Usual Morning Dose Research Articles

A Pharmacologic Evaluation of Buprenorphine in Pregnancy and the Postpartum Period.

The dosing regimen in the package insert for sublingual buprenorphine is similar for pregnant and nonpregnant people despite the physiologic changes seen during pregnancy. To compare plasma buprenorphine pharmacokinetics during and after pregnancy and relate buprenorphine concentration to the pharmacodynamic endpoints of pupil diameter, Clinical Opioid Withdrawal Scale (COWS), and craving scores. Prospective cohort of 22 pregnant people undergoing 33 pharmacologic studies (6-8 hours each) during pregnancy or postpartum. Participants were on a stable daily dose of 2-8 mg sublingual buprenorphine every 6 or 8 hours. The dosing frequency was selected by the participant. On study day, baseline measurements of plasma buprenorphine, pupil diameter, COWS, and craving scores were obtained, then the usual morning dose was taken, and measurements were repeated several times over 1 dosing interval. The dose-normalized area under the plasma buprenorphine concentration time curve was significantly (P = 0.036) lower during pregnancy (155 ± 52 ng × min/mL) than postpartum (218 ± 113 ng × min/mL). Buprenorphine trough concentrations were similar at the start (1.1 ± 0.7 ng/mL) and end of a dosing cycle (1.2 ± 0.8 ng/mL) regardless of dosing frequency. Pupillary diameter, COWS, and craving scores returned to baseline as buprenorphine concentrations approached ~1 ng/mL. Pregnant people require a higher dose of buprenorphine to achieve concentrations comparable to nonpregnant people. There is a temporal relationship between the plasma buprenorphine concentration and the pharmacodynamic markers of pupillary diameter, COWS, and craving scores. An average plasma concentration of ~1 ng/mL was associated with the lowest level of COWS and craving scores.

Objective assessment of the effects of opicapone in Parkinson’s disease through kinematic analysis

BackgroundOpicapone (OPC) is a third-generation, selective peripheral COMT inhibitor that improves peripheral L-DOPA bioavailability and reduces OFF time and end-of-dose motor fluctuations in Parkinson’s disease (PD) patients.ObjectivesIn this study, we objectively assessed the effects of adding OPC to L-DOPA on bradykinesia in PD through kinematic analysis of finger movements.MethodsWe enrolled 20 treated patients with PD and motor fluctuations. Patients underwent two experimental sessions (L-DOPA, L-DOPA + OPC), separated by at least 1 week. In each session, patients were clinically evaluated and underwent kinematic movement analysis of repetitive finger movements at four time points: (i) before their usual morning dose of L-DOPA (T0), (ii) 30 min (T1), (iii) 1 h and 30 min (T2), and (iv) 3 h and 30 min after the L-DOPA intake (T3).ResultsMovement velocity and amplitude of finger movements were higher in PD patients during the session with OPC compared to the session without OPC at all the time points tested. Importantly, the variability of finger movement velocity and amplitude across T0–T3 was significantly lower in the L-DOPA + OPC than L-DOPA session.ConclusionsThis study is the first objective assessment of the effects of adding OPC to L-DOPA on bradykinesia in patients with PD and motor fluctuations. OPC, in addition to the standard dopaminergic therapy, leads to significant improvements in bradykinesia during clinically relevant periods associated with peripheral L-DOPA dynamics, i.e., the OFF state in the morning, delayed-ON, and wearing-OFF periods.

Comparison of dyskinesia profiles after L-DOPA dose challenges with or without dopamine agonist coadministration

