Metabolic Monitoring Research Articles

The Effect of Reperfusion on Cerebral Activity in Donors after Circulatory Death Following Normothermic Regional Perfusion

Purpose To investigate brain activity and intracerebral physiological parameters following no-touch and normothermic regional perfusion (NRP) in donors after circulatory death. Methods The study comprised 16 female pigs of 85 kg. Following anesthesia, five burr holes were placed in the skull targeting the parasagittal cortex bilaterally. To assess cortical brain activity two needles were used to record electroencephalography (EEG) and somatosensory evoked potentials (SSEP). Two probes measuring intracranial pressure and cerebral blood perfusion (CBF), temperature, and oxygen were inserted. Additionally, a microdialysis catheter for metabolic monitoring of lactate, pyruvate, glycerol, and glucose was inserted. The animals were cannulated for the heart-lung machine and baseline measurements were performed before withdrawal from life support. Before NRP, the animals were randomized into two groups: Clamp or non-clamp of the aortic arch vessels. After mechanical asystole, a no-touch period of 8 minutes was observed before the institution of NRP. The animals were weaned from NRP after 30 minutes and subsequently monitored for 3 hours after weaning. Results In the clamp group, flatline EEG and no-SSEPs were recorded after weaning in all pigs. In the non-clamp group, SSEPs were observed after weaning in 6/8 pigs. In all pigs, a peculiar EEG activity of periodic 4-5 Hz complexes, amplitude up to 300 μV, with a repetition interval of one in every 8-60 seconds was recorded. In two pigs, continuous EEG activity was observed alongside the periodic complexes. Additionally, spontaneous respiratory movements were observed in 6/8 pigs in the non-clamp group during a brief pause of ventilation. Preliminary analysis of intracranial measurements of CBF, oxygen, and temperature indicates successful occlusion of the arch vessels in the clamp group and as such cessation of cerebral perfusion. All results await final statistical analysis. Conclusion Some degree of cerebral function returns following circulatory death and resuscitation with NRP and cerebral reperfusion. We observed continuous EEG activity alongside periodic complexes resembling the so-called Nu-complexes thought to originate in the hippocampus. In addition, SSEP response and negative apnea tests suggest that brain stem function returns following NRP with preserved cerebral perfusion.

Multi-Year Monitoring of Ecosystem Metabolism in Two Branches of a Cold-Water Stream

Climate change is likely to have large impacts on freshwater biodiversity and ecosystem function, especially in cold-water streams. Ecosystem metabolism is affected by water temperature and discharge, both of which are expected to be affected by climate change and, thus, require long-term monitoring to assess alterations in stream function. This study examined ecosystem metabolism in two branches of a trout stream in Minnesota, USA over 3 years. One branch was warmer, allowing the examination of elevated temperature on metabolism. Dissolved oxygen levels were assessed every 10 min from spring through fall in 2017–2019. Gross primary production (GPP) was higher in the colder branch in all years. GPP in both branches was highest before leaf-out in the spring. Ecosystem respiration (ER) was greater in the warmer stream in two of three years. Both streams were heterotrophic in all years (net ecosystem production—NEP < 0). There were significant effects of temperature and light on GPP, ER, and NEP. Stream discharge had a significant impact on all GPP, ER, and NEP in the colder stream, but only on ER and NEP in the warmer stream. This study indicated that the impacts of temperature, light, and discharge differ among years, and, at least at the local scale, may not follow expected patterns.

Metabolic monitoring via on-line analysis of 13C-enriched carbon dioxide in exhaled mouse breath using substrate-integrated hollow waveguide infrared spectroscopy and luminescence sensing combined with Bayesian sampling

