Resting Heart Rate Affects Heart Response to Cold-Water Face Immersion Associated with Apnea.

The regular cardiac response to immersion of the face in cold water is reduction in heart rate (HR). The highly individualized and unpredictable course of the cardiodepressive response prompted us to investigate the relationship between the cardiac response to face immersion and the resting HR. The research was conducted with 65 healthy volunteers (37 women and 28 men) with an average age of 21.13 years (20-27 years) and a BMI of 21.49 kg/m2 (16.60-28.98). The face-immersion test consisted of stopping breathing after maximum inhaling and voluntarily immersing the face in cold water (8-10 °C) for as long as possible. Measurements included determination of minimum, average, and maximum HR at rest and minimum and maximum HR during the cold-water face-immersion test. The results indicate a strong relationship between the cardiodepressive reaction of the immersion of the face and the minimum HR before the test, as well as a relationship between the maximum HR during the test and the maximum HR at rest. The results also indicate a strong influence of neurogenic HR regulation on the described relationships. The parameters of the basal HR can, therefore, be used as prognostic indicators of the course of the cardiac response of the immersion test.

Successful Implementation of Menstrual Cycle Biomarkers in the Treatment of Infertility in Polycystic Ovary Syndrome-Case Report.

Polycystic ovary syndrome (PCOS) is the most common cause of anovulatory infertility. Absent, impaired, or rare ovulation induces progesterone deficiency in the luteal phase, which is a critical problem in PCOS. A usual pattern of progesterone administration from a fixed and arbitrary pre-determined day of a menstrual cycle may preserve infertility but can easily be avoided. We present the case of a 29-year-old infertile woman who had been ineffectively treated for over two years. We introduced a line of therapy that was suited to her individual menstrual cycle by implementing biomarker recording. Supplementation based on a standardized observation of the basal body temperature (BBT) and cervical mucus stopped the vicious circle of absent ovulation and hyperandrogenism, restoring regular bleeding, ovulation cycles, and fertility. The implementation of a reliable fertility awareness method (FAM), accompanied by a standardized teaching methodology and periodic review of the observations recorded by the patient, validated through an ultrasound examination and plasma gonadotropins, estrogens, and progesterone concentrations, is key to achieving therapeutic success. The presented case is an example of a clinical vignette for many patients who have successfully managed to improve their fertility and pregnancy outcomes by applying the principles of a personalized treatment approach together with gestagens by recording their fertility biomarkers.

Heart Rate Variability at Rest Predicts Heart Response to Simulated Diving.

A characteristic feature of the cardiac response to diving is the uncertainty in predicting individual course. The aim of the study was to determine whether resting regulatory heart rate determinants assessed before diving may be predictors of cardiac response in a simulated diving test. The research was conducted with 65 healthy volunteers (37 women and 28 men) with an average age of 21.13 years (20-27 years) and a BMI of 21.49 kg/m2 (16.60-28.98). The simulated diving test consisted of stopping breathing after maximum inhaling and voluntarily immersing the face in water (8-10 °C) for as long as possible. The measurements included heart rate variability (HRV) analysis before diving and determination of the course of the cardiac response to diving-minimum and maximum heart rate (HR). The results indicate that minimum HR during diving (MIN_div) is dependent on the short-term HRV measures, which proves the strong influence of the parasympathetic system on the MIN_div. The lack of dependence of MIN_div on short-term HRV in women may be associated with differences in neurogenic HR regulation in women and men. In conclusion, cardiac response to simulated diving is strictly dependent on the autonomic regulation of the heart rhythm under resting conditions. The course of the cardiac response to diving and its relationship with resting HRV appears to be gender dependent.

Promising effects of xanthine oxidase inhibition by allopurinol on autonomic heart regulation estimated by heart rate variability (HRV) analysis in rats exposed to hypoxia and hyperoxia.

