Why are US military personnel prescribed transdermal fentanyl patches?

INTRODUCTION: Transdermal fentanyl is a continuous release opioid delivery system intended for use in opioid-tolerant patients requiring around-the-clock opioid therapy. The purpose of this study is to identify the most common indications for transdermal fentanyl prescriptions in active duty US military personnel, and determine whether these prescriptions meet US Food and Drug Administration (FDA) labelling. METHODS: Active duty US military personnel initiating transdermal fentanyl therapy with prescriptions filled at Military Health System pharmacies between 2015 and 2019 were identified in the Military Data Repository. Electronic health records were searched for patient demographic information, clinical information and prescription data. A total of 225 patients with complete data were identified. RESULTS: The most common reason for transdermal fentanyl initiation was chronic non-cancer musculoskeletal pain. Among patients with non-cancer pain, 36% received their initial prescription from an internal medicine/primary care provider, and 35% did not meet published US FDA criteria for opioid tolerance prior to treatment initiation. There was an 81% decrease in patients initiating therapy between 2015 and 2019. CONCLUSIONS: While a substantial minority of transdermal fentanyl prescriptions to US military personnel did not meet FDA guidelines on appropriate use, the overall number of prescriptions fell dramatically over the study period. This suggests that automated profile review or additional targeted policies to limit transdermal fentanyl prescribing are unnecessary at this time.

The National Institute of Health and the Italian Poison Centers Network: results of a collaborative study for the surveillance of exposures to chemicals.

Background: The Public Health Surveillance Systems are essential to improve and protect public health, as highlighted by the World Health Organization. According with this consideration, a systematic collaboration between the National Institute of Health and the Poison Centers of Northern, Central and Southern Italy was established. Its aim was to improve the national network for the surveillance of dangerous exposures to chemicals. The developed network provided harmonized data essential for evidence-based interventions and significantly ameliorated the data flow between the Poison Centers and the Central Health Institutions. Methods: The improvement of the system was obtained through several actions, such as the development of the "Online Surveillance Card" for the detection of sentinel events in real time and the harmonization of the data collection flow, including the product categorization according to the European Product Categorization System. Data analysis was carried out by Microsoft's IBM SPSS Statistics version 26, Access and Excel. Results: Important information was obtained, regarding also exposures to chemicals and their management in pediatric populations. The surveillance network was proved effective not only under "normal" conditions but also to promptly monitor changes during exceptional health emergencies, such as the COVID-19 pandemic. During the 2020 lockdown the surveillance system registered a significant increase in the frequency of exposures to disinfectants (p-value=0.002), an evidence that highlighted the need of tailored intervention. Conclusions: This Italian Project model proves to be reliable and suitable to be transferred to other European countries, in order to realize an European Poison Centers' Network, able to overcome unsolved health problems and to globally improve the "evidence-based" prevention of exposures to chemicals.

Two distinct GUCY2C circuits with PMV (hypothalamic) and SN/VTA (midbrain) origin.

Guanylyl cyclase C (GUCY2C) is the afferent central receptor in the gut-brain endocrine axis regulated by the anorexigenic intestinal hormone uroguanylin. GUCY2C mRNA and protein are produced in the hypothalamus, a major center regulating appetite and metabolic homeostasis. Further, GUCY2C mRNA and protein are expressed in the ventral midbrain, a principal structure regulating hedonic reward from behaviors including eating. While GUCY2C is expressed in hypothalamus and midbrain, its precise neuroanatomical organization and relationship with circuits regulating satiety remain unknown. Here, we reveal that hypothalamic GUCY2C mRNA is confined to the ventral premammillary nucleus (PMV), while in midbrain it is produced by neurons in the ventral tegmental area (VTA) and substantia nigra (SN). GUCY2C in the PMV is produced by 46% of neurons expressing anorexigenic leptin receptors, while in the VTA/SN it is produced in most tyrosine hydroxylase-immunoreactive neurons. In contrast to mRNA, GUCY2C protein is widely distributed throughout the brain in canonical sites of PMV and VTA/SN axonal projections. Selective stereotaxic ablation of PMV or VTA/SN neurons eliminated GUCY2C only in their respective canonical projection sites. Conversely, specific anterograde tracer analyses of PMV or VTA/SN neurons confirmed distinct GUCY2C-immunoreactive axons projecting to those canonical locations. Together, these findings reveal two discrete neuronal circuits expressing GUCY2C originating in the PMV in the hypothalamus and in the VTA/SN in midbrain, which separately project to other sites throughout the brain. They suggest a structural basis for a role for the GUCY2C-uroguanylin gut-brain endocrine axis in regulating homeostatic and behavioral components contributing to satiety.

