Treatment-resistant depression (TRD) is a major contributor to the disability caused by major depressive disorder (MDD). Primary care electronic health records provide an easily accessible approach ...to investigate TRD clinical and genetic characteristics. MDD defined from primary care records in UK Biobank (UKB) and EXCEED studies was compared with other measures of depression and tested for association with MDD polygenic risk score (PRS). Using prescribing records, TRD was defined from at least two switches between antidepressant drugs, each prescribed for at least 6 weeks. Clinical-demographic characteristics, SNP-based heritability (h
) and genetic overlap with psychiatric and non-psychiatric traits were compared in TRD and non-TRD MDD cases. In 230,096 and 8926 UKB and EXCEED participants with primary care data, respectively, the prevalence of MDD was 8.7% and 14.2%, of which 13.2% and 13.5% was TRD, respectively. In both cohorts, MDD defined from primary care records was strongly associated with MDD PRS, and in UKB it showed overlap of 71-88% with other MDD definitions. In UKB, TRD vs healthy controls and non-TRD vs healthy controls h
was comparable (0.25 SE = 0.04 and 0.19 SE = 0.02, respectively). TRD vs non-TRD was positively associated with the PRS of attention deficit hyperactivity disorder, with lower socio-economic status, obesity, higher neuroticism and other unfavourable clinical characteristics. This study demonstrated that MDD and TRD can be reliably defined using primary care records and provides the first large scale population assessment of the genetic, clinical and demographic characteristics of TRD.
Non-coding mutations at the far end of a large gene desert surrounding the SOX9 gene result in a human craniofacial disorder called Pierre Robin sequence (PRS). Leveraging a human stem cell ...differentiation model, we identify two clusters of enhancers within the PRS-associated region that regulate SOX9 expression during a restricted window of facial progenitor development at distances up to 1.45 Mb. Enhancers within the 1.45 Mb cluster exhibit highly synergistic activity that is dependent on the Coordinator motif. Using mouse models, we demonstrate that PRS phenotypic specificity arises from the convergence of two mechanisms: confinement of Sox9 dosage perturbation to developing facial structures through context-specific enhancer activity and heightened sensitivity of the lower jaw to Sox9 expression reduction. Overall, we characterize the longest-range human enhancers involved in congenital malformations, directly demonstrate that PRS is an enhanceropathy, and illustrate how small changes in gene expression can lead to morphological variation.
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•Extreme long-range enhancer clusters overlap PRS patient mutations at the SOX9 locus•PRS enhancers drive stage-specific SOX9 expression in the cranial neural crest•Mandible development has heightened sensitivity to perturbation of SOX9 gene dosage•Deletion of mouse EC1.45 leads to quantitative changes in mandible morphology
Non-coding mutations over a megabase from SOX9 cause the craniofacial disorder Pierre Robin sequence (PRS). Long et al. leverage a human neural crest model to demonstrate that PRS is caused by loss of extreme long-range enhancers active during a restricted developmental window and explore mechanisms underlying the specificity of disease manifestations.
Relaxation Mechanism of the Hydrated Electron Elkins, Madeline H.; Williams, Holly L.; Shreve, Alexander T. ...
Science (American Association for the Advancement of Science),
12/2013, Letnik:
342, Številka:
6165
Journal Article
Recenzirano
The relaxation dynamics of the photoexcited hydrated electron have been subject to conflicting interpretations. Here, we report time-resolved photoelectron spectra of hydrated electrons in a liquid ...microjet with the aim of clarifying ambiguities from previous experiments. A sequence of three ultrashort laser pulses (~100 femtosecond duration) successively created hydrated electrons by charge-transfer-to-solvent excitation of dissolved anions, electronically excited these electrons via the s→p transition, and then ejected them into vacuum. Two distinct transient signals were observed. One was assigned to the initially excited p-state with a lifetime of ~75 femtoseconds, and the other, with a lifetime of ~400 femtoseconds, was attributed to s-state electrons just after internal conversion in a nonequilibrated solvent environment. These assignments support the nonadiabatic relaxation model.
Background:
Proper lower extremity biomechanics during bilateral landing is important for reducing injury risk in athletes returning to sports after anterior cruciate ligament reconstruction (ACLR). ...Although landing is a quick ballistic movement that is difficult to modify, squatting is a slower cyclic movement that is ideal for motor learning.