BACKGROUND: It has long been suggested that reactive oxygen species (ROS) play a role in oxygen sensing via peripheral chemoreceptors, which would imply their involvement in chemoreflex activation and autonomic regulation of heart rate. We hypothesize that antioxidant affect neurogenic cardiovascular regulation through activation of chemoreflex which results in increased control of sympathetic mechanism regulating heart rhythm. Activity of xanthine oxidase (XO), which is among the major endogenous sources of ROS in the rat has been shown to increase during hypoxia promote oxidative stress. However, the mechanism of how XO inhibition affects neurogenic regulation of heart rhythm is still unclear. AIM: The study aimed to evaluate effects of allopurinol-driven inhibition of XO on autonomic heart regulation in rats exposed to hypoxia followed by hyperoxia, using heart rate variability (HRV) analysis. MATERIAL AND METHODS: 16 conscious male Wistar rats (350 g): control-untreated (N = 8) and pretreated with Allopurinol-XO inhibitor (5 mg/kg, followed by 50 mg/kg), administered intraperitoneally (N = 8), were exposed to controlled hypobaric hypoxia (1h) in order to activate chemoreflex. The treatment was followed by 1h hyperoxia (chemoreflex suppression). Time-series of 1024 RR-intervals were extracted from 4kHz ECG recording for heart rate variability (HRV) analysis in order to calculate the following time-domain parameters: mean RR interval (RRi), SDNN (standard deviation of all normal NN intervals), rMSSD (square root of the mean of the squares of differences between adjacent NN intervals), frequency-domain parameters (FFT method): TSP (total spectral power) as well as low and high frequency band powers (LF and HF). At the end of experiment we used rat plasma to evaluate enzymatic activity of XO and markers of oxidative stress: protein carbonyl group and 8-isoprostane concentrations. Enzymatic activity of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) were measures in erythrocyte lysates. RESULTS: Allopurinol reduced oxidative stress which was the result of hypoxia/hyperoxia, as shown by decreased 8-isoprostane plasma concentration. XO inhibition did not markedly influence HRV parameters in standard normoxia. However, during hypoxia, as well as hyperoxia, allopurinol administration resulted in a significant increase of autonomic control upon the heart as shown by increased SDNN and TSP, with an increased vagal contribution (increased rMSSD and HF), whereas sympathovagal indexes (LF/HF, SDNN/rMSSD) remained unchanged. CONCLUSIONS: Observed regulatory effects of XO inhibition did not confirm preliminary hypothesis which suggested that an antioxidant such as allopurinol might activate chemoreflex resulting in augmented sympathetic discharge to the heart. The HRV regulatory profile of XO inhibition observed during hypoxia as well as post-hypoxic hyperoxia corresponds to reported reduced risk of sudden cardiovascular events. Therefore our data provide a new argument for therapeutical use of allopurinol in hypoxic conditions.

Effect of ethyl pyruvate on skeletal muscle metabolism in rats fed on a high fat diet.

Impaired mitochondrial capacity may be implicated in the pathology of chronic metabolic diseases. To elucidate the effect of ethyl pyruvate supplementation on skeletal muscles metabolism we examined changes in activities of mitochondrial and antioxidant enzymes, as well as sulfhydryl groups oxidation (an indirect marker of oxidative stress) during the development of obesity. After 6 weeks feeding of control or high fat diet, Wistar rats were divided into four groups: control diet, control diet and ethyl pyruvate, high fat diet, and high fat diet and ethyl pyruvate. Ethyl pyruvate was administered as 0.3% solution in drinking water, for the following 6 weeks. High fat diet feeding induced the increase of activities 3-hydroxyacylCoA dehydrogenase, citrate synthase, and fumarase. Moreover, higher catalase and superoxide dismutase activities, as well as sulfhydryl groups oxidation, were noted. Ethyl pyruvate supplementation did not affect the mitochondrial enzymes' activities, but induced superoxide dismutase activity and sulfhydryl groups oxidation. All of the changes were observed in soleus muscle, but not in extensor digitorum longus muscle. Additionally, positive correlations between fasting blood insulin concentration and activities of catalase (p = 0.04), and superoxide dismutase (p = 0.01) in soleus muscle were noticed. Prolonged ethyl pyruvate consumption elevated insulin concentration, which may cause modifications in oxidative type skeletal muscles.