Many patients with Parkinson's disease (PD) experiencing l-DOPA-induced dyskinesia (LID) receive adjunct treatment with dopamine agonists, whose functional impact on LID is unknown. We set out to compare temporal and topographic profiles of abnormal involuntary movements (AIMs) after l-DOPA dose challenges including or not the dopamine agonist ropinirole. Twenty-five patients with PD and a history of dyskinesias were sequentially administered either l-DOPA alone (150% of usual morning dose) or an equipotent combination of l-DOPA and ropinirole in random order. Involuntary movements were assessed by two blinded raters prior and every 30 min after drug dosing using the Clinical Dyskinesia Rating Scale (CDRS). A sensor-recording smartphone was secured to the patients' abdomen during the test sessions. The two raters’ CDRS scores were highly reliable and concordant with models of hyperkinesia presence and severity trained on accelerometer data. The dyskinesia time curves differed between treatments as the l-DOPA-ropinirole combination resulted in lower peak severity but longer duration of the AIMs compared with l-DOPA alone. At the peak of the AIMs curve (60–120 min), l-DOPA induced a significantly higher total hyperkinesia score, whereas in the end phase (240–270 min), both hyperkinesia and dystonia tended to be more severe after the l-DOPA-ropinirole combination (though reaching statistical significance only for the item, arm dystonia). Our results pave the way for the introduction of a combined l-DOPA-ropinirole challenge test in the early clinical evaluation of antidyskinetic treatments. Furthermore, we propose a machine-learning method to predict CDRS hyperkinesia severity using accelerometer data.

ISPAD Clinical Practice Consensus Guidelines 2022: Ramadan and other religious fasting by young people with diabetes.

ISPAD Clinical Practice Consensus Guidelines 2022: Ramadan and other religious fasting by young people with diabetes.

Neurophysiological Predictors of Response to Medication in Parkinson's Disease.

Background: Although dopaminergic medication has been the foundation of Parkinson's disease (PD) therapy for decades, sensitive and specific therapeutic response biomarkers that allow for better treatment optimization are lacking.Objective: We tested whether the features of Transcranial Magnetic Stimulation-based neurophysiological measures taken off-medication are associated with dopaminergic medication-induced clinical effects.Method: Motor cortex excitability [short-latency intracortical inhibition (SICI), intracortical facilitation (ICF), short-latency afferent inhibition (SAI), and input-output (IO) curve], and plasticity [paired associative stimulation (PAS) protocol] neurophysiological measures were examined in 23 PD patients off-medication. Clinical features were quantified by the motor section of the Unified Parkinson's Disease Scale (total score and lateralized total, bradykinesia, and rigidity sub-scores), and the differences between measures off-medication and on-medication (following the usual morning dose), were determined. Total daily dopaminergic medication dose (expressed as levodopa equivalent daily dose-LEDD), was also determined.Results: SICI significantly correlated with changes in lateralized UPDRS motor and bradykinesia sub-scores, suggesting that patients with stronger basal intracortical inhibition benefit more from dopaminergic treatment than patients with weaker intracortical inhibition. Also, ICF significantly negatively correlated with LEDD, suggesting that patients with stronger intracortical facilitation require less dopaminergic medication to achieve optimal therapeutic benefit. Both associations were independent of disease severity and duration.Conclusions: The results suggest variability of (patho) physiological phenotypes related to intracortical inhibitory and facilitatory mechanisms determining clinical response to dopaminergic medication in PD. Measures of intracortical excitability may help predict patients' response to dopaminergic therapy, thus potentially providing a background for developing personalized therapy in PD.

Serum Inhaled Corticosteroid Detection for Monitoring Adherence in Severe Asthma

Daily inhaled corticosteroids (ICSs) are fundamental to asthma management, but adherence is low. To investigate (1) whether LC-MS/MS could be used to detect ICSs in serum and (2) whether serum levels related to markers of disease severity. We collected blood samples over an 8-hour period from patients with severe asthma prescribed at least 1000 μg daily of beclomethasone dipropionate equivalent. Following baseline sampling, patients were observed taking their usual morning dose. Subsequent blood samples were obtained 1, 2, 4, and 8 hours postinhalation and analyzed by LC-MS/MS. Correlations between serum ICS levels and severity markers were investigated. A total of 60 patients were recruited (41 females; 39 prescribed maintenance prednisolone; mean age, 49 ± 12 years; FEV1, 63 ± 20 %predicted). Eight hours postinhalation, all patients using budesonide (n= 10) and beclomethasone dipropionate (15), and all but 1 using fluticasone propionate (28), had detectable serum drug levels. Fluticasone furorate was detected in 2 patients (of 4), ciclesonide in none (of 7). Low adherence by repeat prescription records (<80%) was identified in 43%. Blood ICS levels correlated negatively with exacerbation rate, and (for fluticasone propionate only) positively with FEV1 %predicted. Commonly used ICSs can be reliably detected in the blood at least 8 hours after dosing, and could therefore be used as a measure of adherence in severe asthma. Higher exacerbation rates and poorer lung function (for fluticasone propionate) were associated with lower blood levels.

