Pilot Studies on the Novel Hypothesis that TSPO (Peripheral Benzodiazepine Receptor) Is Involved in Benzodiazepine/“Z-Drug” Physical Dependence and/or Withdrawal

Benzodiazepines and other benzodiazepine receptor agonists, such as the “Z” drugs, are widely prescribed medications mainly used for treating anxiety and seizures, and for inducing sedation. Unfortunately, despite their popularity, benzodiazepine prescribing often exceeds recommendations and the consequences can be severe. On September 23, 2020, the United States FDA announced a new requirement for a Boxed Warning for benzodiazepines prescribing. Along with this announcement, the FDA stated that relevant information regarding the initiation, continuation, and discontinuation of benzodiazepines is lacking. Here, we describe initial pilot studies intended to investigate the questions 1) can animal models be developed that demonstrate benzodiazepine physical dependence and/or withdrawal symptoms, and 2) determine whether translocator protein (TSPO) plays a role in benzodiazepine dependence and/or withdrawal processes. The former was demonstrated, methodological limitations prevented the latter.

Microstructure and mechanical properties of curved AZ31 magnesium alloy profiles produced by differential velocity sideways extrusion

Lightweight curved profiles are widely utilised in the transportation industry considering the increasing need for improving aerodynamic efficiency,aesthetics and cutting emissions.In this paper,curved AZ31 Mg alloy profiles were manufactured in one operation by a novel process,differential velocity sideways extrusion(DVSE),in which two opposed rams were used.Effects of extrusion temperature and velocity(strain rate) on curvature,microstructure,and mechanical properties of the formed profiles were examined.Profile curvature was found to be more readily controlled by the velocity ratio of the bottom ram v2to the top ram v1,whereas extrusion temperature(T=250,300,350℃)and extrusion velocity(v_(1)=0.1,1 mm/s) slightly affect curvature for a given velocity ratio.A homogeneous microstructure with equiaxed grains(~4.5 μm) resulted from dynamic recrystallisation(DRX),was observed after DVSE(v_(2)/v_(1)=1/2) at 300 ℃ and v_(1)=0.1 mm/s,where the initial billet had an average grain size of ~25 um.Increasing extrusion temperature leads to grain growth(~5 μm) at 350 ℃ and v_(1)=0.1 mm/s.DRX is incomplete at the relatively low temperature of 250℃(v_(1)=0.1 mm/s),and higher strain rate with v1=1mm/s(T=300℃),resulting in inhomogeneous bi-modal necklace pattern grains ranging in size around 1-25 μm for the former and 2-20μm for the latter.Grain refinement is attributed to DRX during the severe plastic deformation(SPD) arising in DVSE,and initiates at the prior boundaries of coarse grains in a necklace-like manner.Compared with the billet,micro-hardness and ultimate tensile strength of the profiles have been enhanced,which is compatible with grain refinement.Also,an obvious increase in tensile ductility was found.However,yield strength slightly decreases except for the complete DRXed case(300℃,v_(1)=0.1 mm/s),where a slightly higher value was found,indicating strengthening by grain refinement is greater than softening caused by texture modification.The initial billet had a strong basal texture wherein the {0002} basal plane is oriented parallel to the extrusion direction(’hard’ orientation),while DVSE results in the profiles having weak basal textures and the {0002} basal plane oriented ~5-10° to the extrusion direction(i.e.towards the orientation for easier slip).This significantly modified texture contributes to the softening of the profiles in the extrusion direction,in which tensile tests were performed,and the related elongation improvement.

