Human Analogue Research Articles

A preliminary investigation to determine the suitability of pigs as human analogues for post-mortem lipid analysis

The determination of time since death is a major challenge to law enforcement when faced with the discovery of human remains. This is due to the fact that decomposition is a complex, dynamic process influenced by several abiotic and biotic factors. For decades, post-mortem decomposition studies have used pigs as human analogues due to ethical and legal restrictions surrounding the use of human cadavers for such research. However, few comparative studies have been conducted to assess the suitability of these analogues. Recent forensic studies have successfully demonstrated the use of post-mortem lipids in textiles as a method to obtain vital information about decomposition process. The current investigation involved two studies: Trial 1 (summer) and Trial 2 (winter). Each trial with n = 1 human cadaver and n = 2 pigs. Samples were collected over a timeline of 105 days post-placement and analyzed using attenuated total reflectance (ATR-) Fourier-transform infrared (FTIR) spectroscopy. The data was then statistically assessed using functional principal component analysis, semi-parametric regression modeling and analysis of variance. The results demonstrated a clear statistically significant interspecies difference between pigs and humans in both trials. The preliminary implications of this study suggest that pigs are not suitable analogues for humans in decomposition research and have broader implications that caution the direct translation of decomposition data obtained from pigs to real human casework, particularly with respect to time since death estimations.

B cell-dependent EAE induces visual deficits in the mouse with similarities to human autoimmune demyelinating diseases

BackgroundIn the field of autoimmune demyelinating diseases, visual impairments have extensively been studied using the experimental autoimmune encephalomyelitis (EAE) mouse model, which is classically induced by immunization with myelin oligodendrocyte glycoprotein peptide (MOG35–55). However, this model does not involve B cells like its human analogs. New antigens have thus been developed to induce a B cell-dependent form of EAE that better mimics human diseases.MethodsThe present study aimed to characterize the visual symptoms of EAE induced with such an antigen called bMOG. After the induction of EAE with bMOG in C57BL/6J mice, visual function changes were studied by electroretinography and optomotor acuity tests. Motor deficits were assessed in parallel with a standard clinical scoring method. Histological examinations and Western blot analyses allowed to follow retinal neuron survival, gliosis, microglia activation, opsin photopigment expression in photoreceptors and optic nerve demyelination. Disease effects on retinal gene expression were established by RNA sequencing.ResultsWe observed that bMOG EAE mice exhibited persistent loss of visual acuity, despite partial recovery of electroretinogram and motor functions. This loss was likely due to retinal inflammation, gliosis and synaptic impairments, as evidenced by histological and transcriptomic data. Further analysis suggests that the M-cone photoreceptor pathway was also affected.ConclusionTherefore, by documenting visual changes induced by bMOG and showing similarities to those seen in diseases such as multiple sclerosis and neuromyelitis optica, this study offers a new approach to test protective or restorative ophthalmic treatments.

Positional scanning of natural product hispidol’s ring-B: discovery of highly selective human monoamine oxidase-B inhibitor analogues downregulating neuroinflammation for management of neurodegenerative diseases

Multifunctional molecules might offer better treatment of complex multifactorial neurological diseases. Monoaminergic pathways dysregulation and neuroinflammation are common convergence points in diverse neurodegenerative and neuropsychiatric disorders. Aiming to target these diseases, polypharmacological agents modulating both monoaminergic pathways and neuroinflammatory were addressed. A library of analogues of the natural product hispidol was prepared and evaluated for inhibition of monoamine oxidases (MAOs) isoforms. Several molecules emerged as selective potential MAO B inhibitors. The most promising compounds were further evaluated in vitro for their impact on microglia viability, induced production of proinflammatory mediators and MAO-B inhibition mechanism. Amongst tested compounds, 1p was a safe potent competitive reversible MAO-B inhibitor and inhibitor of microglial production of neuroinflammatory mediators; NO and PGE2. In-silico study provided insights into molecular basis of the observed selective MAO B inhibition. This study presents compound 1p as a promising lead compound for management of neurodegenerative disease.

Time-series analysis of recent antihyperglycemic medication prescribing trends for a diverse sample of Medicare enrollees with type 2 diabetes mellitus in an integrated health system.

