Technical evaluation and usability of a quantitative G6PD POC test in cord blood: a mixed-methods study in a low-resource setting.

OBJECTIVES: New point-of-care (POC) quantitative G6PD testing devices developed to provide safe radical cure for Plasmodium vivax malaria may be used to diagnose G6PD deficiency in newborns at risk of severe neonatal hyperbilirubinaemia, improving clinical care, and preventing related morbidity and mortality. METHODS: We conducted a mixed-methods study analysing technical performance and usability of the 'STANDARD G6PD' Biosensor when used by trained midwives on cord blood samples at two rural clinics on the Thailand-Myanmar border. RESULTS: In 307 cord blood samples, the Biosensor had a sensitivity of 1.000 (95% CI: 0.859 to 1.000) and a specificity of 0.993 (95% CI: 0.971 to 0.999) as compared with gold-standard spectrophotometry to diagnose G6PD-deficient newborns using a receiver operating characteristic (ROC) analysis-derived threshold of ≤4.8 IU/gHb. The Biosensor had a sensitivity of 0.727 (95% CI: 0.498 to 0.893) and specificity of 0.933 (95% CI: 0.876 to 0.969) for 30%-70% activity range in girls using ROC analysis-derived range of 4.9-9.9 IU/gHb. These thresholds allowed identification of all G6PD-deficient neonates and 80% of female neonates with intermediate phenotypes.Need of phototherapy treatment for neonatal hyperbilirubinaemia was higher in neonates with deficient and intermediate phenotypes as diagnosed by either reference spectrophotometry or Biosensor.Focus group discussions found high levels of learnability, willingness, satisfaction and suitability for the Biosensor in this setting. The staff valued the capacity of the Biosensor to identify newborns with G6PD deficiency early ('We can know that early, we can counsel the parents about the chances of their children getting jaundice') and at the POC, including in more rural settings ('Because we can know the right result of the G6PD deficiency in a short time, especially for the clinic which does not have a lab'). CONCLUSIONS: The Biosensor is a suitable tool in this resource-constrained setting to identify newborns with abnormal G6PD phenotypes at increased risk of neonatal hyperbilirubinaemia.

Amphetamine toxicity masked by concomitant γ-hydroxybutyrate (GHB) ingestion.

We report a case of a young male with amphetamine toxicity initially obscured by concomitant use of gamma-hydroxybutyrate (GHB), and the sympathomimetic symptoms emerged after GHB's effects receded. A 24-year-old unconscious man presented to emergency department showed the following vital signs upon admission: blood pressure 136/58 mmHg; heart rate 79 bpm; SpO2 87% under ambient air; body temperature 36.1 °C; Glasgow Coma Scale score 3. The pupils were not dilated. Arterial blood gas test revealed respiratory acidosis (pH = 7.229, pCO2 = 64.4 mmHg, pO2 = 42.3 mmHg, HCO3 = 26.3 mmol/L). Intubation was performed and the patient was transferred to intensive care unit. The patient regained consciousness and became agitated in association with sinus tachycardia (heartrate 143 bpm; blood pressure 173/61 mmHg). A few hours later, he experienced abrupt desaturation (SpO2 65%) and profuse, pinkish, frothy sputum. Chest radiography revealed a bat-wing perihilar shadowing, and computed tomography showed bilateral ground-glass opacity and an alveolar pattern from acute pulmonary edema. A high dose of benzodiazepine with a midazolam pump at 50 mg/h was administered to relieve symptoms. The patient's friends confessed to concomitant use of amphetamine and GHB. The urine toxicology result was positive for amphetamine (≧500 ng/mL). The patient improved later and was extubated at 4 days after the mitigation of pneumonia and discharged uneventfully 8 days later. In our patient, amphetamine intoxication was initially masked by concomitant use of GHB but appeared as GHB's effect attenuated. We wish to remind clinicians of variable clinical presentations of polydrug abuse.

Treatment of central disorders of hypersomnolence: an American Academy of Sleep Medicine systematic review, meta-analysis, and GRADE assessment.