Hypothesis:
There is a relationship between lower extremity biomechanics during bilateral landing and bilateral squatting in patients with an ACLR.
Study Design:
Descriptive laboratory study.
Methods:
A total of 41 patients after a unilateral ACLR (24 men, 17 women; 5.9 ± 1.4 months after ACLR) completed 15 unweighted bilateral squats and 10 bilateral stop-jumps. Three-dimensional lower extremity kinematics and kinetics were collected, and peak knee abduction angle, knee abduction/adduction range of motion, peak vertical ground-reaction force limb symmetry index (LSI), vertical ground-reaction force impulse LSI, and peak knee extension moment LSI were computed during the descending phase of the squatting and landing tasks. Wilcoxon signed-rank tests were used to compare each outcome between limbs, and Spearman correlations were used to compare outcomes between the squatting and landing tasks.
Results:
The peak vertical ground reaction force, the vertical ground reaction force impulse, and the peak knee extension moment were reduced in the surgical (Sx) limb relative to the nonsurgical (NSx) limb during both the squatting and landing tasks (P < .001). The relationship between squatting and landing tasks was strong for the peak knee abduction angle (R = 0.697-0.737; P < .001); moderate for the frontal plane knee range of motion (NSx: R = 0.366, P = .019; Sx: R = 0.418, P = 0.007), the peak knee extension moment LSI (R = 0.573; P < .001), the vertical ground reaction force impulse LSI (R = 0.382; P < .014); and weak for the peak vertical ground reaction force LSI (R = 0.323; P = .039).
Conclusion:
Patients who have undergone an ACLR continue to offload their surgical limb during both squatting and landing. Additionally, there is a relationship between movement deficits during squatting and movement deficits during landing in patients with an ACLR preparing to return to sports.
Clinical Relevance:
As movement deficits during squatting and landing were related before return to sports, this study suggests that interventional approaches to improve squatting biomechanics may translate to improved landing biomechanics in patients with an ACLR.
Cerebral malaria (CM) is a severe manifestation of malaria that commonly occurs in children and is hallmarked by neurologic symptoms and significant Plasmodium falciparum parasitemia. It is currently ...hypothesized that cerebral hypoperfusion from impaired microvascular oxygen transport secondary to parasitic occlusion of the microvasculature is responsible for cerebral ischemia and thus disease severity. Animal models to study CM, are known as experimental cerebral malaria (ECM), and include the C57BL/6J infected with Plasmodium berghei ANKA (PbA), which is ECM-susceptible, and BALB/c infected with PbA, which is ECM-resistant. Here we sought to investigate whether changes in oxygen (O2) delivery, O2 flux, and O2 utilization are altered in both these models of ECM using phosphorescence quenching microscopy (PQM) and direct measurement of microvascular hemodynamics using the cranial window preparation. Animal groups used for investigation consisted of ECM-susceptible C57BL/6 (Infected, n = 14) and ECM-resistant BALB/c (Infected, n = 9) mice. Uninfected C57BL/6 (n = 6) and BALB/c (n = 6) mice were included as uninfected controls. Control animals were manipulated in the exact same way as the infected mice (except for the infection itself). C57BL/6 ECM animals at day 6 of infection were divided into two cohorts: Early-stage ECM, presenting mild to moderate drops in body temperature (>34 < 36 °C) and Late-stage ECM, showing marked drops in body temperature (<33 °C). Data taken from new experiments conducted with these animal models were analyzed using a general linear mixed model. We constructed three general linear mixed models, one for total O2 content, another for total O2 delivery, and the third for total O2 content as a function of convective flow. We found that in both the ECM-susceptible C57BL/6J model and ECM-resistant BALB/c model of CM, convective and diffusive O2 flux along with pial hemodynamics are impaired. We further show that concomitant changes in p50 (oxygen partial pressure for 50% hemoglobin saturation), only 5 mmHg in the case of late-stage CM C57BL/6J mice, and O2 diffusion result in insufficient O2 transport by the pial microcirculation, and that both these changes are required for late-stage disease. In summary, we found impaired O2 transport and O2 affinity in late-stage ECM, but only the former in either early-stage ECM and ECM-resistant strains.