Polar features in the flagellar propulsion of E. coli bacteria.

E. coli bacteria swim following a run and tumble pattern. In the run state all flagella join in a single helical bundle that propels the cell body along approximately straight paths. When one or more flagellar motors reverse direction the bundle unwinds and the cell randomizes its orientation. This basic picture represents an idealization of a much more complex dynamical problem. Although it has been shown that bundle formation can occur at either pole of the cell, it is still unclear whether these two run states correspond to asymmetric propulsion features. Using holographic microscopy we record the 3D motions of individual bacteria swimming in optical traps. We find that most cells possess two run states characterized by different propulsion forces, total torque, and bundle conformations. We analyze the statistical properties of bundle reversal and compare the hydrodynamic features of forward and backward running states. Our method is naturally multi-particle and opens up the way towards controlled hydrodynamic studies of interacting swimming cells.

Three-axis digital holographic microscopy for high speed volumetric imaging.

Digital Holographic Microscopy allows to numerically retrieve three dimensional information encoded in a single 2D snapshot of the coherent superposition of a reference and a scattered beam. Since no mechanical scans are involved, holographic techniques have a superior performance in terms of achievable frame rates. Unfortunately, numerical reconstructions of scattered field by back-propagation leads to a poor axial resolution. Here we show that overlapping the three numerical reconstructions obtained by tilted red, green and blue beams results in a great improvement over the axial resolution and sectioning capabilities of holographic microscopy. A strong reduction in the coherent background noise is also observed when combining the volumetric reconstructions of the light fields at the three different wavelengths. We discuss the performance of our technique with two test objects: an array of four glass beads that are stacked along the optical axis and a freely diffusing rod shaped E.coli bacterium.

Targeted delivery of colloids by swimming bacteria.

The possibility of exploiting motile microorganisms as tiny propellers represents a fascinating strategy for the transport of colloidal cargoes. However, delivery on target sites usually requires external control fields to steer propellers and trigger cargo release. The need for a constant feedback mechanism prevents the design of compact devices where biopropellers could perform their tasks autonomously. Here we show that properly designed three-dimensional (3D) microstructures can define accumulation areas where bacteria spontaneously and efficiently store colloidal beads. The process is stochastic in nature and results from the rectifying action of an asymmetric energy landscape over the fluctuating forces arising from collisions with swimming bacteria. As a result, the concentration of colloids over target areas can be strongly increased or depleted according to the topography of the underlying structures. Besides the significance to technological applications, our experiments pose some important questions regarding the structure of stationary probability distributions in non-equilibrium systems.

A vitamin/nutriceutical formulation improves memory and cognitive performance in community-dwelling adults without dementia.

Adults of both genders without dementia consumed a nutriceutical formulation ("NF," consisting of folic acid, B12, Vitamin E, S-adenosylmethionine, N-acetyl cysteine and Acetyl-L-carnitine), previously shown to improve cognitive performance in Alzheimer's disease, or placebo. Participants receiving NF but not placebo improved statistically and clinically in the California Verbal Learning Test II and the Trail-Making Test. Both groups improved further during a 3-month open-label extension. Additional individuals displayed identical improvement during a separate 6-month open-label trial. Performance declined to baseline following withdrawal of NF, and statistically improved when participants resumed taking NF. Additional participants receiving NF but not placebo demonstrated improvement within 2 weeks in Trail-making and Digit-Memory tests; both groups improved in a 2-week open-label extension. An increased percentage of participants > or = 74 years of age did not show improvement with NF, which may relate to age-related difficulties in adsorption and/or basal nutritional deficiencies, or age-related cognitive decline during the course of this study. These findings support the benefit of nutritional supplements for cognitive performance and suggest that additional supplementation may be required for the elderly.