Despite high type 2 diabetes mellitus (T2DM) prevalence in Medicare enrollees, newer therapeutic options, and revised treatment guidelines, little is known about US antihyperglycemic prescribing trends after 2015. This research describes recent monthly antihyperglycemic prescribing trends in a large, diverse population of Medicare enrollees from the US Mid-Atlantic region. Encounter data (July 2018-July 2020) for Medicare enrollees 65 years of age or older with T2DM were extracted from electronic health records of a large integrated health system. Descriptive time-series regression models were estimated to describe monthly prescribing rates (ie, prescription orders per 100 eligible plan members with T2DM) overall and by medication subgroups for all-eligible and continuously-eligible samples. Trends in monthly prescription orders per 100 eligible plan members with T2DM were reported. The monthly all-eligible member sample (n > 22,000) exhibited an overall positive baseline monthly prescribing rate of 23.88 T2DM medication orders per 100 members with T2DM and a significant positive monthly prescribing rate trend (ie, change) of 0.12 T2DM medication orders per 100 members with T2DM (P < 0.05). Subgroup T2DM medication order rates per 100 members with T2DM at baseline were 16.28 for first-generation medications, 3.87 for human insulins, 3.04 for insulin analogs, 0.58 for second-generation medications, and 0.11 for combination medications. Human insulins, insulin analogs, and second-generation medications had positive monthly trends (P < 0.05). Among second-generation medications, sodium-glucose cotransporter 2 (SGLT-2) inhibitors and glucagon-like peptide 1 (GLP-1) agonists had positive monthly trends (P < 0.05). Continuously eligible members with T2DM (n = 19,185) had no significant overall monthly prescribing trend; however, human insulins, insulin analogs, and second-generation medications and the SGLT-2 inhibitor class had positive monthly prescribing trends (P < 0.05). In a diverse Medicare sample, this study observed increasing monthly trends for second-generation medications, human insulins, and insulin analogs consistent with emerging evidence. Among second-generation medications, SGLT-2 inhibitors became the most commonly prescribed over time.

Comparison between human liver microsomes and the fungus Cunninghamella elegans for biotransformation of the synthetic cannabinoid JWH-424 having a bromo-naphthyl moiety analysed by high-resolution mass spectrometry.

JWH-424, (8-bromo-1-naphthyl)(1-pentyl-1H-indol-3-yl)methanone, is a synthetic cannabinoid, which is a brominated analogue of JWH-018, one of the best-known synthetic cannabinoids. Despite the structural similarity to JWH-018, little is known about JWH-424 including its metabolism. The aim of the study was to compare human liver microsomes (HLM) and the fungus Cunninghamella elegans as the metabolism catalysts for JWH-424 to better understand the characteristic actions of the fungus in the synthetic cannabinoid metabolism. JWH-424 was incubated with HLM for 1h and Cunninghamella elegans for up to 72h. The HLM incubation mixtures were diluted with methanol and fungal incubation mixtures were extracted with dichloromethane and reconstituted in methanol before analyses by liquid chromatography-high-resolution mass spectrometry (LC-HRMS). HLM incubation resulted in production of ten metabolites through dihydrodiol formation, hydroxylation, and/or ipso substitution of the bromine with a hydroxy group. Fungal incubation led to production of 23 metabolites through carboxylation, dihydrodiol formation, hydroxylation, ketone formation, glucosidation and/or sulfation. Generally, HLM models give good predictions of human metabolites and structural analogues are metabolised in a similar fashion. However, major hydroxy metabolites produced by HLM were those hydroxylated at naphthalene instead of pentyl moiety, the major site of hydroxylation for JWH-018. Fungal metabolites, on the other hand, had undergone hydroxylation mainly at pentyl moiety. The metabolic disagreement suggests the necessity to verify the human metabolites in authentic urine samples, while H9 and H10 (hydroxynaphthalene), H8 (ipso substitution), F22 (hydroxypentyl), and F17 (dihydroxypentyl) are recommended for monitoring of JWH-424 in urinalysis.

The Subjective Habitability & Acceptability Questionnaire (SHAQ): Development and Validation.

