Blood Pressure Response and Symptoms During Active Standing Test Among Hospitalized and Outpatients With Heart Failure: Results From the GRAVITY-HF Prospective Observational Cohort Study.

BACKGROUND: We conducted a multicenter, prospective, observational study to describe the incidence of orthostatic hypotension (OH) and orthostatic hypertension (OHtn) and its association with symptoms at standing and outcomes in patients with heart failure (HF). METHODS AND RESULTS: 321 active standing tests were performed in 87 inpatients during admission, and 316 tests were performed in 208 outpatients during follow-up. Blood pressure (BP) was measured by an automatic device 4 times in the supine position and at 1, 3 and 5 minutes of standing. Patients were queried about symptoms of orthostatic intolerance. The incidence of OH and OHtn was similar in both groups at baseline (classical OH 11%-22%, OHtn 3%-8%, depending on definition and timing). Reproducibility of BP changes with standing was low. Up to 50% of cases with abnormal responses were asymptomatic. Symptoms were variable and occurred mainly during the first minute of standing and had a U-shaped association with BP changes. OH in outpatients with HF was associated with a higher risks of death or readmission due to HF. CONCLUSIONS: Patients with HF have variable hemodynamic responses and symptoms during repeated active standing tests. OH might identify outpatients with HF who are at risk of long-term negative outcomes.

The effect of substituent position and solvent on thermal Z‒E isomerization of dihydroquinolylazotetrazole dyes: kinetic, thermodynamic, and spectral approaches.

Kinetic and thermodynamic parameters have been investigated for the thermal Z‒E isomerization of dihydroquinolylazotetrazole dyes with alkyl substituents (Me, t-Bu, and Adm) at positions 1 (dyes 2) and 2 (dyes 3) of the tetrazole moiety in two solvents of different polarity, acetonitrile (MeCN) and toluene. The experimental results show crucial dependence of these parameters on a substituent position in the tetrazole moiety and on a solvent. For dyes 2, Eact and ΔH‡ are lower in MeCN than in toluene that results in a high increase in the lifetimes of the Z isomers: from milliseconds in MeCN to minutes in toluene. For dyes 3, the difference in Eact and ΔH‡ in the two solvents is opposite: Eact and ΔH‡ are by more than 20 kJ mol-1 higher in MeCN, nevertheless, the rate constants for 3 in toluene are comparable with those in MeCN at the ambient temperature and the difference in the behavior is determined by the value of negative entropy of activation. Quantum-chemical calculations of the thermal Z‒E isomerization show the possibility of the process to occur via crossing from the S0 to the thermally induced T1 state. The contribution of this path is highest for 3 in toluene. The analysis of the absorption spectra demonstrates that for the E isomers, the n‒π* and π‒π* transitions are within the long-wavelength absorption band and their positions relative each other are opposite in the solvents: the n‒π* transition is blue-shifted relative to the π‒π* transition in MeCN and is red-shifted in toluene.

Family still matters: Human social motivation across 42 countries during a global pandemic.

The COVID-19 pandemic caused drastic social changes for many people, including separation from friends and coworkers, enforced close contact with family, and reductions in mobility. Here we assess the extent to which people's evolutionarily-relevant basic motivations and goals-fundamental social motives such as Affiliation and Kin Care-might have been affected. To address this question, we gathered data on fundamental social motives in 42 countries (N = 15,915) across two waves, including 19 countries (N = 10,907) for which data were gathered both before and during the pandemic (pre-pandemic wave: 32 countries, N = 8998; 3302 male, 5585 female; M age  = 24.43, SD = 7.91; mid-pandemic wave: 29 countries, N = 6917; 2249 male, 4218 female; M age  = 28.59, SD = 11.31). Samples include data collected online (e.g., Prolific, MTurk), at universities, and via community sampling. We found that Disease Avoidance motivation was substantially higher during the pandemic, and that most of the other fundamental social motives showed small, yet significant, differences across waves. Most sensibly, concern with caring for one's children was higher during the pandemic, and concerns with Mate Seeking and Status were lower. Earlier findings showing the prioritization of family motives over mating motives (and even over Disease Avoidance motives) were replicated during the pandemic. Finally, well-being remained positively associated with family-related motives and negatively associated with mating motives during the pandemic, as in the pre-pandemic samples. Our results provide further evidence for the robust primacy of family-related motivations even during this unique disruption of social life.

Fundamental social motives measured across forty-two cultures in two waves.

How does psychology vary across human societies? The fundamental social motives framework adopts an evolutionary approach to capture the broad range of human social goals within a taxonomy of ancestrally recurring threats and opportunities. These motives-self-protection, disease avoidance, affiliation, status, mate acquisition, mate retention, and kin care-are high in fitness relevance and everyday salience, yet understudied cross-culturally. Here, we gathered data on these motives in 42 countries (N = 15,915) in two cross-sectional waves, including 19 countries (N = 10,907) for which data were gathered in both waves. Wave 1 was collected from mid-2016 through late 2019 (32 countries, N = 8,998; 3,302 male, 5,585 female; Mage = 24.43, SD = 7.91). Wave 2 was collected from April through November 2020, during the COVID-19 pandemic (29 countries, N = 6,917; 2,249 male, 4,218 female; Mage = 28.59, SD = 11.31). These data can be used to assess differences and similarities in people's fundamental social motives both across and within cultures, at different time points, and in relation to other commonly studied cultural indicators and outcomes.