Targeted stem cell transplantation strategies in ALS.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder that results in paralysis and ultimately death due to respiratory failure. Transplantation of neural precursor cells (NPCs) derived from the central nervous system is a promising therapeutic strategy for treatment of brain and spinal cord disorders such as ALS. ALS is a particularly challenging disease for designing relevant therapies, and presently no effective treatment exists. Despite such daunting challenges, a number of the potential benefits of NPC transplantation coincide with the neuropathological obstacles associated with ALS, including neuronal and glial replacement and non-replacement functions such as delivery of trophic support. Knowledge of the underlying disease-specific pathways involved in neurodegeneration and the contributions of different cellular subtypes to the disease go hand-in-hand with advances in NPC transplantation biology, and will aid in targeting cell-specific therapies to neurodegenerative disorders such as ALS. It is with these multiple cell targets that NPC transplantation may lend itself well to understanding and possibly slowing disease processes. A number of studies have already demonstrated the potential benefits of cell transplantation in ALS models. Lastly, practical issues such as timing and method of cell delivery, immune suppression, and the need for combinatorial approaches with non-cell based strategies must all be considered for eventual translation to the clinic.

Long-term fate of neural precursor cells following transplantation into developing and adult CNS.

Successful strategies for transplantation of neural precursor cells for replacement of lost or dysfunctional CNS cells require long-term survival of grafted cells and integration with the host system, potentially for the life of the recipient. It is also important to demonstrate that transplants do not result in adverse outcomes. Few studies have examined the long-term properties of transplanted neural precursor cells in the CNS, particularly in non-neurogenic regions of the adult. The aim of the present study was to extensively characterize the fate of defined populations of neural precursor cells following transplantation into the developing and adult CNS (brain and spinal cord) for up to 15 months, including integration of graft-derived neurons with the host. Specifically, we employed neuronal-restricted precursors and glial-restricted precursors, which represent neural precursor cells with lineage restrictions for neuronal and glial fate, respectively. Transplanted cells were prepared from embryonic day-13.5 fetal spinal cord of transgenic donor rats that express the marker gene human placental alkaline phosphatase to achieve stable and reliable graft tracking. We found that in both developing and adult CNS grafted cells showed long-term survival, morphological maturation, extensive distribution and differentiation into all mature CNS cell types (neurons, astrocytes and oligodendrocytes). Graft-derived neurons also formed synapses, as identified by electron microscopy, suggesting that transplanted neural precursor cells integrated with adult CNS. Furthermore, grafts did not result in any apparent deleterious outcomes. We did not detect tumor formation, cells did not localize to unwanted locations and no pronounced immune response was present at the graft sites. The long-term stability of neuronal-restricted precursors and glial-restricted precursors and the lack of adverse effects suggest that transplantation of lineage-restricted neural precursor cells can serve as an effective and safe replacement therapy for CNS injury and degeneration.

MR imaging of lineage-restricted neural precursors following transplantation into the adult spinal cord.

Neural precursor cell (NPC) transplantation is a promising strategy for treatment of CNS injuries and neurodegenerative disorders because of potential for cell replacement. An important element of future clinical applications is development of a non-invasive procedure to follow NPC fate. We show that neuronal-restricted precursors (NRPs) and glial-restricted precursors (GRPs), NPCs with lineage restrictions for neurons and glia, respectively, can be labeled in vitro with the superparamagnetic iron oxide contrast agent Feridex. Following engraftment into intact adult spinal cord, labeled cells robustly survived in white and gray matter and migrated selectively along white matter tracts up to 5 mm. Localization of cells was reliably established using ex vivo magnetic resonance imaging of spinal cords. Imaging coincided with histological detection of iron and the human alkaline phosphatase transgene in most grafting sites, including the stream of migrating cells. Following transplantation, magnetically labeled cells exhibited mature morphologies and differentiated into neurons, astrocytes, and oligodendrocytes, similar to grafts of unlabeled NRPs and GRPs. Interestingly, Feridex-labeled cells, but not unlabeled cells, induced influx of ED1-positive macrophages/microglia. Small numbers of these phagocytic cells took up iron from grafted cells, while the majority of Feridex label was found in transplanted cells. We conclude that Feridex labeling does not inhibit NPC differentiation and can be used to reliably localize NPCs by MRI following engraftment into adult CNS, with the possible exception of areas of rapidly proliferating cells. The present results are relevant for MR-guided clinical application of transplantation strategies in treatment of spinal cord injury and other CNS pathologies.