Novel Bradykinin Analogues Modified in the N-Terminal Part of the Molecule with a Variety of Acyl Substituents.

In the current work we present some pharmacological characteristics of ten new analogues of bradykinin (Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg) modified in the N-terminal part of the molecule with a variety of acyl substituents. Of the many acylating agents used previously with B(2) receptor antagonists, the following residues were chosen: 1-adamantaneacetic acid (Aaa), 1-adamantanecarboxylic acid (Aca), 4-tert-butylbenzoic acid (t-Bba), 4-aminobenzoic acid (Aba), 12-aminododecanoic acid (Adc), succinic acid (Sua), 4-hydroxybenzoic acid, 4-hydroxy-3-methoxybenzoic acid, 3-(4-hydroxyphenyl)propionic acid and 6-hydroxy-2-naphthoic acid. Biological activity of the compounds was assessed in the in vivo rat blood pressure test and the in vitro rat uterus test. Surprisingly, N-terminal substitution of the bradykinin peptide chain itself with aforementioned groups resulted in antagonists of bradykinin in the pressor test and suppressed agonistic potency in the uterotonic test. These interesting findings need further studies as they can be helpful for designing more potent B(2) receptor blockers.

[Complex profile of the reflex diving response]. / Zlozony profil odruchowej odpowiedzi na nurkowanie.

Breath-holding coupled with face cooling triggers a set of the reflex cardiovascular responses, defined as a diving reflex. The major reflex responses include a decrease in heart rate and peripheral vasoconstriction with an increase of arterial pressure to evoke central blood pooling with preferential provision of the brain and heart perfusion. Due to high individual variability and situational dependence the individual course of the reflex response is hardly predictable. Heart rhythm disturbances are the major, sometimes fatal complications of the response. This review is an outline of causing factors, circumstances, mechanisms and the effects of the diving reflex and their practical implications, including risk factors of the critical arrhythmias occurred in diving.

Body composition and physical capacity of elite adolescent female tennis players.

The study was performed to evaluate relationships among the major anthropological parameters: (body mass - BM, height, body mass index - BMI, lean body mass - FFM, proportion of fat mass -Fat%), physical capacity, and the tennis federations ranking position as an index of the temporal sport success. Seventeen elite female tennis players, divided into three age-matched groups (15, 16, and 17 yr) participated in this study. All the players had a national singles ranking (positions between 1st-80th) and in International Tennis Federation's Junior Circuit ranking (ITFJC; 21st to 990th position of ITF). Body composition was assessed via bioelectrical impedance. Maximal aerobic capacity (VO2max) was calculated from the distance covered in 12-min run test via Cooper's formula. Wingate test with lactate assay was used as an index of anaerobic capacity. There was a significant age-related trend for an increase in BM, height, FFT, and Fat%, associated with impressive shift of the anthropological indexes of body weight and height, assessed by the percentile chart analysis. The unexpected body growth spurt evidently observed between aged 15 and 17 is supposed to reflect a delay in somatic development, related to extensive exercise load. Body composition did not correlate to the ranking positions. All tested tennis players revealed excellent aerobic capacity associated with poor indices of anaerobic fitness. The position in the tennis federations rankings correlated to VO2max but not with maximal power or maximal work output assessed by Wingate test. In the whole group the maximal power and work output were proportional to BMI and FFM, but not to Fat%. In conclusion, in light of the contradictory reports concerning a possible link between strenuous regular exercise performed by young children and adolescent elite sportsmen our data indicate a delayed growth spurt in the elite female tennis players to occur between ages 15 and 17. The other important finding in terms of prospective for future professional career is the evident link between aerobic capacity and ranking positions.

Variable profile of individual heart rate responses to cold water immersion apnea in healthy late adolescent men.