Describe the development and validation of the Subjective Habitability & Acceptability Questionnaire (SHAQ). Habitat area size, layout, and design may impact individual and team behavioral health and performance (BHP) outcomes in operational environments. However, there are no standardized measures of these relationships. SHAQ is a modular survey consisting of two 6-item scales: BHP Outcomes (Performance of Individual Activities, Performance of Group Activities, Mood, Psychological Stress, Sleep, and Social Interactions) and Habitability Moderators (Privacy, Social Density, Efficiency, Control, Comfort, and Convenience). We collected SHAQ data from NASA's Human Exploration Research Analog (HERA) crews (n = 19) in reference to multiple habitat areas (Sleep/Bedroom, Hygiene/Bathroom, Work/Office/Workshop, and Food Preparation/Kitchen/Galley) in the HERA operational environment, private hotel rooms, and individual home habitats. SHAQ has high construct validity (single factor solutions, mean item factor loading = 0.760, mean % variance = 60.37), internal consistency and reliability (item mean α = 0.880, mean ω=0.894, mean ICC = 0.430), concurrent validity (mean item r with System Usability Scale = 0.42), and discriminant validity (e.g., significantly higher facilitation of group activities in HERA Work/Office/Workshop and Food Preparation/Kitchen/Galley areas vs. Hygiene/Bathroom and Sleep/Bedroom areas; significantly higher ratings of privacy, comfort, and convenience in hotel vs. HERA). SHAQ is a reliable, valid, and sensitive measure of BHP impacts of habitat size and layout. SHAQ can be used to inform evidence-based recommendations and thresholds for habitat area size, layout, and design options to support individual and team BHP in operational environments.

Assessment of Physiological Responses During Field Science Task Performance: Feasibility and Future Needs.

ObjectiveBy understanding the physiological demands of different types of tasks that will be performed during extravehicular activity (EVA) on Mars, human performance safety risks can be mitigated. In addition, such understanding can assist in planning EVAs with an appropriate balance of human health and safety with scientific mission return.BackgroundThis paper describes the results of a study of technical feasibility performed within a Mars human research analog, with participants conducting scientifically relevant planetary science sample analysis and return tasks in two distinct field locations.MethodsThe authors collected heart rate, respiration rate, and heart rate variability (HRV) data, using commercial off-the-shelf hardware and software from study participants as they performed field science tasks within a concept of operations for a Mars science return human expedition mission. These data were remotely monitored, shared in real time, and later analyzed to identify different responses to different tasks in order to determine if there were any predictable or consistent patterns among participants.ResultsIt was ultimately determined that, while differences exist between responses to tasks, they are highly subject to multiple sources of individual variability, dynamics of evolving field science tasks, and demands of a demanding physical environment. Further, distributional analyses of participants do not support parametric statistical analysis techniques.ConclusionThe authors conclude that the physiology of individual astronauts should be extensively studied and modeled to support individualized automated monitoring tools for each crew member that is sent to Mars. Application: Physiological monitoring for specialized populations will require significant individual-level analysis, baselining, and bootstrap statistical methods to enable appropriate human performance determinations.

Efficacy of fibroblast growth factor 21 in non-alcoholic fatty liver disease in guinea pigs.

Fibroblast growth factor 21 (FGF21) agonists have shown promising effects in preclinical models of non-alcoholic fatty liver disease (NAFLD) as well as in short-term clinical trials in patients with non-alcoholic steatohepatitis (NASH). Comparing drug formulation, dose, administration route and age, this exploratory study investigated effects of FGF21 on NAFLD-associated measures in a validated guinea pig model. In three separate studies, female guinea pigs received a high-fat diet prior to intervention with escalating doses of either recombinant native human FGF21 or a human FGF21 human recombinant analogue (FGF21/19 chimer) with an extended half-life. While no significant effects of native FGF21 on the investigated endpoints were observed, the long-acting FGF21/19 chimer significantly altered the levels of circulating lipids, increasing plasma concentrations of cholesterol (TC, LDLc and HDLc) in young guinea pigs (p < 0.01 for all three parameters). Relative liver weights were reduced in FGF21/19-treated young animals (p < 0.05) compared to mature animals, whereas FGF21/19 reduced body weights in both age groups (p < 0.001). The FGF21/19 chimer effects on dyslipidemia, body and liver weights particularly in young animals, support an age-associated difference in the FGF21 response. The limited effects of the native human FGF21 highlights potential species-associated differences of this compound.

The evolving epidemiology and differential etiopathogenesis of eating disorders: implications for prevention and treatment.

The evolving epidemiology and differential etiopathogenesis of eating disorders: implications for prevention and treatment.

Left Ventricular Ejection Time Measured by Echocardiography Differentiates Neurobehavioral Resilience and Vulnerability to Sleep Loss and Stress.