Family Matters: Rethinking the Psychology of Human Social Motivation.

What motives do people prioritize in their social lives? Historically, social psychologists, especially those adopting an evolutionary perspective, have devoted a great deal of research attention to sexual attraction and romantic-partner choice (mate seeking). Research on long-term familial bonds (mate retention and kin care) has been less thoroughly connected to relevant comparative and evolutionary work on other species, and in the case of kin care, these bonds have been less well researched. Examining varied sources of data from 27 societies around the world, we found that people generally view familial motives as primary in importance and mate-seeking motives as relatively low in importance. Compared with other groups, college students, single people, and men place relatively higher emphasis on mate seeking, but even those samples rated kin-care motives as more important. Furthermore, motives linked to long-term familial bonds are positively associated with psychological well-being, but mate-seeking motives are associated with anxiety and depression. We address theoretical and empirical reasons why there has been extensive research on mate seeking and why people prioritize goals related to long-term familial bonds over mating goals. Reallocating relatively greater research effort toward long-term familial relationships would likely yield many interesting new findings relevant to everyday people's highest social priorities.

A Blood-Brain-Barrier-Penetrating Anti-human Transferrin Receptor Antibody Fusion Protein for Neuronopathic Mucopolysaccharidosis II.

Mucopolysaccharidosis II (MPS II) is an X-linked recessive lysosomal storage disease caused by mutations in the iduronate-2-sulfatase (IDS) gene. Since IDS catalyzes the degradation of glycosaminoglycans (GAGs), deficiency in this enzyme leads to accumulation of GAGs in most cells in all tissues and organs, resulting in severe somatic and neurological disorders. Although enzyme replacement therapy with human IDS (hIDS) has been used for the treatment of MPS II, this therapy is not effective for defects in the CNS mainly because the enzyme cannot cross the blood-brain barrier (BBB). Here, we developed a BBB-penetrating fusion protein, JR-141, which consists of an anti-human transferrin receptor (hTfR) antibody and intact hIDS. The TfR-mediated incorporation of JR-141 was confirmed by using human fibroblasts in vitro. When administrated intravenously to hTfR knockin mice or monkeys, JR-141, but not naked hIDS, was detected in the brain. In addition, the intravenous administration of JR-141 reduced the accumulation of GAGs both in the peripheral tissues and in the brain of hTfR knockin mice lacking Ids, an animal model of MPS II. These data provide a proof of concept for the translation of JR-141 to clinical study for the treatment of patients with MPS II with CNS disorders.

Complex formation of albumin with tricarbocyanine dyes containing phosphonate groups.

The spectral characteristics, binding constants with bovine (BSA) and human serum albumin (HSA) and lifetimes of fluorescence in PBS and EtOH solutions and in the presence of BSA in PBS were measured for novel indotricarbocyanine dyes bearing remote phosphonate groups. These parameters are close to those for indocyanine green (ICG) indicating that the Coulomb interaction does not play a significant role in complex formation, and the binding is determined by the interaction of the dye polymethine chain with albumin. The fluorescence lifetimes of the complexes with BSA strongly indicate the formation of complexes of two types with different lifetimes. The complex with a longer fluorescence lifetime (740-800 ps) and major contribution (up to 88%) is bound to the more hydrophobic site and that with a shorter fluorescence lifetime (300-340 ps) to the more hydrophilic site.

Syncope, seizure-induced bradycardia and asystole: two cases and review of clinical and pathophysiological features.

Episodes of transient loss of consciousness (TLOC) are commonly due to syncope or epileptic seizures. The distinction between both entities on clinical grounds and eyewitness accounts can be challenging and is often hampered by similar clinical features. We briefly summarize syncope-related symptoms and present the case of a female patient who suffered from TLOC episodes due to both reflex syncope and epileptic seizures. Seizure-induced syncope is a rare complication particularly of non-generalized temporal lobe seizures and may be suspected in people with epilepsy who report new semiological features with sudden onset of atonia, TLOC and seizure-related falls. We review epidemiological, clinical and electroencephalographic aspects of seizure-related asystole and syncope and discuss their clinical relevance. The implantation of a cardiac pacemaker appears to efficiently prevent seizure-related falls and consecutive injuries and is an important treatment option if full seizure-control cannot be achieved in these patients. We describe a second case of a patient with refractory temporal lobe epilepsy and seizure-related syncope which ceased after the implantation of a cardiac pacemaker.

Differential binding preference of methylpheophorbide a and its diboronated derivatives to albumin and low density lipoproteins.