In studies that target specific functions or organs, the response is often overlaid by indirect effects of the intervention on global metabolism. The metabolic side of these interactions can be assessed based on total energy expenditure (TEE) and the contributions of the principal energy sources, carbohydrates, proteins and fat to whole body CO2 production. These parameters can be identified from indirect calorimetry using respiratory oxygen intake and CO2 dioxide production data that are combined with the response of the 13CO2 release in the expired air and the glucose tracer enrichment in plasma following a 13C glucose stable isotope infusion. This concept is applied to a mouse protocol involving anesthesia, mechanical respiration, a disease model, like hemorrhage and therapeutic intervention. It faces challenges caused by a small sample size for both breath and plasma as well as changes in metabolic parameters caused by disease and intervention. Key parameters are derived from multiple measurements, all afflicted with errors that may accumulate leading to unrealistic values. To cope with these challenges, a sensitive on-line breath analysis system based on substrate-integrated hollow waveguide infrared spectroscopy and luminescence (iHWG-IR-LS) was used to monitor gas exchange values. A Bayesian statistical model is developed that uses established equations for indirect calorimetry to predict values for respiratory gas exchange and tracer data that are consistent with the corresponding measurements and also provides statistical error bands for these parameters. With this new methodology, it was possible to estimate important metabolic parameters (respiratory quotient (RQ), relative contribution of carbohydrate, protein and fat oxidation fcarb, ffat and fprot , total energy expenditure TEE) in a resolution never available before for a minimal invasive protocol of mice under anesthesia.

In-vitro and in-vivo monitoring of gold(III) ions from intermediate metabolite of sodium aurothiomalate through water-soluble ruthenium (II) complex-based luminescent probe

Real-time monitoring of drug metabolism in vivo is of great significance to drug development and toxicology research. The purpose of this study is to establish a rapid and visual in vivo detection method for the detection of an intermediate metabolite of the gold (I) drug. Gold (I) drugs such as sodium aurothiomalate (AuTM) have anti-inflammatory effects in the treatment of rheumatoid arthritis. Gold(III) ions (Au3+) are the intermediate metabolite of gold medicine, and they are also the leading factor of side effects in the treatment of patients. However, the rapid reduction of Au3+ to Au+ by thiol proteins in organisms limits the in-depth study of metabolism of gold drugs in vivo. Here we describe a luminescence Au3+ probe (RA) based on ruthenium (II) complex for detecting Au3+ in vitro and in vivo. RA with large Stokes shift, good water solubility and biocompatibility was successfully applied to detect Au3+ in living cells and vivo by luminescence imaging, and to trap the fluctuation of Au3+ level produced by gold (I) medicine. More importantly, the luminescent probe was used to the detection of the intermediate metabolites of gold (I) drugs for the first time. Overall, this work offers a new detection tool/method for a deeper study of gold (I) drugs metabolite.

Evaluation of metabolic monitoring practices for mental health consumers in the Southern District Health Board Region of New Zealand.

WHAT IS KNOWN ON THIS SUBJECT?: The physical health of people with serious mental illness (SMI) is an issue of growing concern in New Zealand and internationally. Metabolic syndrome is prevalent among people with severe mental illness and increases the likelihood of developing cardiovascular disease and diabetes. No previous international research has investigated rates of metabolic monitoring in specialist mental health services and in primary care. WHAT THIS PAPER ADDS TO EXISTING KNOWLEDGE?: Rates of metabolic monitoring are low in this specialist mental health service and in primary care. Primary care nurses are positive in their views of their role in providing care for people with mental illness, and would value further education in this area. WHAT ARE THE IMPLICATIONS FOR PRACTICE?: Services need to consider ways in which nurses can be supported to improve rates of metabolic monitoring. Guidelines may have a role to play in improved monitoring but need service-level support in order to be effective. ABSTRACT: Introduction People with serious mental illness experience significant disparities in their physical health compared with the general population. One indicator of health impairment is metabolic syndrome, which increases the likelihood of developing cardiovascular disease and diabetes. No international studies have reported both primary care and mental health nurses' rates of metabolic monitoring among people with serious mental illness, and no New Zealand studies have investigated rates of metabolic monitoring. Aim To evaluate metabolic monitoring practices within one of New Zealand's 20 district health board regions. Method An audit of clinical records in primary care (n=46) and secondary care (n=47) settings and a survey of practice nurses were conducted. A survey was sent to 127 practice nurses with a response rate of 19% (n=24). Data were analysed using descriptive statistics. Results Rates of metabolic monitoring were low in both services. Survey participants expressed positive views towards physical health monitoring and confidence in relating to mental health consumers. Rates of treatment of metabolic abnormalities were low, and communication between primary and secondary services was limited. Conclusion Despite existence of guidelines and protocols, metabolic monitoring rates in both primary and secondary health services are low. Incorporating metabolic monitoring systems into service delivery, supported by appropriate tools and resourcing, is essential to achieve better clinical outcomes for people experiencing mental illness.