There are substantial individual differences (resilience and vulnerability) in performance resulting from sleep loss and psychosocial stress, but predictive potential biomarkers remain elusive. Similarly, marked changes in the cardiovascular system from sleep loss and stress include an increased risk for cardiovascular disease. It remains unknown whether key hemodynamic markers, including left ventricular ejection time (LVET), stroke volume (SV), heart rate (HR), cardiac index (CI), blood pressure (BP), and systemic vascular resistance index (SVRI), differ in resilient vs. vulnerable individuals and predict differential performance resilience with sleep loss and stress. We investigated for the first time whether the combination of total sleep deprivation (TSD) and psychological stress affected a comprehensive set of hemodynamic measures in healthy adults, and whether these measures differentiated neurobehavioral performance in resilient and vulnerable individuals. Thirty-two healthy adults (ages 27–53; 14 females) participated in a 5-day experiment in the Human Exploration Research Analog (HERA), a high-fidelity National Aeronautics and Space Administration (NASA) space analog isolation facility, consisting of two baseline nights, 39 h TSD, and two recovery nights. A modified Trier Social Stress Test induced psychological stress during TSD. Cardiovascular measure collection [SV, HR, CI, LVET, BP, and SVRI] and neurobehavioral performance testing (including a behavioral attention task and a rating of subjective sleepiness) occurred at six and 11 timepoints, respectively. Individuals with longer pre-study LVET (determined by a median split on pre-study LVET) tended to have poorer performance during TSD and stress. Resilient and vulnerable groups (determined by a median split on average TSD performance) showed significantly different profiles of SV, HR, CI, and LVET. Importantly, LVET at pre-study, but not other hemodynamic measures, reliably differentiated neurobehavioral performance during TSD and stress, and therefore may be a biomarker. Future studies should investigate whether the non-invasive marker, LVET, determines risk for adverse health outcomes.

Comparison of Efficacy and Safety of Analog Insulins Vs Human Insulins-Basal Bolus Regimen and Premix Twice Daily Regimen in Indian Hyperglycemia in Pregnancy

Type 2 diabetes during the course of pregnancy is linked with an unfavourable outcome of maternal foetal. Human insulin is considered as the first choice of drug due to the province safety of use full stop however they are many questions regarding the use of insulin analogues during the time of pregnancy full stop the main objective of the study is to compare the safety and efficacy of human insulin and analogue insulin by understanding the premix daily regimen in hyperglycaemia during pregnancy. All the articles have been classified with an intermediate too high or moderate risk of biasness by showing the favourable results for using the insulin analogue and human insulin as an age of gestation. Therefore, the result evidence that "moderate to high risk of biasness does not allow the conclusion” that the insulin analogue is considered to be more effective while comparing it with the “human insulin for the treatment of pregnant women” suffering from “type 2 diabetes”.

A particulate blood analogue based on artificial viscoelastic blood plasma and RBC-like microparticles at a concentration matching the human haematocrit.

There has been enormous interest in the production of fluids with rheological properties similar to those of real blood over the last few years. Application fields range from biomicrofluidics (microscale) to forensic science (macroscale). The inclusion of flexible microparticles in blood analogue fluids has been demonstrated to be essential in order to reproduce the behaviour of blood flow in these fields. Here, we describe a protocol to produce a whole human blood analogue composed of a proposed plasma analogue and flexible spherical microparticles that mimic the key structural attributes of RBCs (size and mechanical properties), at a concentration matching the human haematocrit (∼42% by volume). Polydimethylsiloxane (PDMS) flexible microparticles were used to mimic RBCs, whose capability to deform is tunable by means of the mixing ratio of the PDMS precursor. Their flow through glass micronozzles allowed us to find the appropriate mixing ratio of PDMS to have approximately the same Young's modulus (E) as that exhibited by real RBCs. Shear and extensional rheology and microrheology techniques were used to match the properties exhibited by human plasma and whole blood at body temperature (37 °C). Finally, we study the flow of our proposed fluid through a microfluidic channel, showing the in vitro reproduction of the multiphase flow effects taking place in the human microcirculatory system, such as the cell-free layer (CFL) and the Fåhræus-Lindqvist effect. A macroscale application in the field of forensic science is also presented, concerning the impact of our blood analogue droplets on a solid surface for bloodstain pattern analysis.