Holding breath combined with immersion of face in cool water induces diving reflex consisting in bradycardia, peripheral vasoconstriction, and preferential redistribution of blood to the vital organs. The individual responses are variable, highly expressed in young children to weaken with age. Detailed assessment of the cardiac response to diving in late adolescents who are mostly prone to unexpected diving experiments and related complications are of practical importance. The study was performed to the investigate the heart rate (HR) response to controlled breath-hold diving in cold water in young healthy late adolescents aged 17.5 - 20.4. Twenty volunteers performed a procedure consisting in immersion of face in cold water during possibly long breath-holding. Beat-to-beat HR was assessed from the continuous ECG recording. Average diving time (tD) was 77.5±10.5 s, ranging from 61.7 to 95.4 s. Apnea and face immersion induced a biphasic response: an increase in HR was followed by its gradual decrease to reach a final limit of the response 47.7±9.0 beats/min at 55.2±16.1 s of dive. Within a variable time course of the evoked responses, two patterns of the HR decrease were distinguished: monoexponential decay functions fitted best for 8 (40%) subjects with a constant rate τ 31.3±11.4 s-1, whereas the 60% majority displayed a two phase negative chronotropic effect with constant rates: τ1 10.3±4.2 s-1 and τ1 25.5±10.1 s-1. The initial, anticipatory excitation influenced the HR response: the higher was the initial HR increase, the more pronounced was bradycardia. Disturbances of heart rhythm were observed in majority of subjects: supraventricular ectopic beats (40%), ventricular beats (20%), I-degree AV block (30%), II-degree Mobitz I block (15%), junctional rhythm (60%). In one case pair of ventricular ectopic beats looked severe and the trial was rapidly terminated. In conclusion, the unquestionable potency of late adolescents towards diving challenges, accompanied with a vigorous emotionally driven initial cardioexcitation meets a relevant vulnerability for arrhythmias.

Novel analogues of bradykinin conformationally restricted in the C-terminal part of the molecule.

In the present work, achiral non-coded amino acids, N-(Bzl)-Gly, X(1) or X(2) , were substituted at position 7 of the model B(2) receptor antagonist [D-Arg(0) , Hyp(3) , Thi(5, 8) , D-Phe(7) ]-BK. The N-terminal amino group of the analogues was either free or acylated with 1-Aca or Aaa. Biological activity of the compounds was assessed in the in vitro rat uterus test and the in vivo rat blood pressure test. The X(1) (7) substitution resulted in a decrease in antagonistic potency of the new peptide in both assays. The X(2) (7) and N-(Bzl)-Gly(7) substituted analogues showed weak agonistic properties in the rat uterus test. Interestingly, the latter compound exhibited dual activity in the pressor test, i.e. intrinsic vasodepressor action and at the same time a weak antagonistic effect. Acylation of the N-terminus enhanced antagonistic properties of the resulting peptides in the rat blood pressure test in the case of compounds containing X(1) or X(2) modification. Our studies provide new information about structure-activity relationship of the BK antagonists which may be helpful for designing more potent B(2) receptor blockers.

New bradykinin B(2) receptor antagonists - influence of C-terminal segment modifications on their pharmacological properties.

In the present study we describe the synthesis and some pharmacological properties of eight new analogues of bradykinin (BK). Two peptides were designed by substitution of position 7 or 8 of the known [D-Arg(0),Hyp(3),Thi(5,8),D-Phe(7)]BK antagonist (Stewart's antagonist) with L-pipecolic acid (L-Pip). The next two analogues were obtained by replacement of the d-Phe residue in position 7 of the Stewart's peptide with L-beta(2)-isoproline (L-beta(2)-iPro) or L-beta(3)-homoproline (L-beta(3)-hPro). The four analogues mentioned above were also prepared in N-acylated form with 1-adamantaneacetic acid (Aaa). Biological activity of the compounds was assessed by isolated rat uterus and rat blood pressure tests. Our results showed that L-Pip in position 7 slightly increased antagonistic potency in the blood pressure test, but it turned the analogue into an agonist in the rat uterus test. Replacement of Thi by L-Pip in position 8 also enhanced antagonism in the rat pressure test but preserved the antagonism in the rat uterus test. L-beta(2)-iPro or L-beta(3)-hPro in position 7 decreased the potencies in both tests. We also demonstrated that acylation of the N-terminus did not increase, as was claimed previously, the antagonistic potencies of the resulting peptides. The results thus support the hypothesis about the existence of different types of BK receptors in the rat uterus and blood vessels. Our studies provide new information about the structure-activity relationship of BK antagonists which may help in designing more potent BK receptor blockers.