The tetrapyrrolic macrocycle and the functional groups at its periphery allow for a variety of modifications aimed at multifunctional therapeutic compounds. In particular, conjugation of boron polyhedra yields dual efficacy antitumor photo/ radiosensitizers. Structural optimization of these agents presumes the identification of macromolecules that bind and transport boronated tetrapyrroles. Using spectroscopic methods we demonstrated that methylpheophorbide a forms complexes with serum albumin and low density lipoproteins (LDL) whereas two diboronated derivatives, 13(2),17(3)-[di(o-carboran-1-yl)methoxycarbonyl]pheophorbide a and 13(2),17(3)-[di(1-carba-closo-dodecaboran-1-yl)methoxycarbonyl]pheophorbide a, were capable of binding to LDL but not to albumin. Molecular modeling showed a mode of interaction of methylpheophorbide a with the amino acid residues in the albumin's hemin binding site. In contrast, for diboronated derivatives such interactions are sterically hindered by boron polyhedra, in line with experimentally determined lack of complex formation with albumin. These data strongly suggest that LDL might be the preferred carrier for polycarborane containing methylpheophorbide a derivatives.

Can the result of a tilt test be predicted in the first five minutes?

BACKGROUND: Head-up tilt testing (HUT) plays a pivotal role in the management of vasovagal syncope (VVS). Heart rate variability (HRV) is a well-known method used for noninvasive evaluation of autonomic nervous system activity. However, different results have been obtained in studies that have evaluated the HRV response to HUT in patients with VVS. METHODS: One hundred fourteen patients with recurrent VVS were enrolled in the study. According to the results of HUT, patients were divided into five groups: positive (n = 30) and negative (n = 23) Westminster; positive (n = 44) and negative (n = 11) Italian. Fourteen healthy volunteers with no history of syncope comprised the control group. Spectral indices of HRV variability were analyzed for three short-term intervals. RESULTS: Both protocols showed similar distribution of responses to tilt-testing. In the supine position, significant differences were observed between patients from groups 1, 2 and 3 in comparison with the control and Italian negative groups. They had significantly lower initial results of LF(1) [nu] and LF(1)/HF(1) ratio, and higher HF(1) [nu] values. The onset of HUT in patients with positive Westminster protocol was characterized by an almost two-fold increase in LF [nu] and decrease in HF [nu] compared to all other patients. LF(2)/HF(2) ratio in the Westminster positive group had increased more than five times since the baseline level, while during the last period, LF(3)/HF(3) ratio had increased more than six times. CONCLUSIONS: Patients with VVS have disturbed sympathovagal balance at rest. Our data suggests that the results of HUT could be predicted by analyzing the spectral parameters of HRV during the first five minutes of the test. The reaction to orthostasis in patients with syncope during the Westminster protocol was more severe compared to the Italian protocol group and the control group. Vasovagal response during the Italian protocol may be triggered by drug-induced vasodilatation.

Is it possible to accurately differentiate neurocardiogenic syncope from epilepsy?

Global cerebral hypoperfusion resulting in syncope, and asynchronous discharge of cerebral neurons leading to seizure, are two major mechanisms of transient loss of consciousness. They both have a lot in common in clinical and historical settings, although with a high prevalence of incorrect diagnosis, even by well-trained staff. The aim of this review was to try to combine data from both a cardiologist's and a neurologist's perspective (history taking, special questionnaires, serum prolactin, EEG, CT/MRI, tilt-testing, loop recorders).

Novel boronated chlorin e6-based photosensitizers: synthesis, binding to albumin and antitumour efficacy.

Chlorins, a class of plant porphyrins, are perspective as photosensitizing agents due to light absorption in the long wavelength spectral region and deeper photodamage of tissues. Aiming at optimization of antitumour properties of chlorins, we synthesized a series of boronated derivatives of chlorin e(6) and their complexes containing Zn(II), Pd(II) or Sn(IV). The compounds were synthesized by alkylation of amino or hydroxy derivatives of chlorin e(6) with 1-trifluoromethanesulfonylmethyl-o-carborane. Chlorin e(6) 13(1)-N-{2-[N-(o-carboran-1-yl)methyl]aminoethyl}amide-15(2), 17(3)-dimethyl ester (compound 5) formed complexes with serum albumin, a major porphyrin carrier. The binding constant of these complexes was approximately 4 times bigger than the respective value for the complexes of albumin with boron-free aminochlorin e(6). Compound 5 potently sensitized rat fibroblasts to illumination with monochromatic red light: >98% of cells were necrotic by 24h post-illumination with 1 microM of 5. This compound demonstrated high efficacy in photodynamic therapy of rat M-1 sarcoma. After PDT with 25mg/kg of 5 the residual tumours were significantly smaller than in animals subjected to PDT with equal concentration of boron-free aminochlorin e(6). No signs of general toxicity were detectable after PDT with 5. Thus, boronation can enhance the potency of chlorins in PDT, in particular, due to an increased binding to albumin. Our data expand the therapeutic applicability of boronated chlorins beyond boron neutron capture therapy; these agents emerge as dual efficacy photoradiosensitizers.