INTRODUCTION: This systematic review provides supporting evidence for the accompanying clinical practice guideline on the treatment of central disorders of hypersomnolence in adults and children. The review focuses on prescription medications with U.S. Food & Drug Administration approval and nonpharmacologic interventions studied for the treatment of symptoms caused by central disorders of hypersomnolence. METHODS: The American Academy of Sleep Medicine commissioned a task force of experts in sleep medicine to perform a systematic review. Randomized controlled trials and observational studies addressing pharmacological and nonpharmacological interventions for central disorders of hypersomnolence were identified. Statistical analyses were performed to determine the clinical significance of all outcomes. Finally, the Grading of Recommendations Assessment, Development and Evaluation (GRADE) process was used to assess the evidence for the purpose of making specific treatment recommendations. RESULTS: The literature search identified 678 studies; 144 met the inclusion criteria and 108 provided data suitable for statistical analyses. Evidence for the following interventions is presented: armodafinil, clarithromycin, clomipramine, dextroamphetamine, flumazenil, intravenous immune globulin (IVIG), light therapy, lithium, l-carnitine, liraglutide, methylphenidate, methylprednisolone, modafinil, naps, pitolisant, selegiline, sodium oxybate, solriamfetol, and triazolam. The task force provided a detailed summary of the evidence along with the quality of evidence, the balance of benefits and harms, patient values and preferences, and resource use considerations. CITATION: Maski K, Trotti LM, Kotagal S, et al. Treatment of central disorders of hypersomnolence: an American Academy of Sleep Medicine systematic review, meta-analysis, and GRADE assessment. J Clin Sleep Med. 2021;17(9):1895-1945.

γ-Hydroxybutyric Acid: Pharmacokinetics, Pharmacodynamics, and Toxicology.

Gamma-hydroxybutyrate (GHB) is a short-chain fatty acid present endogenously in the brain and used therapeutically for the treatment of narcolepsy, as sodium oxybate, and for alcohol abuse/withdrawal. GHB is better known however as a drug of abuse and is commonly referred to as the "date-rape drug"; current use in popular culture includes recreational "chemsex," due to its properties of euphoria, loss of inhibition, amnesia, and drowsiness. Due to the steep concentration-effect curve for GHB, overdoses occur commonly and symptoms include sedation, respiratory depression, coma, and death. GHB binds to both GHB and GABAB receptors in the brain, with pharmacological/toxicological effects mainly due to GABAB agonist effects. The pharmacokinetics of GHB are complex and include nonlinear absorption, metabolism, tissue uptake, and renal elimination processes. GHB is a substrate for monocarboxylate transporters, including both sodium-dependent transporters (SMCT1, 2; SLC5A8; SLC5A12) and proton-dependent transporters (MCT1-4; SLC16A1, 7, 8, and 3), which represent significant determinants of absorption, renal reabsorption, and brain and tissue uptake. This review will provide current information of the pharmacology, therapeutic effects, and pharmacokinetics/pharmacodynamics of GHB, as well as therapeutic strategies for the treatment of overdoses. Graphical abstract.

A Case of Narcolepsy Type 2 and Postural Tachycardia Syndrome Secondary to Lesions of the Thalamus and Amygdala.

ABSTRACT: Although there are reports of narcolepsy type 1 caused by lesions of the central nervous system, there are far fewer reports of narcolepsy type 2 (NT2) caused by discrete brain lesions. We report a case of a patient in whom NT2 was diagnosed after a viral illness, and inflammatory lesions in the right thalamus and amygdala were found. In addition, symptoms of autonomic impairment developed and postural tachycardia syndrome was subsequently diagnosed in this patient. To our knowledge this is the first reported case of NT2 resulting from central nervous system lesions in these discrete locations, as well as the first reported case of postural tachycardia syndrome associated with narcolepsy.

Melatonin successfully rescues hippocampal bioenergetics and improves cognitive function following drug intoxication by promoting Nrf2-ARE signaling activity.