Mutational and genotype-phenotype correlation analyses in 28 Polish patients with Cornelia de Lange syndrome.

Cornelia de Lange syndrome (CdLS) is a multisystem congenital anomaly disorder characterized by prenatal and postnatal growth retardation, developmental delay, distinctive facial dysmorphism, limb malformations, and multiple organ defects. Mutations in the NIPBL gene have been discovered recently as a major etiology for this syndrome, and were detected in 27-56% of patients. Two groups have found significant differences in the severity or penetrance of some phenotypes between mutation positive and mutation negative patients. Different clinical features have also been described among patients with missense versus truncating mutations. In this study, we identified 13 NIPBL mutations in 28 unrelated Polish CdLS patients (46.4%), 11 were novel. Mutation positive patients were more severely affected in comparison to mutation negative individuals with respect to weight, height, and mean head circumference at birth, facial dysmorphism and speech impairment. Analyses of combined data from this and the two previous studies revealed that the degree of growth, developmental delay and limb defects showed significant differences between patients with and without mutations and between patients with missense and truncating mutations, whereas only a portion of these features differed significantly in any individual study. Furthermore, bioinformatic analyses of the NIPBL protein revealed several novel domains, which may give further clues about potential functions of this protein.

New bradykinin analogues modified in the C-terminal part with sterically restricted 1-aminocyclohexane-1-carboxylic acid.

In the present work, a sterically constrained noncoded amino acid, 1-aminocyclohexane-1-carboxylic acid (Acc), was substituted in position 8 of the peptide chain of bradykinin (BK) and position 6, 7, or 8 of its B2 receptor antagonist [D-Arg0,Hyp3,Thi,(5,8)D-Phe7]BK, previously synthesized by Stewart's group, to reduce the flexibility of the peptides, thus forcing the peptide backbone and side chains to adopt specific orientations. Knowing that acylation of the N-terminus of several known B2 blockers with a variety of bulky groups has consistently improved their antagonistic potency in the rat blood pressure assay, the Acc substituted analogues were also synthesized in the N-acylated form with 1-adamantaneacetic acid (Aaa). The activity of eight new analogues was assayed in isolated rat uterus and in rat blood pressure tests. The results clearly demonstrated the importance of the position in the peptide chain into which the sterically restricted Acc residue was inserted. Meanwhile, Acc at positions 6 and 7 led to reduction of antagonistic qualities or even restored the agonism, respectively. Acc at position 8 enhanced antagonistic qualities in both tests. The Acc at position 8 of BK strongly reduced the agonistic potency. In most cases acylation of the N-terminus led either to enhancement of antagonistic potencies or to further decrease of agonistic potency. Our findings offer new possibilities for designing new potent and selective B2 blockers.

[Unexpected failure of antioxidant clinical trials]. / Nieoczekiwane niepowodzenia prób klinicznych z antyoksydantami.

Data from a variety of experimental studies suggesting benefits of the antioxidant supplementation were confronted with those from clinical trials and large metaanalyses which have failed to prove those benefits. Major directions of the biological effects of reactive oxygen species (ROS) and antioxidants were specified. In particular, plausible mechanisms through antioxidants may disturb physiological functions were discussed. The regulatory aspects of ROS potency, and the ways antioxidants may disturb homeostasis were taken particularly into account. Directions of prospective research towards practical use of antioxidants were suggested.