The impact of force, time, and rotation on the transfer of ammonium nitrate: A reductionist approach to understanding evidence dynamics

Empirical studies evaluating the conditions under which the transfer of forensic materials occurs can provide contextual information and offer insight into how that material may have been transferred in a given scenario. Here, a reductionist approach was taken to assess the impact of force, time, and rotation on the transfer of an explosive compound. An Instron ElectroPuls E3000 material testing instrument was used to bring porous and non-porous surfaces adulterated with an ammonium nitrate into direct contact with a human skin analogue, controlling for the force of contact, duration of contact, and rotation applied during contact. Quantifiable amounts of ammonium nitrate were recovered from all of the recipient surfaces demonstrating that ammonium nitrate is readily transferred from one surface to another, even when contact occurs for a short duration with a relatively low force. More particulates were transferred from non-porous surfaces onto the human skin analogue, but the amount of ammonium nitrate transferred did not depend upon the force of contact, duration of contact, or the amount of rotation applied. However, when contact occurred and involved rotation, a greater transfer of ammonium nitrate was observed, compared to those contacts occurring without rotation being applied. This approach complements more commonly-used holistic experiments that test multiple interacting variables in a realistic setting by isolating these variables, allowing them to be examined individually. This can be utilised to better understand the individual impact that specific variables have on the transfer of trace evidence in relevant crime reconstruction contexts.

Teriparatide Therapy in a 4-Month-Old With Severe Hypoparathyroidism.

Teriparatide is a human parathyroid hormone analog approved for the treatment of osteoporosis in adult patients. Its use for hypocalcemia and hypoparathyroidism in the pediatric population is described through case reports and small case series; however, larger studies that demonstrate long-term efficacy and safety are limited. At our institution, a 4-month-old premature (gestational age: 32 weeks) infant with multiple congenital anomalies, functional athymia, and severe hypoparathyroidism and receiving calcitriol, vitamin D, and calcium carbonate supplementation was initiated on subcutaneous injection of teriparatide. During the course of treatment, her calcium carbonate, vitamin D, and calcitriol supplementation requirements substantially decreased. Teriparatide effectively increased serum ionized calcium concentrations and decreased serum phosphorus concentrations in the present case-study over a 6-month period. Teriparatide was well tolerated, and no evidence of hypercalcemia was observed throughout treatment.

Pharmacoeconomic analysis of insulin aspart+nicotinamide versus insulin aspart in patients with diabetes mellitus

Glycemic control is a clinical goal in the treatment of diabetes mellitus. Currently available bolus insulin analogues do not follow the physiological pattern of insulin secretion after meals because they are slowly absorbed from the injection site. Insulin aspart+nicotinamide is an ultra-fast acting human insulin analog that can be administered before or after meals and the nicotinamide (vitamin B3) molecule provides optimal glycemic control. Aim. To evaluate clinical and economic efficacy of the drug insulin aspart+nicotinamide in comparison with insulin aspart in patients with diabetes mellitus. Materials and Methods. Clinical and economic analysis was performed in accordance with the standards and recommendations valid in the Russian Federation, the method of cost-effectiveness analysis for the first model population of patients with type 1 diabetes and the method of cost-minimization analysis for the second model population of patients with type 2 diabetes, modeling horizon was 26 weeks. Since the study is conducted from the per- spective of the health care system only direct medical costs were considered, that is, the cost of insulin therapy and the cost of complications treatment (hypoglycemia). During the budget impact analysis, the source of data on the target population was the registry of patients with diabetes mellitus of the Russian Federation. Probabilistic sensitivity analysis was performed to assess the impact of changes in the input parameters of the models. Results. Insulin aspart+nicotinamide has a clinical advantage in the effective- ness of HbA1c reduction in type 1 diabetes population. In patients with type 2 diabetes, the effectiveness of insulin aspart+nicotinamide and insulin aspart is comparable by a similar criterion. Direct medical costs of insulin aspart+nicotinamide are 10.64% lower in comparison with insulin aspart use in type 1 and type 2 diabetes patients’ population. The CER value in type 1 diabetes patient population for insulin aspart is 70% higher compared to insulin aspart+nicotinamide (7,410,353.83 and 4,348,513.94 RUR respectively). Budget impact analysis results are the following: that complete replacement of insulin aspart with insulin aspart+nicotinamide over 3 years is accompanied by a 5.3% reduction of regional drug benefit budget costs. Conclusion. The clinical and economic analysis confirms the economic feasibility of insulin aspart + nicotinamide use

Needle Technology for Insulin Administration: A Century of Innovation.