Cannabidiol in Pharmacoresistant Epilepsy: Clinical Pharmacokinetic Data From an Expanded Access Program.

Background and Aim: Data on the clinical pharmacokinetics of cannabidiol (CBD) are scanty. We explored the effect of demographic and clinical variables on plasma concentrations of purified CBD in patients with Dravet (DS) and Lennox–Gastaut syndrome (LGS). Methods: The study design was an open, prospective, multicenter expanded access program (EAP). Venous blood samples were drawn from patients between 8 and 9 am, before the CBD morning dose, 12 h apart from the last evening dose, and then 2.5 h after their usual morning dose. Results: We collected 127 plasma samples (67-morning pre-dosing and 60 post-dosing) from 43 patients (24 females, 19 males), 27 with LGS and 16 with DS. Mean ± standard deviation age was 26 ± 15 years. Duration of CBD treatment averaged 4.2 ± 2.9 months at 13.2 ± 4.6 mg/kg/day. CBD median trough plasma concentration was 91 ng/ml; it doubled to 190 ng/ml 2.5 h post-dosing (p < 0.001). Cannabidiol trough plasma concentrations were linearly related to daily doses (r = 0.564, p < 0.001). Median trough CBD plasma concentration-to-weight-adjusted dose ratio (C/D) was 32% higher (p < 0.02) in plasma samples from subjects aged 18 and over than in those under 18. Sex and concomitant antiseizure medications (ASMs) were not associated with significant variations in CBD C/D, but caution is required due to the potential influence of confounders. Conclusion: These are the first data on CBD pharmacokinetics in children and adults with LGS or DS in a real-world setting. The most relevant finding was the higher CBD C/D in adults. In practice, reduced weight-normalized doses might be required with aging to achieve the same CBD plasma levels.

Base-peak assessment of levodopa response and detection of fluctuating patients in Parkinson's disease.

This study aims to evaluate the base-peak difference in levodopa response for detecting patients with motor fluctuations in Parkinson's disease (PD). Two independent PD samples were evaluated at baseline and 2 h after the administration of the usual morning dose of levodopa using the Unified Parkinson's Disease Rating Scale part III (UPDRS-III). The presence of motor fluctuations was defined by the UPDRS-IV. We quantified the magnitude of motor variation as absolute (Δ) and percentage (Δ%) change in UPDRS-IIIscores. Optimal cut-offs for each index distinguishing patients with or without fluctuations were calculated on the exploratory population. The accuracy of the identified cut-offs was then verified in a testing population. In the exploratory population (N = 26), the optimal cut-off for detecting fluctuations was a Δ of 6 points and a Δ% of 18.4%. When we applied the identified thresholds to the testing population (N = 139), we found a sensitivity of 93.8% (95% CI: 89.7 to 97.8) and a specificity of 91.2% (95% CI: 86.5 to 95.9) for Δ, 83.3% (95% CI: 77.1 to 89.5) and 86.8% (95% CI: 81.2 to 92.4) for Δ%, respectively. The assessment of levodopa usual morning dose response through the base-peak evaluation represents an accurate method for detecting parkinsonian patients with motor fluctuations, and for defining the Minimal Important Difference (MID) in levodopa response suggesting the presence of motor fluctuations in PD patients demanding further therapeutic interventions.

Management of adrenal insufficiency during Ramadan fasting: a survey of physicians.

Introduction:Appropriate dose adjustments of glucocorticoids replacement therapy for adrenal insufficiency (AI) is vital.Objective:We sought to scope physicians’ perceptions, and practices regarding Ramadan fasting (RF) impact on the management of AI.Methods:A web-based survey of a convenience sample of endocrinologists.Results:Nearly two-thirds of 145 respondents (64.1%) were adult endocrinologists and almost half (49%) saw more than 10 hypoadrenal patients per year. Most respondents (78.6%) prescribed hydrocortisone, while the minority prescribed other preparations. The glucocorticoid doses were reportedly divided twice daily by 70.8% and thrice daily by 22.2% of respondents. Respondents recognized RF as having potential consequences in adrenal insufficiency patients included causing hypoglycaemia, undue tiredness, and fatigue, hypotension, feeling dizzy, and light-headedness. Symptoms of under-replacement were thought to happen in the late afternoon by 59.3% of respondents. Almost half (45.5%) of respondents thought that RF has some probable or definite impact on glucocorticoid therapy that certainly warrants specific concern and possible action. Three quarters (76.4%) of respondents confirmed providing specific management recommendations during RF. The most frequently reported recommendation was taking in the usual morning dose of hydrocortisone just before pre-dawn meal (Suhor) (57.8%). A third switch patients from hydrocortisone to prednisolone/prednisone. Half reported providing patients with specific recommendations regarding breaking their fast and/or seeking help if hypoadrenal symptoms occur.Conclusions:There is a remarkable variation in the physicians’ perceptions and practices regarding the management of AI during Ramadan. This warrants professional effort to increase the awareness and dissemination of evidence-based guidelines.

