. These obstacles can to a certain extent be overcome by using animal models.In a study on dogs, Morgan et al. studied the gradient over the LC. A micropipette linked to a servonull pressure system was moved through the LC and into the optic nerve subarachnoid space (ONSAS). IOP and ICP were monitored continuously, and the gradient over LC was measured at various IOP and ICP levels. They found that there was a strong correlation between the gradient and TLCPD when ICP was higher than 0 mmHg . In anotYang et al. studied the effects of chronically lowered ICP in a monkey model. Compared to controls, they showed that low ICP caused optic neuropathy while IOP remained stable within normal range, supporting the hypothesis that alternation on one side of the LC is sufficient to cause disturbed balance between IOP and ICP and may cause a harmful effect on the ONH . In an eMorgan et al.  showed iTaken together, these animal studies show that there is a relationship between effects on the LC and TLCPD, particularly if ICP is low. Furthermore, there is an indication of a protective mechanism against too low retrolaminar pressure in cases of negative ICP.The approach to investigate TLCPD is to assess the pressure difference between the anterior and posterior side of the LC. In clinical settings, these parameters are not trivial to measure.For the posterior side, the challenges are much greater than for the anterior side and require some critical assumptions. In published clinical studies on TLCPD, assessment of retrolaminar pressure is based on invasive CSF space accessed through lumbar puncture and the assumption of a communicating CSF system from the lumbar space through the intracranial compartment to the subarachnoid space retrolaminarily. In clinical routine, ICP is commonly measured invasively through direct lumbar puncture and has been shown to agree well with pressure measured intracranially , 36. Due® [® [Regarding the anterior side, IOP measured indirectly trans corneally must be considered a reasonable substitute, especially if corrected for hydrostatic distance to LC. In clinical practice, the measurement of IOP is always an indirect measurement, i.e., an estimation of the true pressure inside the eye, and all tonometry methods suffer from sources of error –43. The ® , which c® [® , 47, whiIn this section, we will first briefly discuss findings related to IIH and SANS, which are conditions related to reduced TLCPD. We will then put the main focus on the importance of TLCPD in glaucoma with a suspected elevated TLCPD.Classic signs and symptoms of intracranial hypertension are optic disc edema, headaches, pulsatile tinnitus, transient visual obscurations, and radicular pain. Some patients also demonstrate choroidal folds and hyperopic shift. IIH affects mostly obese females of child-bearing age, and reasons for this remain poorly understood. The disease can cause visual field defects similar to glaucoma, i.e., nerve fiber bundle defects, and can potentially cause blindness . For theAnother examples of the importance of ICP/IOP relationship, and not only absolute ICP values, in patients with IIH can be seen in reports on glaucoma patients who have developed papilloedema after successful IOP-lowering surgery with normal postoperative IOP levels. Further work up revealed that the patients also had IIH –52. ThesDuring the last decade, it has become apparent that astronauts traveling in space are at risk to acquire ocular abnormalities such as optic disc edema, choroidal folds, and hyperopic shift. This disease has similar ocular characteristics as found in IIH patients but the symptomatology differs since IIH symptoms of headaches, tinnitus, and transient visual obscurations are not common in SANS patients . HoweverThe hypothesis that glaucoma is caused by an increased translamina cribrosa pressure gradient has led to the assumption that particularly normal-tension glaucoma (NTG) may be caused by a low ICP, which would create a similar mechanical condition as an elevated IOP , 14•, 59Numerous articles have been written on the subject. However, if the literature is critically evaluated, there are limited scientific studies that investigate this hypothesis. Most of the publications are reviews •, 60–66,There are several controversies in the literature regarding TLCPD. One concerns the methods used to measure ICP. As stated before, invasive direct measurement of ICP is the golden standard in clinical practice. A number of different indirect methods to estimate or indicate ICP have been described. Although non-invasive methods would be preferable due to the risk of complications with the invasive ones, the indirect methods are not considered to be sufficiently reliable for clinical practice –40. StilStarting with the non-invasive ICP approaches, it has been shown that the width of the optic nerve subarachnoid space (ONSASW) estimated with magnetic resonance imaging (MRI) is positively correlated to ICP measured with lumbar puncture (LP) . Wang etContrary to these findings, both Jaggi et al. and Pircher et al. used computerized tomography (CT) to measure optic nerve sheath diameter (ONSD) in NTG compared with controls and found significantly increased diameter in NTG patients. Pircher et al. also compared ONSD to ICP measured with LP in NTG patients and found no correlation between the parameters. Their results can be interpreted as speaking against the hypothesis of NTG patients having low ICP, but the authors discussed other possible explanations for their findings, e.g., compartmentation , 79. Furn = 9/group), they found a non-significant tendency towards reduced ICP and a higher TLCPD in glaucoma patients. Note