Prolonged exposure to gamma-hydroxybutyric acid (GHB) would cause drug intoxication in which impaired cognitive function results from enhanced hippocampal oxidative stress may serve as a major symptom in this deficiency. Considering melatonin possesses significant anti-oxidative efficacy, this study aimed to determine whether melatonin would successfully promote the nuclear factor erythroid 2-related factor 2 and antioxidant responsive element (Nrf2-ARE) signaling, depress oxidative stress, and rescue hippocampal bioenergetics and cognitive function following drug intoxication injury. Adolescent rats subjected to 10 days of GHB were received melatonin at doses of either 10 or 100 mg/kg. Time-of-flight secondary ion mass spectrometry, biochemical assay, quantitative histochemistry, [14 C]-2-deoxyglucose analysis, together with Morris water maze were employed to detect the molecular signaling, oxidative status, bioenergetic level, as well as the cognitive performances, respectively. Results indicated that in GHB-intoxicated rats, enhanced oxidative stress, increased cholesterol level, and decreased anti-oxidative enzymes activities were detected in hippocampal regions. Intense oxidative stress paralleled well with reduced bioenergetics and poor performance in behavioral testing. However, in rats treated with melatonin following GHB intoxication, all above parameters and cognitive function were gradually returned to nearly normal levels. Melatonin also remarkably promoted the translocation of Nrf2 from cytoplasm to nucleus in a dose-dependent manner, thereby increased the Nrf2-ARE signaling-related downstream anti-oxidative enzymes activities. As melatonin effectively rescues hippocampal bioenergetics through depressing the oxidative stress by promoting Nrf2-ARE molecular machinery, this study thus highlights for the first time that clinical use of melatonin may serve as a therapeutic strategy to improve the cognitive function in unsuspecting victims suffered from GHB intoxication injury.

EULAR revised recommendations for the management of fibromyalgia.

OBJECTIVE: The original European League Against Rheumatism recommendations for managing fibromyalgia assessed evidence up to 2005. The paucity of studies meant that most recommendations were 'expert opinion'. METHODS: A multidisciplinary group from 12 countries assessed evidence with a focus on systematic reviews and meta-analyses concerned with pharmacological/non-pharmacological management for fibromyalgia. A review, in May 2015, identified eligible publications and key outcomes assessed were pain, fatigue, sleep and daily functioning. The Grading of Recommendations Assessment, Development and Evaluation system was used for making recommendations. RESULTS: 2979 titles were identified: from these 275 full papers were selected for review and 107 reviews (and/or meta-analyses) evaluated as eligible. Based on meta-analyses, the only 'strong for' therapy-based recommendation in the guidelines was exercise. Based on expert opinion, a graduated approach, the following four main stages are suggested underpinned by shared decision-making with patients. Initial management should involve patient education and focus on non-pharmacological therapies. In case of non-response, further therapies (all of which were evaluated as 'weak for' based on meta-analyses) should be tailored to the specific needs of the individual and may involve psychological therapies (for mood disorders and unhelpful coping strategies), pharmacotherapy (for severe pain or sleep disturbance) and/or a multimodal rehabilitation programme (for severe disability). CONCLUSIONS: These recommendations are underpinned by high-quality reviews and meta-analyses. The size of effect for most treatments is relatively modest. We propose research priorities clarifying who will benefit from specific interventions, their effect in combination and organisation of healthcare systems to optimise outcome.

The main constituents of Tulipa systola Stapf. roots and flowers; their antioxidant activities.

People living on the mountains of the Kurdistan Region, Iraq make a large use of herbs in the local traditional medicine. Among them, Tulipa systola, which grows under and between rocks, is very popular as an anti-inflammatory remedy and pain-relief. The phytochemical study of an ethanolic extract obtained from flowers and roots of Tulip (T systola Stapf.) afforded three compounds, identified as (+)-1-O-E-feruloyl-3-O-E-p-coumaroylglycerol (1), (+)-6-tuliposide A (2), and (-)-kaempferol-3-O-rutinoside (3). The significant radical scavenging and antioxidant activity of the isolated compounds were evaluated on three tests, by determining the DPPH free radical scavenging activity, the total antioxidant activity and the hydrogen peroxide scavenging activity. Tuliposide A shows potent allergenic activity.

Thalamic mechanisms underlying alpha-delta sleep with implications for fibromyalgia.