Distinct roles for spinophilin and neurabin in dopamine-mediated plasticity.

Protein phosphatase 1 plays a major role in the governance of excitatory synaptic activity, and is subject to control via the neuromodulatory actions of dopamine. Mechanisms involved in regulating protein phosphatase 1 activity include interactions with the structurally related cytoskeletal elements spinophilin and neurabin, synaptic scaffolding proteins that are highly enriched in dendritic spines. The requirement for these proteins in dopamine-related neuromodulation was tested using knockout mice. Dopamine D1-mediated regulation of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptor activity was deficient in both striatal and prefrontal cortical neurons from neurabin knockout mice; in spinophilin knockout mice this deficit was manifest only in striatal neurons. At corticostriatal synapses long-term potentiation was deficient in neurabin knockout mice, but not in spinophilin knockout mice, and was rescued by a D1 receptor agonist. In contrast, long-term depression was deficient in spinophilin knockout mice but not in neurabin knockout mice, and was rescued by D2 receptor activation. Spontaneous excitatory post-synaptic current frequency was increased in neurabin knockout mice, but not in spinophilin knockout mice, and this effect was normalized by D2 receptor agonist application. Both knockout strains displayed increased induction of GluR1 Ser(845) phosphorylation in response to D1 receptor stimulation in slices, and also displayed enhanced locomotor activation in response to cocaine administration. These effects could be dissociated from cocaine reward, which was enhanced only in spinophilin knockout mice, and was accompanied by increased immediate early gene induction. These data establish a requirement for synaptic scaffolding in dopamine-mediated responses, and further indicate that spinophilin and neurabin play distinct roles in dopaminergic signal transduction and psychostimulant response.

Long-term fate of neural precursor cells following transplantation into developing and adult CNS.

Successful strategies for transplantation of neural precursor cells for replacement of lost or dysfunctional CNS cells require long-term survival of grafted cells and integration with the host system, potentially for the life of the recipient. It is also important to demonstrate that transplants do not result in adverse outcomes. Few studies have examined the long-term properties of transplanted neural precursor cells in the CNS, particularly in non-neurogenic regions of the adult. The aim of the present study was to extensively characterize the fate of defined populations of neural precursor cells following transplantation into the developing and adult CNS (brain and spinal cord) for up to 15 months, including integration of graft-derived neurons with the host. Specifically, we employed neuronal-restricted precursors and glial-restricted precursors, which represent neural precursor cells with lineage restrictions for neuronal and glial fate, respectively. Transplanted cells were prepared from embryonic day-13.5 fetal spinal cord of transgenic donor rats that express the marker gene human placental alkaline phosphatase to achieve stable and reliable graft tracking. We found that in both developing and adult CNS grafted cells showed long-term survival, morphological maturation, extensive distribution and differentiation into all mature CNS cell types (neurons, astrocytes and oligodendrocytes). Graft-derived neurons also formed synapses, as identified by electron microscopy, suggesting that transplanted neural precursor cells integrated with adult CNS. Furthermore, grafts did not result in any apparent deleterious outcomes. We did not detect tumor formation, cells did not localize to unwanted locations and no pronounced immune response was present at the graft sites. The long-term stability of neuronal-restricted precursors and glial-restricted precursors and the lack of adverse effects suggest that transplantation of lineage-restricted neural precursor cells can serve as an effective and safe replacement therapy for CNS injury and degeneration.

Lineage-restricted neural precursors survive, migrate, and differentiate following transplantation into the injured adult spinal cord.