Surface Microdialysis for Detection of Colorectal Anastomosis Ischemia—An Experimental Study

BackgroundInadequate blood supply is one of the major risk factors for anastomotic leak after low anterior rectal resection. Early detection of ischemia might predict complicated healing and enable anastomotic salvage, which is associated with better outcomes. A microdialysis offers a real-time evaluation of adequate bowel perfusion through monitoring of tissue metabolism. In this experimental study, we assessed the role of microdialysis in detecting early ischemia after colorectal anastomosis. Materials and methodsColorectal anastomosis was performed in six miniature pigs. A microdialysis catheter was placed on the bowel serosa 5 mm proximal to the anastomosis. Metabolic changes were monitored hourly before and after initiating ischemia, which was induced by ligation of the inferior mesenteric artery and skeletonization of the mesocolon. ResultsSignificant increase in tissue levels of lactate was detected after 60 min of ischemia (13.6 [10.4-16.1] versus 6.75 [1.8-9.6] mmol/L at baseline; P < 0.005). The lactate/pyruvate ratio increased accordingly. The concentration of glycerol increased significantly after 2 hours—from a baseline value of 29.5 (3-84) to 125 (79-201) mmol/L (P < 0.005). The decrease in glucose levels was also significant after 60 minutes—0 (0-0.2) versus 4.7 (3.3-6.8) mmol/L at baseline. However, its values started to decline before ischemia. ConclusionsSurface microdialysis can detect ischemic changes early and may be a promising method in postoperative monitoring of colorectal anastomosis.

Assessment of the in vivo genotoxicity of pendimethalin via mitochondrial bioenergetics and transcriptional profiles during embryogenesis in zebrafish: Implication of electron transport chain activity and developmental defects

Pendimethalin, an herbicide used to control weeds, acts by inhibiting plant cell division and mitosis. Several studies have reported the detrimental effects of pendimethalin on non-target organisms. It has been found to be especially toxic to aquatic life. Additionally, there is some evidence that pendimethalin induces mitochondrial stress. However, none of the studies have provided information about the functional defects in mitochondria and toxicity during embryogenesis. In this study, we evaluated the impact of pendimethalin on the electron transport chain (ETC) activity and mitochondrial complexes via in vivo screening of oxidative phosphorylation and transcriptional profiles in zebrafish embryos. The results showed that pendimethalin interferes with mitochondrial complexes I and V, which inhibit embryo energy metabolism, thereby leading to developmental defects. Transgenic zebrafish, fli1:eGFP and olig2:dsRed, were used to confirm pendimethalin-induced functional depletion in neurogenesis and vasculogenesis during embryo development. This study provides new insights into the methodology of environmental assessment of biohazard chemicals that target ETC activity in mitochondria. Additionally, the results suggest that real-time respiratory and metabolic monitoring in zebrafish will be useful for the genotoxicity assessment of environmentally hazardous substances and may be used as an alternative model for the control of aquatic environmental pollutants.

Differentiation of Heterogeneous Mouse Liver from HCC by Hyperpolarized 13C Magnetic Resonance

The clinical characterization of small hepatocellular carcinoma (HCC) lesions in the liver and differentiation from heterogeneous inflammatory or fibrotic background is important for early detection and treatment. Metabolic monitoring of hyperpolarized 13C-labeled substrates has been suggested as a new avenue for diagnostic magnetic resonance. The metabolism of hyperpolarized [1-13C]pyruvate was monitored in mouse precision-cut liver slices (PCLS) of aged MDR2-KO mice, which served as a model for heterogeneous liver and HCC that develops similarly to the human disease. The relative in-cell activities of lactate dehydrogenase (LDH) to alanine transaminase (ALT) were found to be 0.40 ± 0.06 (n = 3) in healthy livers (from healthy mice), 0.90 ± 0.27 (n = 3) in heterogeneously inflamed liver, and 1.84 ± 0.46 (n = 3) in HCC. Thus, the in-cell LDH/ALT activities ratio was found to correlate with the progression of the disease. The results suggest that the LDH/ALT activities ratio may be useful in the assessment of liver disease. Because the technology used here is translational to both small liver samples that may be obtained from image-guided biopsy (i.e., ex vivo investigation) and to the intact liver (i.e., in a noninvasive MRI scan), these results may provide a path for differentiating heterogeneous liver from HCC in human subjects.