Alpha-delta sleep is the abnormal intrusion of alpha activity (8- to 13-Hz oscillations) into the delta activity (1- to 4-Hz oscillations) that defines slow-wave sleep. Alpha-delta sleep is especially prevalent in fibromyalgia patients, and there is evidence suggesting that the irregularities in the sleep of these patients may cause the muscle and tissue pain that characterizes the disorder. We constructed a biophysically realistic mathematical model of alpha-delta sleep. Imaging studies in fibromyalgia patients suggesting altered levels of activity in the thalamus motivated a thalamic model as the source of alpha activity. Since sodium oxybate helps to alleviate the symptoms of fibromyalgia and reduces the amount of alpha-delta sleep in fibromyalgia patients, we examined how changes in the molecular targets of sodium oxybate affected alpha-delta activity in our circuit. Our model shows how alterations in GABAB currents and two thalamic currents, Ih (a hyperpolarization-activated current) and a potassium leak current, transform a circuit that normally produces delta oscillations into one that produces alpha-delta activity. Our findings suggest that drugs that reduce Ih conductances and/or increase potassium conductances, without necessarily increasing GABAB conductances, might be sufficient to restore delta sleep. Furthermore, they suggest that delta sleep might be restored by drugs that preferentially target these currents in the thalamus; such drugs might have fewer side effects than drugs that act systemically.

Treating the psychological sequelae of proactive drug-facilitated sexual assault: knowledge building through systematic case based research.

BACKGROUND: Drug-facilitated sexual assault (DFSA) has emerged as a distinct category of sexual victimization and precipitates posttraumatic stress disorder (PTSD). Few studies have examined the distinct psychological aspects of PTSD caused by DFSA. Gauntlett-Gilbert, Keegan and Petrak (2004) represent a notable exception and draw on cases, from their clinical experience, treated using Ehlers and Clarks' (2000) cognitive therapy (CT). AIMS: This paper aims to further develop and refine clinical knowledge on CT for PTSD arising from DFSA and advance the findings of Gauntlett-Gilbert et al. (2004). METHOD: Systematic case based research was used to investigate the applicability of CT for PTSD related to DFSA. Three survivors were treated with CT within the South African context. RESULTS: The case series corroborated existing findings but also documented the presence of somatic and visual intrusions among survivors with partial or complete amnesia for rape and illustrated the utility of imagery interventions in targeting intrusions. The study highlighted the role of physical paralysis in DFSA in compounding helplessness/powerlessness and the necessity of enhancing physical agency and building social support. CONCLUSION: Distinctive aspects of PTSD related to DFSA can be effectively treated by adapting CT to suit this population group.

[Diagnostic and therapeutic update in narcolepsy]. / Actualizacion diagnostica y terapeutica en narcolepsia.

Narcolepsy is an emblematic, unique disease within sleep disorders that is characterised by excessive daytime sleepiness, cataplexy and other abnormal manifestations of REM sleep. In the last 14 years truly spectacular progress has been made in our knowledge of this disease, since the discovery of its cause, i.e. a loss of the hypothalamic neurons that synthesise hypocretin, a previously unknown neurotransmitter, and its probable aetiopathogenic mechanisms, i.e. an autoimmune process in a patient with very precise immunological characteristics - a specific type of HLA and a specific type of T-cell receptor. The cause of this autoimmune process remains unknown. The definitive treatment - the administration of hypocretin, which is the substance missing in the organism - is still unavailable, but there are powerful drugs for treating its main symptoms, the sleepiness and the cataplexy. Some of these are classic compounds (methylphenidate, clomipramine), while others are more recent (modafinil, venlafaxine, sodium oxybate), but together they allow many patients to experience significant improvements. Lack of knowledge about the disease, both on the part of patients and their relatives as well as physicians, is the reason for the great delay in its diagnosis, with even more dramatic consequences when the disease begins in infancy.

Case series of 226 γ-hydroxybutyrate-associated deaths: lethal toxicity and trauma.