More than Meets the Eye: A Qualitative Investigation of the Complex Weight History Constructions of Brazilian Women Who Underwent Bariatric Surgery

Most studies on bariatric surgery identify personal factors such as“non-compliance”to lifestyle changes as the cause of weight gain and subsequent inability to lose weight.Prior qualitative studies suggest that weight loss patients have complicated relationships with both self and weight,with significant emotional and psychological implications.But how do patients themselves understand the trajectories of their weight gain as related to intrinsic versus extrinsic factors?A qualitative analysis examined the aspects involved in the construction of higher body weight from the perspectives and life experiences of Brazilian women who underwent bariatric surgery,considering that Brazil has previously been reported as a highly anti-fat society.Individual,semi-structured interviews were conducted with thirty women(15 aged 33-59 and 15 aged 63-72).Data were analyzed identifying the regular,expressive,and meaningful significance units identified through the interviews.Although it was expected that different life events were reported as crucial to the perceived aetiology of individual weight gain stories,the participants reported that the emotional aspects had more impact.The extremely high value attached to having a particular body weight negatively influenced the participants’concept of identity and harmed their interactions and understanding of what it meant to be fully loved and accepted.Most of the participants underscored the importance of food in women’s lived experiences and explanations of weight gain.Despite this somatic response being dysfunctionally directed to food,this mechanism seemed to be vital to keeping them alive and engaged in the world.Finally,the participants faced layered vulnerabilities,which decreased their opportunities to access resources aimed at better body weight management.Broad approaches that consider emotional and physical care strategies must be proposed to this population.

The FDA Mandate to Reassess Benzodiazepines: Alprazolam Induces a Positive Conditioned Place-Preference in Male Rats

On September 23, 2020, in order “To address the serious risks of abuse, addiction, physical dependence, and withdrawal reactions, the U.S. Food and Drug Administration (FDA) is requiring the Boxed Warning be updated for all benzodiazepine medicines”. With this announcement, the FDA proclaimed that much more needs to be known about the initiation, continuation, and discontinuation of these widely-used drugs. Unfortunately, relevant information is lacking, since for many years, there has been a notable sparsity in the funding and conduct of basic and clinical research on these drugs. In order to begin to fill the void, it is valuable to (re)examine animal models. We here describe a model of conditioned place-preference (CPP) for rats and for the first time, to our knowledge, show that the representative benzodiazepine alprazolam induces positive place-preference in male rats.

Test of the Popular Benzodiazepine Alprazolam in a Positive Conditioned Place-Preference Model in Female Rats

The benzodiazepines were introduced into medical practice during the 1960s. At the time, they represented a safer alternative to extant therapies used for anxiety, such as the barbiturates. However, on September 23, 2020, the United States FDA indicated that more is needed to be known about the initiation, continuation, and discontinuation of the use of these widely-used drugs with publication of the announcement “to address the serious risks of abuse, addiction, physical dependence, and withdrawal reactions, the U.S. Food and Drug Administration (FDA) is requiring the Boxed Warning be updated for all benzodiazepine medicines.” Because for many years, there has been a sparsity of research on these drugs, relevant information is unfortunately lacking at this critical time. It is therefore valuable to (re)establish animal models and begin to collect relevant data. We here use a model of conditioned place preference (CPP) which suggests that the representative benzodiazepine alprazolam induces positive place preference in female rats.

Fluconazole Prophylaxis in Neonates (Non-Systematic) Literature Review

Background: Nosocomial infection remains an important contributing factor for morbidity and mortality in neonates. Coagulase-negative staphylococci have emerged as the predominant pathogens of late onset sepsis. This is followed by staphylococcus aurous, gram negative bacilli, and fungi. Old studies noted that mortality due to candidemia was higher in infants weigh less than 2000 g after being exposed to risk factors. The prophylactic use of fluconazole for the prevention of IC in extremely low birth weight was first reported in 2001. Methods: Current guidelines from Europe and North America that refer to the treatment of fungal infections are included. Literature search was performed using Medline, Scopus and Cochrane Central Register of Controlled Trials through March, 2016. Conclusion: Mortality was not different in early studies. However, recent studies concluded that mortality was reduced in the fluconazole arms. Risk-based approach towards fluconazole prophylaxis seems to be safe and effective.