Provider Specialty and Receipt of Metabolic Monitoring for Children Taking Antipsychotics.

Metabolic monitoring is important for children taking antipsychotic medication, given the risk for increased BMI, impaired glucose metabolism, and hyperlipidemia. The purpose was to examine the influence of provider specialty on the receipt of metabolic monitoring. Specifically, differences in the receipt of recommended care when a child receives outpatient care from a primary care provider (PCP), a mental health provider with prescribing privileges, or both was examined. Medicaid enrollment and health care and pharmacy claims data from 2 states were used in the analyses. Providers were assigned to specialties by using a crosswalk of the National Provider Identifier numbers to specialty type. A total of 41 078 children were included. For both states, 61% of children saw ≥1 provider type and had adjusted odds ratios for receiving metabolic monitoring that were significantly higher than those of children seeing PCPs only. For example, children seeing a PCP and a mental health provider with prescribing privileges during the year had adjusted odds of receiving metabolic monitoring that were 42% higher than those seeing a PCP alone (P < .001). Shared care arrangements significantly increased the chances that metabolic monitoring would be done. For states, health plans, and clinicians to develop meaningful quality improvement strategies, identifying the multiple providers caring for the children and potentially responsible for ordering tests consistent with evidence-based care is essential. Provider attribution in the context of shared care arrangements plays a critical role in driving quality improvement efforts.

Consensus on strategies for implementing high priority mental health care practices within the US Department of Veterans Affairs.

Identifying feasible and effective implementation strategies remains a significant challenge. At present, there is a gap between the number of strategies prospectively included in implementation trials, typically four or fewer, and the number of strategies utilized retrospectively, often 20 or more. This gap points to the need for developing a better understanding of the range of implementation strategies that should be considered in implementation science and practice. This study elicited expert recommendations to identify which of 73 discrete implementation strategies were considered essential for implementing three mental health care high priority practices (HPPs) in the US Department of Veterans Affairs: depression outcome monitoring in primary care mental health (n = 20), prolonged exposure therapy for treating posttraumatic stress disorder (n = 22), and metabolic safety monitoring for patients taking antipsychotic medications (n = 20). Participants had expertise in implementation science, the specific HPP, or both. A highly structured recommendation process was used to obtain recommendations for each HPP. Majority consensus was identified for 26 or more strategies as absolutely essential; 53 or more strategies were identified as either likely essential or absolutely essential across the three HPPs. The large number of strategies identified as essential starkly contrasts with existing research that largely focuses on application of single strategies to support implementation. Systematic investigation and documentation of multi-strategy implementation initiatives is needed. Most implementation studies focus on the impact of a relatively small number of discrete implementation strategies on the uptake of a practice. However, studies that systematically survey providers find that dozens or more discrete implementation strategies can be identified in the context of the implementation initiative. This study engaged experts in implementation science and clinical practice in a structured recommendation process to identify which of the 73 Expert Recommendations for Implementing Change (ERIC) implementation strategies were considered absolutely essential, likely essential, likely inessential, and absolutely inessential for each of the three distinct mental health care practices: depression outcome monitoring in primary care, prolonged exposure therapy for posttraumatic stress disorder, and metabolic safety monitoring for patients taking antipsychotic medications. The results highlight that experts consider a large number of strategies as absolutely or likely essential for supporting the implementation of mental health care practices. For example, 26 strategies were identified as absolutely essential for all three mental health care practices. Another 27 strategies were identified as either absolutely or likely essential across all three practices. This study points to the need for future studies to document the decision-making process an initiative undergoes to identify which strategies to include and exclude in an implementation effort. In particular, a structured approach to this documentation may be necessary to identify strategies that may be endogenous to a care setting and that may not be otherwise be identified as being "deliberately" used to support a practice or intervention.

At a Glance of Biosensors and Their Purposes

The a variety of kinds of biosensors such as enzyme-based, tissue-based, immune sensors, DNA biosensors, thermal and piezoelectric biosensors have been deliberated right here to spotlight their critical functions in multitudinous fields. Some of the famous fields enforcing the use of biosensors are meals enterprise to preserve a take a look at on its fantastic and safety, to assist distinguish between the herbal and artificial; in the fermentation enterprise and in the scarification system to notice unique glucose concentrations; in metabolic engineering to allow in vivo monitoring of cell metabolism. Biosensors and their position in clinical science which includes early stage detection of human interleukin-10 inflicting coronary heart diseases, speedy detection of human papilloma virus, etc. are essential aspects. Fluorescent biosensors play a critical position in drug discovery and in cancer. Biosensor purposes are commonplace in the plant biology quarter to discover out the lacking hyperlinks required in metabolic processes. Other functions are concerned in defense, scientific sector, and for marine applications.