Cerebellar continuous theta burst stimulation reduces levodopa-induced dyskinesias and decreases serum BDNF levels

Patients with Parkinson’s Disease (PD) experience bothersome motor fluctuations and Levodopa-induced Dyskinesias (LIDs). Cerebellar continuous theta burst stimulation (cTBS) was used as an inhibitory protocol of repetitive transcranial magnetic stimulation (rTMS) to reduce LIDs in PD patients. The influence of Val66Met polymorphism of Brain Derived Neurotrophic Factor (BDNF) gene on the therapeutic response to cTBS was investigated and the serum levels of BDNF were measured before and after treatment. Eleven patients were exposed to a session of cTBS and sham stimulation (one week apart) after the administration of 125 % of their usual morning dose of Levodopa and LIDs were video-recorded and evaluated at different time points (0, 15, 30, 45, 60, 90 min after Levodopa). Cerebellar cTBS significantly reduced LIDs with respect to sham stimulation and decreased serum BDNF levels. These effects were evident in the Val66Val group (7 subjects) but not in the Val66Met group (4 subjects). These data confirm the efficacy of cerebellar cTBS in reducing LIDs in PD patients and show that the clinical effect is accompanied by a decrease in serum BDNF levels. Moreover, they suggest that BDNF Val66Met polymorphism may influence the clinical and biological response to cTBS.

Activity With Ambulation Attenuates Diuretic Responsiveness in Chronic Heart Failure

Introduction We hypothesized that discharged heart failure (HF) patients could develop clinical congestion despite adhering to prescribed diuretics, because ambulation attenuates diuretic and natriuretic responsiveness. Methods We studied 9 patients aged 57 ± 13 (mean ± SD) years with New York Heart Association functional class II-III symptoms and ejection fraction <40% (28 ± 7%) and receiving furosemide (≥80 mg/d [113 ± 53 mg/d]) plus renin-angiotensin system antagonists and beta-blockade. Inulin and p-amminohippuric acid were infused to estimate glomerular filtration rate (GFR) and renal plasma flow (RPF). Furosemide was administered intravenously at 75% of the usual oral morning dose. Participants were randomized to supine (90 minutes recumbancy) or upright (90 minutes sitting and treadmill walking) posture and assumed the other position on their second day. Primary outcome variables were urine volume and sodium excretion 90 minutes after furosemide. Results On the upright, compared with the supine, day, urine volume (792 ± 484 vs 1,290 ± 503 mL; P = .02) and sodium (79 ± 55 vs 141 ± 61 mmol; P < .01) were attenuated, whereas plasma norepinephrine (4.4 ± 2.7 vs 2.3 ± 1.8 mmol/L; P = .01) and renin (327 ± 250% of supine; P < .01) were augmented. Urinary K+, mean pressure, GFR, and RPF were similar. Conclusions Activation of the sympathetic nervous system and renin-angiotensin axis by upright ambulation may attenuate diuresis and natriuresis by increasing proximal tubular reabsorption of sodium and water.