γ-Hydroxybutyrate (GHB) and its prodrugs are drugs of abuse that were also sold as "dietary supplements." Users present to emergency departments with overdose, impaired driving, withdrawal, and associated trauma. We compiled a series of GHB-associated deaths to elucidate lethal risks, GHB concentrations, cointoxicants, products, uses, and medical interventions. Death records were reviewed for toxicology, autopsy findings, and history. Inclusion cutoffs were as follows: 5/10 mg/L of GHB (antemortem blood/urine) and 50/20/7 mg/L of GHB (postmortem blood/urine/vitreous). Of 226 deaths included, 213 had cardiorespiratory arrest and 13 had fatal accidents. Seventy-eight deaths (35%) had no cointoxicants. Sixteen deaths involved "supplements" and 1 involved pharmaceutical GHB (Xyrem, Jazz Pharmaceuticals, Palo Alto, CA). Postmortem blood GHB was 18 to 4400 mg/L (median, 347 mg/L) in deaths negative for cointoxicants. Cardiorespiratory arrest occurred prehospital in 100% of 184 cases with available history. Of 72 cases with antemortem adverse effects reported, medical assistance was delayed or absent in 66; of these, acute GHB ingestion was known in 51, including 40 left to "sleep off" adverse effects. Thirty others were left "sleeping" and found dead. γ-Hydroxybutyrate is lethal even without cointoxicants, directly and through fatal accidents. Medical interventions were frequently delayed or absent despite known GHB ingestion, and witnessed adverse events and cardiorespiratory arrest occurred prehospital. Education is needed about the lethality of GHB and the necessity for prompt medical intervention.

Formation pathways of gamma-butyrolactone from the furan ring of tegafur during its conversion to 5-fluorouracil.

Tegafur (FT) is a 5-fluorouracil (5-FU) prodrug that has been clinically used for various cancer chemotherapies. The following metabolites of FT were identified in patients: 5-FU, fluoro-beta-alanine, and gamma-butyrolactone (GBL) and its acidic form, gamma-hydroxybutyrate (GHB). GBL/GHB, which is probably generated from the furan ring of FT, inhibits tumor cell angiogenesis, contributing to the antitumor effect of FT-based therapies. In the present study, we identified the metabolites formed from the furan ring of FT by CYP2A6 and thymidine phosphorylase (TPase) using 2,4-dinitrophenylhydrazine derivatization procedures and clarified the metabolic pathway of FT to GBL/GHB. Succinaldehyde (SA) and 4-hydroxybutanal (4-OH-BTL) were produced as the metabolites because of the cleavage of the furan ring of FT during its conversion to 5-FU in cDNA-expressed CYP2A6 and purified TPase, respectively; however, GBL/GHB was hardly detected in cDNA-expressed CYP2A6 and purified TPase. GBL/GHB was formed after human hepatic microsomes or cDNA-expressed CYP2A6 mixed with cytosol were incubated with FT. Furthermore, 4-OH-BTL was converted to GBL/GHB in the microsomes and cytosol. These results suggest that GBL/GHB is generated from FT through the formation of SA and 4-OH-BTL but not directly from FT. Furthermore, the amount of 5-FU and GBL/GHB formed in the hepatic S9 was markedly decreased in the presence of a CYP2A6 inhibitor, suggesting that GBL/GHB may be mainly generated through the CYP2A6-mediated formation of SA.

Drug treatment of REM sleep behavior disorder: the use of drug therapies other than clonazepam.

STUDY OBJECTIVES: REM sleep behavior disorder (RBD) is characterized by loss of the normal muscle atonia during REM sleep associated with disruptive motor activity related to the acting out of dreams. There is frequently injury to the patient or bed partner, and treatment is usually required. Clonazepam has been the first-line therapy for many years, with 2 large case series reporting efficacy with few side effects in the majority of patients. However, long-acting hypnotics in the elderly or those with cognitive impairment can be associated with adverse events especially unacceptable daytime sedation, confusion, and exacerbation of existing sleep apnea. METHODS: We reviewed 39 patients with confirmed RBD who were treated within our regional sleep center, assessing both efficacy and side effects of drug therapies. RESULTS: Adverse effects were reported by 58% of the patients using clonazepam, with 50% either discontinuing the drug or reducing the dose. This prompted us review the side effects of clonazepam in detail and to look for alternative therapies. We report several novel and effective therapies, in particular zopiclone, in a series of patients under long-term follow-up for RBD. CONCLUSIONS: There are alternatives to clonazepam therapy for RBD which can be as effective and may be better tolerated.