A Taxonomic Revision and Distribution of the Genus Juniperus(Cupressaceae)in Azerbaijan

In order to prevent a decline in its area,mostly caused by problems in natural regeneration,the present study was carried out to revise the list of Juniperus species in wild flora of Azerbaijan Republic.The presented article is devoted to taxonomic revision of Juniperus L.species wildly distributed in Azerbaijan.A simplified key for identification species from wild flora and the distribution map for Juniperus species have been compiled for the area.

<i>Commentary</i>: Benzodiazepine (BZD) and Related BZD-Receptor Agonists: Basic Science Reasons to Limit to Four Weeks or Less

Benzodiazepines and related benzodiazepine-receptor agonists such as the pyrazolopyrimidinezalepl -on;?the imidazopyridine zolpidem;and the cyclopyrroloneszopiclone and eszopiclone, are among the most widely prescribed drugs, and for a variety of conditions. Surprisingly: 1) there are only a few conditions for which there is a good evidence basis, 2) efficacy has only been well demonstrated for short-term use (i.e., less than 4 weeks), and 3) much less is known about the basic science of these drugs than is widely believed. We suggest that the use of these drugs beyond four or less weeks exceeds the available knowledge base, so best-practice use suggests that the prescribing of these drugs for most patients should be limited to only short-term use until more is known about the basic pharmacology of their actions in the brain and in the periphery.

Assessing the Performance of Two Hydrologic Models for Forecasting Daily Streamflows in the Cazones River Basin (Mexico)

Floods have caused significant human and economic losses in the Cazones River Basin, located on the Gulf of Mexico. Despite this knowledge, steps towards the design and implementation of an early warning system for the Cazones are still a pending task. In this study we contributed by establishing a hydrological scheme for forecasting mean daily discharges in the Cazones Basin. For these purposes, we calibrated, validated and compared the HyMod model (HM) which is physics-based, and an autoregressive-based model coupled with the Discrete Kalman Filter (ARX-DKF). The ability of both models to accurately predict discharges proved satisfactory results during the validation period with RMSEHYMOD = 2.77 [mm/day];and RMSEARX-DKF = [2.38 mm/day]. Further analysis based on a Streamflow Assimilation Ratio (SAR) revealed that both models underestimate the discharges in a similar proportion. This evaluation also showed that, under the most common conditions, the simpler stochastic model (ARX-DKF) performs better;however, under extreme hydrological conditions the deterministic HM model reveals a better performance. These results are discussed under the context of future applications and additional requirements needed to implement an early warning hydrologic system for the Cazones Basin.

Treating Insomnia in Older Adult Patients: Limiting Benzodiazepine Use

As aging comes, an increased prevalence of medical maladies and chronic pain independently or interactively disrupt sleep, which in turn can exacerbate either one. Furthermore, anxiety about pain can further negatively impact sleep. Fortunately, good quality sleep can improve pain management. Because benzodiazepine receptor agonists (including the “Z” drugs) can reduce anxiety and improve sleep, they seem a convenient choice. However, their use in this population, particularly for more than short-term (guidelines range from 2 to 6 weeks max), is not recommended because of increased likelihood of falls, further disruption of sleep, dependence, and problems with discontinuation (withdrawal). Besides, this population is often likely to take concomitant medication for pain or other central nervous system depressants leading to potentially serious and even life-threatening interactions involving synergistic amplification of respiratory depression (opioids being a particularly dangerous interaction). Therefore, insomnia in older adults should ideally be treated with a non-benzodiazepine receptor agonist;if indicated, they may be used, but should be closely monitored and tapered to avoid long-term adverse problems (direct or from withdrawal). Older adult patients with insomnia may be more optimally treated with sleep aids that do not interact with the GABAA receptor.