Motor follow-up of parkinsonian patients after deep-brain stimulation

The numerous published studies addressing parkinsonian patients’ motor follow-up after surgery for deep-brain stimulation of the subthalamic nucleus bring to the fore several methodological problems that we consider of major importance. Assessing motor function in these patients is a complex task. They must be preoperatively assessed with and without oral medication, and postoperatively assessed with and without oral medication and with the stimulators turned on and turned off, hence under four conditions MED OFF/STIM OFF, MED ON/STIM OFF, MED OFF/STIM ON, and MED ON/STIM ON. The four conditions combined in various ways offer scope for numerous comparisons yielding a wealth of information. At the same time, there are several problems in clinical practice, which suggest the need to reappraise the existing patient assessment protocols. The Core Assessment Program for Surgical Interventional Therapies in Parkinson’s disease (CAPSIT-PD) recommendations define MED ON as the motor state assessed after the patient takes the usual morning levodopa dose [1]. Because morning doses often vary from patient to patient, this definition introduces inherent interpatient variability that is hard to eliminate. The frequent changes in a patient’s morning dose after the intervention also lead to intrapatient variability. The variability in the morning dose makes it difficult to compare the motor benefits achieved by preoperative oral therapy and postoperative oral therapy and stimulation (MED ON vs. MED ON-STIM ON), a core comparison in the postoperative follow-up of parkinsonian patients after deep-brain stimulation. One way to render this comparison fully homogeneous would be to maintain oral therapy quantitatively unchanged. For example, a patient taking 100 mg of levodopa preoperatively would be assessed postoperatively while taking 100 mg even if they actually require a lower dose. This solution might nevertheless be only partly applicable given that parkinsonian patients in advanced stage of disease often take levodopa in large amounts, the preoperative morning dose often reaching 200 mg, an amount inducing supramaximal post-synaptic dopaminergic receptor stimulation. Using the same levodopa dose preoperatively and postoperatively under these conditions would obviously be meaningless insofar as the dopamine-receptor stimulation induced by a supramaximal levodopa dose could bring no further meaningful motor benefit. The difficulties encountered in clinical practice also reflect differences in patient assessment. Whereas some studies assess patients after they receive their usual morning dose [2, 3], others define MED ON as the motor state reached after patients take 150% of the usual morning dose [4–6]. Yet other studies refer to the best ON medication motor state [7]. Difficulties arise also in assessing patients in the OFF medication motor state. According to the CAPSIT-PD recommendations, patients reach the OFF medication motor state 12 h after dopaminergic withdrawal [1]. Although most studies follow this recommendation, some variability exists given that the time elapsing after withdrawing therapy ranges from 8 to 12 h [5], 10 to 12 h [2], to at least 12 h or exactly 12 h [4, 6, 7]. A 12-h interval seems an acceptable compromise that in patients with advanced disease who are fully G. Caranci (&) F. Lena N. Modugno S. Ruggieri P. Romanelli M. Manfredi Centre for Parkinson’s Disease, IRCCS Neuromed Institute, via Atinense 18, 86077 Pozzilli, Isernia, Italy e-mail: giovannicaranci@tiscali.it

Safety of an IV formulation of carbamazepine

An intravenous formulation of carbamazepine (CBZ) was administered to 113 (60 male; 53 female) persons with epilepsy aged 19-87 years. Subjects received 100mg of study drug as replacement for 100mg of their usual morning dose of CBZ. There were no significant changes in blood pressure or heart rate suggesting that this formulation can be developed as replacement therapy for persons unable to take oral CBZ.

Deficient “sensory” beta synchronization in Parkinson’s disease

Beta rhythm movement-related synchronization (beta synchronization) reflects motor cortex deactivation and sensory afference processing. In Parkinson's disease (PD), decreased beta synchronization after active movement reflects abnormal motor cortex idling and may be involved in the pathophysiology of akinesia. The objectives of the present study were to (i) compare event-related synchronization after active and passive movement and electrical nerve stimulation in PD patients and healthy, age-matched volunteers and (ii) evaluate the effect of levodopa. Using a 128-electrode EEG system, we studied beta synchronization after active and passive index finger movement and electrical median nerve stimulation in 13 patients and 12 control subjects. Patients were recorded before and after 150% of their usual morning dose of levodopa. The peak beta synchronization magnitude in the contralateral primary sensorimotor (PSM) cortex was significantly lower in PD patients after active movement, passive movement and electrical median nerve stimulation, compared with controls. Levodopa partially reversed the drop in beta synchronization after active movement but not after passive movement or electrical median nerve stimulation. If one considers that beta synchronization reflects sensory processing, our results suggest that integration of somaesthetic afferences in the PSM cortex is abnormal in PD during active and passive movement execution and after simple electrical median nerve stimulation. Better understanding of the mechanisms involved in the deficient beta synchronization observed here could prompt the development of new therapeutic approaches aimed at strengthening defective processes. The lack of full beta synchronization restoration by levodopa might be related to the involvement of non-dopaminergic pathways.