Innovations in syringe and pen needle (PN) technology over the last 100 years have led to important advances in insulin delivery for people with diabetes, paralleling the strides made in developing recombinant DNA human insulin and insulin analogs with varying onset and duration of action. In this review, the history of advances in insulin delivery is described, focusing on progress in syringe, needle, and PN technologies. The early glass and metal syringes that required sterilization by boiling have been replaced by disposable, single-use syringes or pens with clear labeling for precise insulin dosing. The early needles ranging in length from 19 to 26 mm that required manual sharpening against a whetstone have been replaced by syringe needles of 6 mm and PNs of 4 mm in length as slender as 34 gauge. Imaging studies using ultrasound and computed tomography measured the thickness of skin and subcutaneous tissue layers to show feasibility of targeted insulin administration with shorter needles. These developments, coupled with innovations in needle/PN wall and tip structure, have led to improved injection experience for people with diabetes. It is also important to acknowledge the role of injection technique education, together with these advances in injection technology, for improving clinical outcomes and patient satisfaction. With continued projected growth of diabetes prevalence, particularly in developing countries where expensive and complex insulin delivery systems may not be practical, insulin syringes and pens will continue to serve as reliable and cost-effective means of insulin delivery for people with diabetes.

Impact of APOE and BDNF Val66Met polymorphisms on spatial navigation and brain morphometry in subjective cognitive decline

AbstractBackgroundThe apolipoprotein E (APOE) ɛ4 allele is associated with episodic memory deficits, less accurate spatial navigation and hippocampal atrophy in nondemented older adults. The brain‐derived neurotrophic factor (BDNF) Met allele may further worsen memory impairment and reduce hippocampal activation in APOE ɛ4 carriers but its role in APOE ɛ4‐related spatial navigation deficits has not been established. We aimed to evaluate the influence of combination of the APOE and BDNF Val66Met polymorphisms on spatial navigation, cognitive functions and volumes of selected brain regions associated with spatial navigation including the hippocampus, entorhinal cortex, precuneus, inferior parietal and posterior cingulate cortex in individuals with subjective cognitive decline (SCD).MethodIn total, 71 older adults with SCD from the Czech Brain Aging Study were stratified based on the APOE and BDNF Val66Met polymorphisms into four groups: ɛ4–/BDNF Val/Val (n =27), ɛ4–/BDNF Met (n = 15), ɛ4+/BDNF Val/Val (n =18), and ɛ4+/BDNF Met (n=11). The participants underwent comprehensive neuropsychological examination, brain MRI and spatial navigation testing of egocentric, allocentric, and allocentric delayed navigation in a real‐space human analogue of the Morris water maze.ResultThe ɛ4+/BDNF Met group, although similar to other polymorphism groups in age, gender, education, depressive symptoms and global cognitive function, had less accurate allocentric and allocentric delayed navigation performance than the ɛ4–/BDNFVal/Val group (p&lt;0.05). There were no significant differences in egocentric navigation performance, cognitive performance in any cognitive domain including attention and working memory, nonverbal memory, executive function, language and visuospatial function and volumes of selected brain regions associated with spatial navigation between the polymorphism groups (p&gt;0.05).ConclusionIndividuals with SCD and the high risk combination of APOE ɛ4 and BDNF Met alleles had less accurate allocentric spatial navigation than those with the low risk combination of APOE ɛ3 and BDNF Val alleles. This finding may indicate that individuals with SCD and two high risk gene polymorphisms are particularly susceptible to hippocampus‐dependent spatial navigation deficits and may be at greater risk of cognitive decline and progression to mild cognitive impairment. Our results also suggest that spatial navigation testing could more reliably assess the deleterious effect of the BDNF Met allele on cognition than other cognitive tests.

Cortisol and C-Reactive Protein Vary During Sleep Loss and Recovery but Are Not Markers of Neurobehavioral Resilience.