Live monitoring of cellular metabolism and mitochondrial respiration in 3D cell culture system using NMR spectroscopy

Background: Because of the interplay between mitochondrial respiration and cellular metabolism, the simultaneous monitoring of both cellular processes provides important insights for the understanding of biological processes. NMR flow systems provide a unique window into the metabolome of cultured cells. Simplified bioreactor construction based on commercially available flow systems increase the practicability and reproducibility of bioreactor studies using standard NMR spectrometers. We therefore aim at establishing a reproducible NMR bioreactor system for metabolic 1H-NMR investigations of small molecules and concurrent oxygenation determination by 19F-NMR, with in depth description and validation by accompanying measures. Methods: We demonstrate a detailed and standardized workflow for the preparation and transfer of collagen based 3D cell culture of high cell density for perfused investigation in a 5 mm NMR tube. Self-constructed gas mixing station enables 5% CO2 atmosphere for physiological pH in carbon based medium and is perfused by HPLC pump. Results & Discussion: Implemented perfused bioreactor allows detection of perfusion rate dependent metabolite content. We show interleaved dynamic profiling of 26 metabolites and mitochondrial respiration. During constant perfusion, sequential injection of rotenone/oligomycin and 2-deoxy-glucose indicated immediate activation and deactivation of glycolytic rate and full inhibition of oxygen consumption. We show sensitivity to detect substrate degradation rates of major mitochondrial fuel pathways and were able to simultaneously measure cellular oxygen consumption.

Monitoring of metabolic adverse events of second-generation antipsychotics in a naive paediatric population followed in mental health outpatient and inpatient clinical settings: MEMAS prospective study protocol

IntroductionSecond-generation antipsychotics (SGAs) are widely used in the paediatric population. It is currently established that SGAs may induce metabolic adverse events (AEs) such as weight gain, perturbation of blood lipids...

Monitoring acid base status in CKD patients: can urinary citrate help?

Metabolic acidosis is an early and deleterious complication of chronic kidney disease. Because it is frequently eubicarbonatemic, diagnosis may be difficult. In this issue, Gianella etal. suggest that lower urinary citrate excretion, considered as an homeostatic response to metabolic acidosis, may be helpful for early diagnosis and monitoring of alkali treatment. This study should be an incentive for further assessment of the tubular handling of urinary citrate in CKD patients and determination of the performance of urinary citrate for the diagnosis of eubicarbonatemic metabolic acidosis and monitoring of alkali therapy.

Calcium metabolism, arterial stiffness and 24-hour blood pressure monitoring data in postmenopausal women with magnesium deficiency, hypertension, and heart failure

Aim. To assess the calcium metabolism, arterial stiffness and 24-hour blood pressure (BP) monitoring data in postmenopausal women with magnesium deficiency, hypertension, and heart failure with preserved ejection fraction (HFpEF) Material and methods . The study involved 140 female patients with hypertension complicated by HFpEF, aged 52 to 76 years. Depending on the results of magnesium-tolerance test, 2 groups were selected. The first group consisted of 72 females with magnesium deficiency, and the second (control) group (n=68) — without magnesium deficiency. Calcium metabolism was assessed using calcium-tolerance test. Twenty-four-hour blood pressure monitoring and arterial stiffness was determined using an automatic blood pressure monitor. Results . Patients with magnesium deficiency had a lower calcium excretion and return to baseline blood calcium levels compared with group 2 (p&lt;0,001). The presence of magnesium deficiency was associated with an increase in 24-hour BP variability (16,9 [13,3; 20,69] mm Hg vs 12,9 [11,7; 17,42] mm Hg; p=0,001), rate of morning BP rise (12,5 [9,7; 13,6] mm Hg/h vs 9,5 [8,1; 10,9] mm Hg/h; p&lt;0,001) and indexed systolic BP (21,2 [19,5; 25,1] mm Hg vs 19,5 [16,5; 23,9] mm Hg; p=0,007). In women with magnesium deficiency, BP pro -files of non-dipper and night-peaker were more common (p&lt;0,05). Pulse wave velocity (11,92 [10,06; 14,47] m/s vs 10,87 [8,41; 13,20] m/s; p=0,005) and central pulse pressure (70,2±13,3 mm Hg vs 63,5±12,5 mm Hg; p=0,003) were also higher in group 1. Also, a correlation ( р=-0,610, p&lt;0,001) was found between the rate of exercise-induced decrease in blood calcium and the pulse wave velocity. Conclusion . In women with hypertension and HFpEF, there were no differences in mean 24-hour BP values, while more unfavorable BP profiles and arterial stiffness indicators were revealed, which is mediated by impaired oalcium metabolism.