Electroconvulsive Therapy in Patients Taking Steroid Medication

Patients who take chronic steroid medication are often prescribed extra "stress doses" before procedures involving general anesthesia. The rationale for this practice is that the chronic steroid use has suppressed the ability of the endogenous hypothalamic-pituitary-adrenal steroid stress-reactivity system to handle the systemic stress of surgery. Whether the stress of treatments is sufficient enough to warrant this practice in electroconvulsive therapy (ECT) has not been broached in the literature. In this case series, we describe our experience treating 27 ECT patients taking prednisone. We conclude that use of "stress doses" of extra steroid medication is unnecessary in ECT practice and recommend that patients receive their usual morning dose of steroid before ECT treatments.

Locomotor response to levodopa in fluctuating Parkinson’s disease

The aim of this study was to quantify the dynamic response of locomotion to the first oral levodopa administration of the day in patients with fluctuating Parkinson's disease (PD). Stride length, walking speed, cadence and gait variability were measured with an ambulatory gait monitor in 13 PD patients (8 males) with a clinical history of motor fluctuations. The Unified Parkinson's Disease Rating Scale (UPDRS) gait score (part 29) was also determined by a movement disorders specialist from video recordings. Subjects arrived in the morning in an 'off' state (no PD medication) and walked for a maximum length of 100 m. They then took their usual morning dose of oral levodopa and repeated the walking task at 13 min intervals (on average) over a 90 min period. Changes in stride length over time were fit with a Hill (Emax) function. Latency (time until stride length increased 15% of the difference between baseline and maximum response) and the Hill coefficient (shape of the 'off-on' transition) were determined from the fitted curve. Latency varied from 4.7 to 53.3 min post-administration [23.31 min (SD 14.9)], and was inversely correlated with age at onset of PD (R = -0.83; P = 0.0004). The Hill coefficient (H) ranged from a smooth hyperbolic curve (0.9) to an abrupt 'off-on' transition (16.9), with a mean of 8.1 (SD 4.9). H correlated with disease duration (R = 0.67; P = 0.01) and latency (R = 0.67; P = 0.01), and increased with Hoehn & Yahr stage in the 'off' state (P = 0.02) from 5.7 (SD 3.5) (H&Y III) to 11.9 (SD 4.7) (H&Y IV). Walking speed correlated with changes in mean stride length, whereas cadence and gait variability did not. UPDRS gait score also reflected improving gait in the majority of subjects (8), providing clinical confirmation of the objective measures of the locomotor response to levodopa. Increasing abruptness (H) of the 'off-on' transition with disease duration is consistent with results from finger-tapping studies, and may reflect reduced buffering capacity of pre-synaptic nigrostriatal dopaminergic neurons. Ambulatory monitoring of gait objectively measures the dynamic locomotor response to levodopa, and this information could be used to improve daily management of motor fluctuations.

Short‐term effects of tetrabenazine on chorea associated with Huntington's disease

We sought to assess the short-term clinical effects of tetrabenazine (TBZ) on choreic movements in Huntington's disease patients. A total of 10 patients on stable doses of TBZ were enrolled in this observational study. Patients took their evening dose of TBZ and presented the next day to the Baylor College of Medicine Movement Disorders Clinic without taking the usual morning dose. They were assessed using the Unified Huntington's Disease Rating Scale (UHDRS) motor assessment and Beck Depression Inventory. The usual morning dose of TBZ was then administered and patients were followed with serial UHDRS motor examinations approximately every 2 hours until choreic movements subsided and then returned. TBZ decreased the UHDRS chorea score on average 42.4% +/- 17.8%. The duration of effect varied from a minimum of 3.2 hours to a maximum of 8.1 hours (mean = 5.4 +/- 1.3). No patient experienced an adverse event related to TBZ or its withdrawal. During short-term follow-up after a single dose, TBZ improves chorea for approximately 5 hours.