Cortisol and C-reactive protein (CRP) typically change during total sleep deprivation (TSD) and psychological stress; however, it remains unknown whether these biological markers can differentiate robust individual differences in neurobehavioral performance and self-rated sleepiness resulting from these stressors. Additionally, little is known about cortisol and CRP recovery after TSD. In our study, 32 healthy adults (ages 27–53; mean ± SD, 35.1 ± 7.1 years; 14 females) participated in a highly controlled 5-day experiment in the Human Exploration Research Analog (HERA), a high-fidelity National Aeronautics and Space Administration (NASA) space analog isolation facility, consisting of two baseline nights, 39 h TSD, and two recovery nights. Psychological stress was induced by a modified Trier Social Stress Test (TSST) on the afternoon of TSD. Salivary cortisol and plasma CRP were obtained at six time points, before (pre-study), during [baseline, the morning of TSD (TSD AM), the afternoon of TSD (TSD PM), and recovery], and after (post-study) the experiment. A neurobehavioral test battery, including measures of behavioral attention and cognitive throughput, and a self-report measure of sleepiness, was administered 11 times. Resilient and vulnerable groups were defined by a median split on the average TSD performance or sleepiness score. Low and high pre-study cortisol and CRP were defined by a median split on respective values at pre-study. Cortisol and CRP both changed significantly across the study, with cortisol, but not CRP, increasing during TSD. During recovery, cortisol levels did not return to pre-TSD levels, whereas CRP levels did not differ from baseline. When sex was added as a between-subject factor, the time × sex interaction was significant for cortisol. Resilient and vulnerable groups did not differ in cortisol and CRP, and low and high pre-study cortisol/CRP groups did not differ on performance tasks or self-reported sleepiness. Thus, both cortisol and CRP reliably changed in a normal, healthy population as a result of sleep loss; however, cortisol and CRP were not markers of neurobehavioral resilience to TSD and stress in this study.

Transdermal Drug Delivery in the Pig Skin.

Transdermal delivery can be accomplished through various mechanisms including formulation optimization, epidermal stratum corneum barrier disruption, or directly by removing the stratum corneum layer. Microneedling, electroporation, a combination of both and also the intradermal injection known as mesotherapy have proved efficacy in epidermal-barrier disruption. Here we analyzed the effects of these methods of epidermal-barrier disruption in the structure of the skin and the absorption of four compounds with different characteristics and properties (ketoprofen, biotin, caffein, and procaine). Swine skin (Pietrain x Durox) was used as a human analogue, both having similar structure and pharmacological release. They were biopsied at different intervals, up to 2 weeks after application. High-pressure liquid chromatography and brightfield microscopy were performed, conducting a biometric analysis and measuring histological structure and vascular status. The performed experiments led to different results in the function of the studied molecules: ketoprofen and biotin had the best concentrations with intradermal injections, while delivery methods for obtaining procaine and caffein maximum concentrations changed on the basis of the lapsed time. The studied techniques did not produce significant histological alterations after their application, except for an observed increase in Langerhans cells and melanocytes after applying electroporation, and an epidermal thinning after using microneedles, with variable results regarding dermal thickness. Although all the studied barrier disruptors can accomplish transdermal delivery, the best disruptor is dependent on the particular molecule.

A novel smaller β-defensin-derived peptide is active against multidrug-resistant bacterial strains.

Antibiotic resistance is becoming a severe obstacle in the fight against acute and chronic infectious diseases that accompany most degenerative illnesses from neoplasia to osteo-arthritis and obesity. Currently, the race is on to identify pharmaceutical molecules or combinations of molecules able to prevent or reduce the insurgence and/or progression of infectivity. Attempts to substitute antibiotics with antimicrobial peptides have, thus far, met with little success against multidrug-resistant (MDR) bacterial strains. During the last decade, we designed and studied the activity and features of human β-defensin analogs, which are salt-resistant, and hence active also under high salt concentrations as, for instance, in cystic fibrosis. Herein, we describe the design, synthesis, and major features of a new 21 aa long molecule, peptide γ2. The latter derives from the γ-core of the β-defensin natural molecules, a small fragment of these molecules still bearing high antibacterial activity. We found that peptide γ2, which contains only one disulphide bond, recapitulates most of the biological properties of natural human β-defensins and can also counteract both Gram-positive and Gram-negative MDR bacterial strains and biofilm formation. Moreover, it has great stability in human serum thereby enhancing its antibacterial presence and activity without cytotoxicity in human cells. In conclusion, peptide γ2 is a promising new weapon also in the battle against intractable infectious diseases.