Fetal spinal cord from embryonic day 14 (E14/FSC) has been used for numerous transplantation studies of injured spinal cord. E14/FSC consists primarily of neuronal (NRP)- and glial (GRP)-restricted precursors. Therefore, we reasoned that comparing the fate of E14/FSC with defined populations of lineage-restricted precursors will test the in vivo properties of these precursors in CNS and allow us to define the sequence of events following their grafting into the injured spinal cord. Using tissue derived from transgenic rats expressing the alkaline phosphatase (AP) marker, we found that E14/FSC exhibited early cell loss at 4 days following acute transplantation into a partial hemisection injury, but the surviving cells expanded to fill the entire injury cavity by 3 weeks. E14/FSC grafts integrated into host tissue, differentiated into neurons, astrocytes, and oligodendrocytes, and demonstrated variability in process extension and migration out of the transplant site. Under similar grafting conditions, defined NRP/GRP cells showed excellent survival, consistent migration out of the injury site and robust differentiation into mature CNS phenotypes, including many neurons. Few immature cells remained at 3 weeks in either grafts. These results suggest that by combining neuronal and glial restricted precursors, it is possible to generate a microenvironmental niche where emerging glial cells, derived from GRPs, support survival and neuronal differentiation of NRPs within the non-neurogenic and non-permissive injured adult spinal cord, even when grafted into acute injury. Furthermore, the NRP/GRP grafts have practical advantages over fetal transplants, making them attractive candidates for neural cell replacement.

Alcohol consumption and micronutrient intake as risk factors for liver cirrhosis: a case-control study. The Provincial Group for the study of Chronic Liver Disease.

PURPOSE: The purpose of this study was to assess the relationship of alcohol consumption and intake of 15 selected micronutrients with risk of liver cirrhosis. METHODS: Data from a case-control study performed in 1989-1990 in central Italy involving 115 incident cases and 167 hospital controls were used. RESULTS: Cases and controls did not differ for mean daily intake of calories, carbohydrates, lipids, and proteins. Significant direct dose-response relationships between the intakes of vitamin A and iron and the risk cirrhosis were observed, while significant protective effects were obtained for the intakes of vitamins B2 (riboflavin) and B12. Different patterns of the joint effect of nutrients and alcohol were also observed. The intakes of vitamin A and iron were significantly associated with the risk of cirrhosis in lifetime teetotalers (odds ratios (OR) and 95% coincidence intervals (CI) of 33.6 (1.2-979.9) and 37.9 (1.8-819.4) for higher intake of vitamin A and iron, respectively) and in consumers of < 50 g/day of alcohol (vitamin A: OR 45.0; 95% CI, (2.6-774.6); iron: OR, 73.6; 95% CI, 4.3-999). The OR associated with intakes of vitamins B2 (riboflavin) and B12 were not significant for the first two categories of alcohol use, while a higher intake of these two vitamins reduced the risk of cirrhosis associated with alcohol consumption above 50 g/day; the ORs (95% CI) were 23.0 (2.7-198.9) and 104.4 (7.2-999), respectively, for higher and lower intakes of riboflavin and 12.8 (1.8-88.1) and 138.4 (14.0-999), respectively, for higher and lower intake of vitamin B12. CONCLUSION: These findings might explain at least a portion of the individual susceptibility to alcohol-induced liver damage.

Is alcohol a risk factor for liver cirrhosis in HBsAg and anti-HCV negative subjects? Collaborative Groups for the Study of Liver Diseases in Italy.

BACKGROUND/AIMS: In order to evaluate the association between alcohol intake and the risk of liver cirrhosis in the absence of B and C hepatitis viruses, we analyzed data from three hospital-based case-control studies performed in various Italian areas. METHODS: From the case and control series we excluded HBsAg and/or anti-HCV positive patients. Cases were 221 cirrhotic patients admitted for the first time to hospital for liver decompensation. Controls were 614 patients admitted to the same hospitals during the same period as the cases for acute diseases unrelated to alcohol. Alcohol consumption was expressed as lifetime daily alcohol intake (LDAI). RESULTS: We found a dose-effect relationship between LDAI and the risk of liver cirrhosis (LC). Considering the extreme LDAI categories (LDAI = 0 g: lifetime teetotallers and LDAI > or = 100 g), the LC odds ratio (OR) increased from 1.0 (reference category) to 44.7 (95% confidence interval: 95% CI: 20.0-99.9). An increased risk of LC associated with the female gender independent of alcohol consumption was also observed (OR = 2.9; 95% CI: 1.8-4.6). CONCLUSIONS: Alcohol intake acts as a risk factor for symptomatic liver cirrhosis also in the absence of HBV and/or HCV infection. Besides alcohol and viruses, some unknown gender-related factors might be involved in the occurrence of the disease.

Mortality in psychiatric hospital patients: a cohort analysis of prognostic factors.