Advocacy for better metabolic monitoring after antipsychotic initiation: based on data from a French health insurance database

ABSTRACT Background: Nearly 3% of the population is treated by antipsychotic. The aim of this study was to assess the conformity of monitoring with guidelines to prevent Metabolic Syndrome. Research design and method: The analysis was conducted using SNIIRAM data (2013 to 2017) on a cohort of patients who received at least eight antipsychotic dispensings in the first year. Glucose and lipid testings were recorded according to refunds at initiation [between −3 and 0.5 months], 3 months [between 2 and 4 months], and 12 months [between 11 and 13 months] after, and assuming optimal testing during hospitalization (exclusive of psychiatric unit). Descriptive and comparative analysis, «chi-squared test or Student’s t-test», were performed as well as multivariate analysis with logistic regression. Results: 18 760 patients were selected, 14 421 were still alive and monitored at the end of the follow up. In the recommended period, only 2.89% of patients had three complete testings and 50.6% one or two complete testings Non-optimal testing was more likely to occur in children and adults (vs elderly), in patients with less than 3 prescribers, and with universal medical coverage. Conclusion: Monitoring remains dramatically insufficient. New actions involving patients, practitioners, and authorities are warranted.

Association of lactate dehydrogenase with mortality in incident hemodialysis patients.

Lactate dehydrogenase (LDH) plays a role in the glucose metabolism of the human body. Higher LDH levels have been linked to mortality in various cancer types; however, the relationship between LDH and survival in incident hemodialysis (HD) patients has not yet been examined. We hypothesized that higher LDH level is associated with higher death risk in these patients. We examined the association of baseline and time-varying serum LDH with all-cause, cardiovascular and infection-related mortality among 109 632 adult incident HD patients receiving care from a large dialysis organization in the USA during January 2007 to December 2011. Baseline and time-varying survival models were adjusted for demographic variables and available clinical and laboratory surrogates of malnutrition-inflammation complex syndrome. There was a linear association between baseline serum LDH levels and all-cause, cardiovascular and infection-related mortality in both baseline and time-varying models, except for time-varying infection-related mortality. Adjustment for markers of inflammation and malnutrition attenuated the association in all models. In fully adjusted models, baseline LDH levels ≥360 U/L were associated with the highest risk of all-cause mortality (hazard ratios = 1.19, 95% confidence interval 1.14-1.25). In time-varying models, LDH >280 U/L was associated with higher death risk in all three hierarchical models for all-cause and cardiovascular mortality. Higher LDH level >280 U/L was incrementally associated with higher all-cause and cardiovascular mortality in incident dialysis patients, whereas LDH <240 U/L was associated with better survival. These findings suggest that the assessment of metabolic functions and monitoring for comorbidities may confer survival benefit to dialysis patients.

Laboratory Testing in Psychiatry

We review common laboratory testing encountered in psychiatric practice. It seems likely that in areas where the most evidence exists driving laboratory testing (e.g., metabolic monitoring for people on atypical antipsychotics), testing still is not universally done, and we often do not adequately address the results. However, in areas where there is little evidence supporting the practice (extensive laboratory testing on people being admitted to a psychiatric hospitals), we order tests extensively. We cover common tests encountered in the use of antipsychotics, antidepressants, mood stabilizers, antiepileptic drugs, and lithium. We also discuss the role of thyroid, vitamin B12, and folate testing and the special circumstance of caring for those with eating disorders. This review contains 2 highly rendered figures, 20 tables, and 44 references. Key words: agranulocytosis, antidepressant, antiepileptic drug, antipsychotic, blood dyscrasia, clozapine, eating disorders, metabolic monitoring, QT interval, urine drug screen

Metabolic and Nutritional Issues Associated with Spinal Muscular Atrophy.