that the glaucoma patients had not undergone washout of IOP-lowering treatment and that IOP was measured in the sitting position, while ICP was measured in the supine position [Another indirect method to estimate ICP is the two-depth transorbital Doppler technique. It uses ophthalmic artery as an intracranial pressure sensor . The metposition .In summary, studies that use ONSASW, BMI, blood pressure, age, ophthalmic blood flow profile, and other indirect indications of ICP show conflicting results which likely reflect the uncertainty in the estimated ICP. This uncertainty calls for invasive ICP assessment for investigation of pathophysiological importance of ICP and TLCPD in glaucoma.We have found six studies where invasive ICP measurement was performed on patients with glaucoma or ocular hypertension Table  7–9, 8282–84. BeRen et al. performed prospective studies on ICP and TLCPD in Chinese patients with OAG and OH. When 43 patients with OAG where compared with 71 non-glaucomatous controls, ICP was significantly lower in patients with NTG than HTG or controls. Accordingly, the TLCPD was elevated in NTG patients . When OHIn a recent non-controlled retrospective study on 38 NTG patients, Pircher et al. found an ICP of 11.6 mmHg and TLCPD of 3.0 mmHg . Thus, tThe only study on glaucoma patients with direct measurement of ICP and simultaneous measurements of IOP and ICP in different postures is a recent investigation by Lindén et al. (2017). In that prospective study on NTG patients compared with healthy age-matched controls, all NTG patients underwent washout of IOP-lowering medication. The findings showed no significant difference between the groups with respect to ICP or TLCPD , so evenAlthough the literature cannot strictly confirm a reduced ICP in NTG, this does not exclude the possibility that an increased TLCPD is a part of the pathophysiology. There are findings of an increased risk of NTG in shunt-treated normal pressure hydrocephalus patients supporting that the ICP lowering effect of the shunt is correlated to development of NTG . AdditioFirstly, the site of measurement of IOP and ICP is not the same. IOP is indirectly measured at the cornea and ICP in the current clinical studies was measured in the spinal canal with a direct measurement through LP. In both IOP and ICP measurements, an assumption is often made that the pressure at LC is the same as at the site of measurement. The finding of Lenfelt et al.  that lumSecondly, body position is crucial in comparison of IOP and ICP. It is well known that both IOP  and ICP Thirdly, the time point of measurement is important. IOP is known to fluctuate depending on the time of the day , but lesFourthly, drugs affecting IOP or ICP need to be considered as they may skew the comparison. Especially in studies on glaucoma and TLCPD, IOP-lowering treatment is often continued during the study, and no washout period is performed. This confounds the results as the IOP will be lower due to treatment.As pointed out previously, a common limitation in studies on TLCPD is that ICP and IOP are not measured in the same posture , 83, 84.An important aspect is the 24-h postural influence on TLCPD in terms of lying down or standing/sitting upright. With the assumption of a communicating system between the intracranial and ONSAS CSF, it has been shown that TLCPD can differ from 12 mmHg in supine to 20 mmHg in upright posture. Assuming that we lie down one third of the time, the 24-h TLCPD average would be approximately 17 mmHg . Thus, iIt is evident that posture plays a key role in the assessment of TLCPD since ICP is much more affected by postural changes than IOP, and that results in large differences in TLCPD during the 24-h cycle. This indicates that there is another control function in the intraocular system compared with the intracranial one. Results from an animal study  have indThere are other theories related to the communication between all spaces of the CSF system. Instead of a deficient occlusion mechanism Fig. , Morgan Another important aspect is whether difference in ICP or TLCPD could be considered clinically relevant. In the case of NTG, a 30% reduction of IOP compared with baseline has been shown to reduce the progression of the disease , 92. ThiA pathological TLCPD is an attractive hypothesis in pathophysiology theories of certain diseases. For IIH, ICP is elevated and for SANS, it is suspected to be elevated and thus reduced or reversed TLCPD is excepted as part of these diseases. For glaucoma and in particular NTG, it is more controversial. The present literature review revealed a large number of review papers, which indicates a great interest in the theory, while only a few research studies in humans have been reported. Initial studies supported the hypothesis while recent findings indicate that simply a reduced ICP might not be a distinct characteristic of the NTG group. Importantly, this does not exclude that elevated TLCPD due to an abnormally low retrolaminar pressure caused by dysfunctional optic nerve sheath mechanisms may be a factor. We note that this is still an emerging field, and interdisciplinary collaboration is required between ophthalmology and neurology expertise and that methodological developments of the current approaches are needed. From the identification of potential postural effects on the CSF communication between the intracranial and retrolaminar space, future challenges include to further study if an occlusion mechanism of the optic nerve sheath exists in the human intraorbital space and if so, investigate elevated TLCPD in relation to failure in this mechanism as a potential pathophysiological component in NTG patients.