Thermo-tectonic history of the Junggar Alatau within the Central Asian Orogenic Belt(SE Kazakhstan,NW China):Insights from integrated apatite U/Pb,fission track and(U-Th)/He thermochronology

The Junggar Alatau forms the northern extent of the Tian Shan within the Central Asian Orogenic Belt(CAOB)at the border of SE Kazakhstan and NW China.This study presents the Palaeozoic-Mesozoic post-collisional thermo-tectonic history of this frontier locality using an integrated approach based on three apatite geo-/thermochronometers:apatite U-Pb,fission track and(U-Th)/He.The apatite U-Pb dates record Carboniferous-Permian post-magmatic cooling ages for the sampled granitoids,reflecting the progressive closure of the Palaeo-Asian Ocean.The apatite fission track(AFT)data record(partial)preservation of the late Palaeozoic cooling ages,supplemented by limited evidence for Late Triassic(~230-210 Ma)cooling and a more prominent record of(late)Early Cretaceous(~150-110 Ma)cooling.The apatite(U-Th)/He age results are consistent with the(late)Early Cretaceous AFT data,revealing a period of fast cooling at that time in resulting thermal history models.This Cretaceous rapid cooling signal is only observed for samples taken along the major NW-SE orientated shear zone that dissects the study area(the Central Kazakhstan Fault Zone),while Permian and Triassic cooling signals are preserved in low-relief areas,distal to this structure.This distinct geographical trend with respect to the shear zone,suggests that fault reactivation triggered the Cretaceous rapid cooling,which can be linked to a phase of slab-rollback and associated extension in the distant Tethys Ocean.Similar conclusions were drawn for thermochronology studies along other major NW-SE orientated shear zones in the Central Asian Orogenic Belt,suggesting a regional phase of Cretaceous exhumation in response to fault reactivation at that time.

Evolution and modeling of mine water inflow and hazard characteristics in southern coalfields of China:A case of Meitanba mine

In this paper,the hydrogeological characteristics in the southern coalfields of China are first briefly outlined.Then,taking the Meitanba mine as an example,the evolution and modeling of mine water inflow are studied.Finally,the hazard characteristics related to mine water and mud inrush are analyzed.The results show that the main mine water sources in the Meitanba mine area are groundwater,surface water and precipitation.The evolution of mine water inflow with time indicates that the water inflow is closely related to the development of karst structures,the amount of water from rainfall infiltration,and the scope of groundwater depression cone.The mine water inflow increases with time due to the increase in mining depth and the expansion of groundwater depression cone.Using the big well method and following the potential superposition principle,a hydrogeological model considering multi-well interactions has been developed to predict the mine water inflow.Based on the monitored data in the Meitanba mine area over a period of nearly 60 years,it is found that with increasing mining depth,the number of water and mud inrush points tended to decrease.However,the average water and mud flow rate per point tended to increase.

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Vegetation Classification of Juniperus communis L. Species in Azerbaijan

The Republic of Azerbaijan, is a country in the south Caucasus having continental influenced climate with warm summer and mild cold, dry winters. Relating to its climate this region has a rich and very interesting vegetation cover. In presented article the vegetation communities with the presence of Juniperus communis L. species and subspecies have been described.

Commentary: “Ockham’s Razor” Doesn’t Apply to “Opioid” Overdose Death

Polysubstance Abuse (PSA) greatly complicates an attempt to implicate a single drug as sole cause of an overdose death. Since PSA now occurs in the majority of cases of drug overdoses, many or most overdose deaths are polysubstance overdose deaths. And since many of the substances involved in a polysubstance Overdose Death (POD) are Central Nervous System (CNS) depressants, many of which can cause overdose death themselves, or synergistically with opioids, it is somewhat puzzling that prescription opioids have been singled out as the cause of these deaths—without reference to PSA. This is particularly puzzling in light of the fact that the issues of PSA and POD have been recognized and discussed in the literature since at least the 1960’s and before. We therefore here consider the question: are we facing an “opioid” crisis or, instead, a “polysubstance crisis”? And we wonder if the issue has been over-simplified, to the detriment of the individuals affected, and to society more broadly. There is a need for an “agnostic” respiratory stimulant that can reverse polysubstance-induced respiratory depression.