Spinal muscular atrophy (SMA), the main genetic cause of infant death, is a neurodegenerative disease characterized by the selective loss of motor neurons in the anterior horn of the spinal cord, accompanied by muscle wasting. Pathomechanically, SMA is caused by low levels of the survival motor neuron protein (SMN) resulting from the loss of the SMN1 gene. However, emerging research extends the pathogenic effect of SMN deficiency beyond motor neurons. A variety of metabolic abnormalities, especially altered fatty acid metabolism and impaired glucose tolerance, has been described in isolated cases of SMA; therefore, the impact of SMN deficiency in metabolic abnormalities has been speculated. Although the life expectancy of these patients has increased due to novel disease-modifying therapies and standardization of care, understanding of the involvement of metabolism and nutrition in SMA is still limited. Optimal nutrition support and metabolic monitoring are essential for patients with SMA, and a comprehensive nutritional assessment can guide personalized nutritional therapy for this vulnerable population. It has recently been suggested that metabolomics studies before and after the onset of SMA in patients can provide valuable information about the direct or indirect effects of SMN deficiency on metabolic abnormalities. Furthermore, identifying and quantifying the specific metabolites in SMA patients may serve as an authentic biomarker or therapeutic target for SMA. Here, we review the main epidemiological and mechanistic findings that link metabolic changes to SMA and further discuss the principles of metabolomics as a novel approach to seek biomarkers and therapeutic insights in SMA.

Medical Treatment of Cushing's Disease: An Overview of the Current and Recent Clinical Trials.

Cushing's disease (CD) is a serious endocrine disorder characterized by chronic hypercortisolism, or Cushing's syndrome (CS), caused by a corticotroph pituitary tumor, which induces an excessive adrenocorticotropic hormone (ACTH) and consequently cortisol secretion. CD presents a severe clinical burden, with impairment of the quality of life and increase in mortality. Pituitary surgery represents the first-line therapy, but it is non-curative in one third of patients, requiring additional treatments. Among second-line treatments, medical therapy is gradually gaining importance, although the current medical treatments are unable to reach optimal efficacy and safety profile. Therefore, new drugs and new formulations of presently available drugs are currently under clinical investigation in international clinical trials, in order to assess their efficacy and safety in CD, or in the general population of CS. Among pituitary-directed agents, pasireotide, in the twice-daily subcutaneous formulation, has been demonstrated to be an effective treatment both in clinical trials and in real-world studies, and extension studies of the phase II and III clinical trials reported evidence of long-term efficacy with general good safety profile, although associated with frequent hyperglycemia, which requires monitoring of glucose metabolism. Moreover, the most recent once-monthly intramuscular formulation, pasireotide long-acting release (LAR), showed similar efficacy and safety, but associated with potential better compliance profile in CD. Roscovitine is an experimental drug currently under investigation. Among adrenal-directed agents, metyrapone is the only historical agent currently under investigation in a prospective, multicenter, international clinical trial, that would likely clarify its efficacy and safety in a large population of patients with CS. Osilodrostat, a novel agent with a mechanism of action similar to metyrapone, seems to offer a rapid, sustained, and effective disease control of CD, according to recently completed clinical trials, whereas levoketoconazole, a different chemical formulation of the historical agent ketoconazole, is still under investigation in clinical trials, with preliminary evidences showing an effective and safe control of CS. ATR-101 is an experimental drug currently under investigation. Among glucocorticoid receptor-directed drugs, mifepristone has been demonstrated to improve clinical syndrome and comorbidities, especially hypertension and impairment of glucose metabolism, but the occurrence of hypokalemia and in women uterine disorders, due to the concomitant action on progestin receptor, requires caution, whereas the preliminary evidence on relacorilant, characterized by high selectivity for glucocorticoid receptor, suggested good efficacy in the control of hypertension and impairment of glucose metabolism, as well as a good safety profile, in CS. Finally, a limited experience has demonstrated that combination therapy might be an interesting approach in the management of CD. The current review provides a summary of the available evidences from current and recent clinical trials on CD, with a specific focus on preliminary data.