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•The study investigated whether changes in oxygen delivery, oxygen flux, and oxygen utilization are altered in experimental cerebral malaria (ECM) models, which are used to study cerebral malaria in animals.•The study found that both ECM-susceptible and ECM-resistant models of cerebral malaria showed impaired oxygen transport and oxygen affinity in late-stage disease, but only impaired oxygen transport in early-stage disease or ECM-resistant strains.•The study highlights the importance of understanding the microvascular hemodynamics in cerebral malaria and the potential for phosphorescence quenching microscopy and direct measurement of microvascular hemodynamics using the cranial window preparation as tools to study this disease.
Abstract
Fluid resuscitation following severe inflammation-induced hypoperfusion is critical for the restoration of hemodynamics and the prevention of multiorgan dysfunction syndrome during septic ...shock. Fluid resuscitation with commercially available crystalloid and colloid solutions only provides transient benefits, followed by fluid extravasation and tissue edema through the inflamed endothelium. The increased molecular weight (M.W.) of polymerized human serum albumin (PolyHSA) can limit fluid extravasation, leading to restoration of hemodynamics. In this prospective study, we evaluated how fluid resuscitation with PolyHSA impacts the hemodynamic and immune response in a lipopolysaccharide (LPS) induced endotoxemia mouse model. Additionally, we evaluated fluid resuscitation with PolyHSA in a model of polymicrobial sepsis induced by cecal ligation and puncture (CLP). Resuscitation with PolyHSA attenuated the immune response and improved the maintenance of systemic hemodynamics and restoration of microcirculatory hemodynamics. This decrease in inflammatory immune response and maintenance of vascular wall shear stress likely contributes to the maintenance of vascular integrity following fluid resuscitation with PolyHSA. The sustained restoration of perfusion, decrease in pro-inflammatory immune response, and improved vascular integrity that results from the high M.W. of PolyHSA indicates that a PolyHSA based solution is a potential resuscitation fluid for endotoxic and septic shock.
The microcirculation is a complex network of vessels ranging from as large as 100 μm to as small as 5 μm. This complex network is responsible for the regulation of oxygen to the surrounding tissues ...and ensures metabolite washout. With a more complete understanding of the microcirculation's physiologic and pathologic tendencies, engineers can create new solutions to combat blood pathologies and shock-related diseases. Over the last number of decades a grown interest in the microcirculation has resulted in the development of fundamental techniques to quantify the microvasculature flow and the release of oxygen to tissues.
For the past thirty years, hemoglobin-based oxygen carriers (HBOCs) have been under development as a red blood cell substitute. Side-effects such as vasoconstriction, oxidative injury, and cardiac ...toxicity have prevented clinical approval of HBOCs. Recently, high molecular weight (MW) polymerized human hemoglobin (PolyhHb) has shown positive results in rats. Studies have demonstrated that high MW PolyhHb increased O
delivery, with minimal effects on blood pressure, without vasoconstriction, and devoid of toxicity. In this study, we used guinea pigs to evaluate the efficacy and safety of high MW PolyhHb, since like humans guinea pigs cannot produce endogenous ascorbic acid, which limits the capacity of both species to deal with oxidative stress. Hence, this study evaluated the efficacy and safety of resuscitation from severe hemorrhagic shock with high MW PolyhHb, fresh blood, and blood stored for 2 weeks. Animals were randomly assigned to each experimental group, and hemorrhage was induced by the withdrawal of 40% of the blood volume (BV, estimated as 7.5% of body weight) from the carotid artery catheter. Hypovolemic shock was maintained for 50 min. Resuscitation was implemented by infusing 25% of the animal's BV with the different treatments. Hemodynamics, blood gases, total hemoglobin, and lactate were not different before hemorrhage and during shock between groups. The hematocrit was lower for the PolyhHb group compared to the fresh and stored blood groups after resuscitation. Resuscitation with stored blood had lower blood pressure compared to fresh blood at 2 h. There was no difference in mean arterial pressure between groups at 24 h. Resuscitation with PolyhHb was not different from fresh blood for most parameters. Resuscitation with PolyhHb did not show any remarkable change in liver injury, inflammation, or cardiac damage. Resuscitation with stored blood showed changes in liver function and inflammation, but no kidney injury or systemic inflammation. Resuscitation with stored blood after 24 h displayed sympathetic hyper-activation and signs of cardiac injury. These results suggest that PolyhHb is an effective resuscitation alternative to blood. The decreased toxicities in terms of cardiac injury markers, vital organ function, and inflammation following PolyhHb resuscitation in guinea pigs indicate a favorable safety profile. These results are promising and support future studies with this new generation of PolyhHb as alternative to blood when blood is unavailable.
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