BACKGROUND: This work followed a group of patients living in a psychiatric hospital in Central Italy in 1978 at the time of enforcement of the Italian reform law (No. 180) for closing down mental hospitals. The study had the following aims: a) to compare in terms of mortality patients discharged into the community with patients who did not experience deinstitutionalization; b) to determine the survival of the cohort of patients and to analyse prognostic risk factors for death; c) to analyse differences in mortality rates between psychiatric patients and the general population. METHODS: The study was designed as an historical follow-up investigation. Univariate (product limit) and multivariate (proportional hazards model) methods were used to estimate prognostic variables and related death risks. Mortality was assessed using standardized mortality ratios (SMR) on the entire cohort as well as after stratification according to age, sex, cause of death and discharge status, assuming the Abruzzo Region's population as standard. RESULTS: Length of hospitalization and discharge from hospital are prognostic variables for death risk, with relative risks respectively of 4.22 (95% confidence interval [CI]: 2.41-7.40) for a length of hospitalization of 10-25 years, and 8.13 (95% CI: 4.73-13.88) for non-discharge. The global SMR of the cohort was 2.68 (95% CI: 2.42-3.07). Non-discharged patients showed higher SMR than discharged. Excess mortality was found both in males and females for circulatory, respiratory and undefined diseases. A significantly lower mortality for cancer was observed in male patients. A strong excess mortality was observed in younger patients (20-29 years: SMRmales = 43.57; SMRfemales = 97.52). CONCLUSIONS: Longer periods of hospitalization and non-discharge from hospital are the main risk factors for death in psychiatric patients, who globally experience higher death rates than the general population for a wide spectrum of causes of death, whatever their diagnosis or gender. These findings strongly suggest positive actions in order to overcome the effects of institutionalization.

Impaired inactive to active kallikrein conversion in human salt-sensitive hypertension.

Active and inactive urinary kallikrein excretion rates were evaluated in 43 essential hypertensive men (45.4 +/- 5.6 yr) after normal-(120 mmol/day), low-(20 mmol/day), and high-(240 mmol/day) NaCl diets were given for 2 wk each. Patients were classified as salt-sensitive, salt-resistant, or counterregulating, on the basis of their blood pressure responses to the different NaCl intakes. Resulting data show that active and inactive kallikrein excretion rates were lower (P < 0.001) in salt-sensitive (active, 0.59 +/- 0.27 U/24 h; inactive, 3.45 +/- 1.31 U/24 h) than in salt-resistant (active, 1.41 +/- 0.35 U/24 h; inactive, 6.93 +/- 2.68 U/24 h) and in counterregulating hypertensive patients (active, 1.37 +/- 0.39 U/24 h; inactive, 6.32 +/- 2.58 U/24 h) after the normal NaCl diet. Salt-sensitive hypertensive patients showed also higher plasma digoxin-like substance (P < 0.001), atrial natriuretic peptide (P < 0.001), and fasting insulin (P < 0.005) levels than the other subgroups. Active kallikrein decreased after high and increased after low-NaCl intake in all groups. Inactive kallikrein varied similarly to active one in salt-resistant patients and counterregulating patients, whereas it increased during salt-loading in salt-sensitive patients. Consequently, the active/total kallikrein ratio decreased in salt-sensitive patients (from 20.2 +/- 3.5 to 5.82 +/- 1.02%, P < 0.05) when they switched from low- to high-NaCl intake, and the ratio was lower in these patients than in the other subgroups (P < 0.0001) after the high-NaCl diet. In conclusion, active and inactive kallikrein excretions after normal-NaCl intake are reduced in salt-sensitive hypertensive patients. The divergent active and inactive kallikrein responses to dietary NaCl changes in salt-sensitive patients could indicate an impairment of inactive to active kallikrein conversion during NaCl loading as a new mechanism in human salt-sensitive hypertension.

Levels of flurithromycin in female genital tissue.

The levels of flurithromycin in gynecological tissue in 20 female patients were studied after preoperative administration. The tissue flurithromycin levels obtained were comparable to those obtained in serum at 3 and 4 h but were frequently higher than those in serum at 6 and 12 h. Flurithromycin reached the highest concentrations in ovary at 4 h and in endometrium at 6 h.