Anti-glutamatergic effect of riluzole: comparison with valproic acid.

Riluzole, an anti-amyotrophic lateral sclerosis drug, known to decrease presynaptic glutamate release, is viewed as a candidate supplementary medication for epilepsy. In the present study, we compared the effects of riluzole and valproate (VPA) in the pilocarpine-induced limbic seizure model and in the gamma-hydroxybutyrate lactone (GBL)-induced absence seizure model. We applied immunohistochemical study for vesicular transporter 1 (VGLUT1) and extracellular recording in the rat dentate gyrus of both pilocarpine- and GBL-induced seizure models to measure effects of riluzole and VPA. Both VPA and riluzole treatments reduced VGLUT1 immunoreactivity. Riluzole treatment completely inhibited pre-ictal spikes and spike-wave discharges in the pilocarpine- and GBL-induced epilepsy models, whereas VPA partially inhibited these phenomena. In both seizure models, the anti-epileptic effects of VPA and riluzole are basically related to anti-glutamatergic (reducing field excitatory postsynaptic potential slope and excitability ratio), not GABAergic (paired-pulse inhibition) effect. Riluzole was more effective at reducing seizure activity in both epilepsy models than VPA. These results suggest that riluzole is a potential antiepileptic drug with activity against limbic seizure and absence seizure.

Use of GHB compounds among college students.

There are increasing reports about the misuse of gamma hydroxybutyric acid (GHB) related compounds. The objective of this article is to examine the use of GHB-containing dietary supplements among college students. An anonymous survey was completed at a university health clinic. The survey asked participants about their experience using GHB compounds and their knowledge about the legal status of GHB and its addictive potential. Two hundred fifteen students responded to the survey. Twenty-eight percent had used GHRE and 19% had used GHB. Growth Hormone Release Extract (GHRE) users reported consumption 2-3 times per month and GHB users reported 1-2 times per month. Males tended to use GHB for euphoria and energy, while females tended to use the compounds for weight loss. GHB was particularly popular among homosexual and bisexual responders. There was little knowledge of the addictive potential and illegal status of GHB and related compounds. GHB compounds are commonly used among college students. Given the different reasons for use according to gender and sexual orientation, prevention programs need to sculpt their message according to the target audience.

Effect of genetically caused excess of brain gamma-hydroxybutyric acid and GABA on sleep.

BACKGROUND: Exogenous gamma-hydroxybutyrate (GHB) increases slow-wave sleep and reduces daytime sleepiness and cataplexy in patients with primary narcolepsy. OBJECTIVE: To examine nighttime sleep and daytime sleepiness in a 13-year-old girl homozygous for succinic semialdehyde dehydrogenase (SSADH) deficiency, a rare recessive metabolic disorder that disrupts the normal degradation of 4-aminobutyric acid (GABA), and leads to an accumulation of GHB and GABA within the brain. METHODS: Sleep interview, nighttime polysomnography, Multiple Sleep Latency Tests, and continuous 24-hour in-lab recordings in the patient; overnight polysomnography in her recessive mother and in a 13-year-old female control. RESULTS: During quiet wakefulness, background electroencephalographic activity was slow and composed of 7-Hz activity. Sleep stage 3/4 was slightly increased (28.1% of total sleep period, norms 15%-28%), and the daytime mean sleep latency was short in the patient (3 minutes 42 seconds, norms > 8 minutes). Stage 2 spindles were infrequent in the child (0.18/minute, norms: 1.2-9.2/minute) and her mother (0.65/minute) but normal (4.6/minute) in the control. At the beginning of the second night, a tonic-clonic seizure occurred, followed by a dramatic increase in stage 3/4 sleep, that lasted 46.3 % of the total sleep period, double the normal value. The mother showed a reduced total sleep time and rapid eye movement sleep percentage. DISCUSSION: This suggests that a chronic excess of GABA and GHB induces subtle sleep abnormalities, whereas increased slow-wave sleep evoked by a sudden event (here an epileptic seizure) may be caused by a supplementary increase in GABA and GHB.