The Impact of Acute Hypoglycemia on Neuropsychological and Neurometabolite Profiles in Children With Type 1 Diabetes

The impact of hypoglycemia on brain is a major factor influencing the clinical management of type 1 diabetes in children. The Diabetes Control and Complications Trial (1) has shown that intensive insulin treatment is the most effective strategy for preventing the microvascular complications of type 1 diabetes, but it is associated with a threefold increase in the incidence of severe hypoglycemia. Before implementing intensified treatments in children, it is important to define the impact on the developing central nervous system associated with the increased risk of hypoglycemia. This report presents three cases of previously well children with type 1 diabetes who were studied after their first episode of severe hypoglycemia with seizure. All case subjects underwent neuropsychological assessment and neuroimaging within 48 h of the seizure and again 6 months later. Case 1 was a 7-year-old girl with a 2-year history of type 1 diabetes who presented to the emergency department, Royal Children’s Hospital, following a severe hypoglycemic event with seizure. She awoke with a blood glucose level of 3.6 mmol/l. This was not treated, and she was given her usual morning dose of short- and intermediate-acting insulin. She had a seizure within 20 min of insulin administration. The seizure resolved within 5 min after treatment with glucagon and glucose gel. Her most recent HbA1c (A1C) was 7.5%. Case 2 was a 9-year-old girl with a 6-year history of type 1 diabetes who experienced a hypoglycemic seizure immediately before breakfast after a nocturnal supplemental dose of rapid-acting insulin. She was treated with glucagon, with seizure resolution within 5 min. Her blood glucose level immediately after glucagon administration was 2.4 mmol/l. Her most recent A1C was 8.7%. Case 3 was a 10-year-old boy with a 3-year history of type 1 diabetes who felt unwell for several days …

Fatigue in the executive cortical network demonstrated in narcoleptics using functional magnetic resonance imaging—a preliminary study

Background and purpose To demonstrate dynamic changes in cerebral functional activation during a working memory task in a state of severe excessive daytime sleepiness. Patients and methods Omitting the usual morning dose of stimulants in three narcoleptics induced sleepiness. Functional magnetic resonance imaging (fMRI) was used to map cerebral activation during the performance of a 2-back verbal working memory task. Repeated 9.5 min scans were performed, until the subjects felt they could not continue. This was the functional imaging equivalent of the maintenance of wakefulness test. Results Bilateral and widespread activation in known nodes of the executive network were seen during the first scan in all subjects, including the lateral prefrontal, posterior parietal and anterior cingulate cortex. There was a reduction in cerebral activation, especially but not exclusively in the prefrontal cortex, associated with slowing of performance from the first to the last tolerated scan. On stimulants, subjective alertness, activation and objective performance were readily maintained. Conclusion This preliminary study suggests that fatigue in the executive cortical network may be demonstrated by a progressive reduction in regional cerebral activation across scans, which may be prevented by stimulant use. Averaging multiple scan runs, a typical practice in fMRI, could blur important dynamic components of activation.

L-arginine reverses the antinatriuretic effect of cyclosporin in renal transplant patients.

Cyclosporin has been shown to facilitate renal vasoconstriction and to have an antinatriuretic effect. The existence of an interference of cyclosporin with the vasodilating properties of endothelium mediated by nitric oxide production could mediate these effects. On the other hand, the infusion of the nitric oxide precursor L-arginine has been shown to induce renal vasodilatation and to facilitate natriuresis in normal volunteers. We have investigated the renal effects of the administration of an infusion of L-arginine in renal transplant patients chronically treated with cyclosporin. To facilitate the analysis of the data the effects of the administration of a similar dose of cyclosporin on renal function during the infusion of a vehicle were also investigated during the administration of a vehicle of L-arginine. Ten male renal transplant patients, chronically treated with cyclosporin and with a stable renal function were studied during 2 consecutive days after the administration of the usual morning dose of cyclosporin. The first day they received an intravenous infusion of vehicle and the second the infusion of graded doses of L-arginine (50, 100, 150 mg/kg/h) during 3 consecutive h. The first day, after cyclosporin administration a significant fall (P < 0.01) was observed in natriuresis and kaliuresis in the absence of changes in renal plasma flow and glomerular filtration rate. After the administration of L-arginine significant (P < 0.01) increases of renal plasma flow, glomerular filtration rate, and natriuresis were seen. The increase in blood levels of cyclosporin after its administration did not differ between days 1 and 2. These results indicate that L-arginine facilitates renal vasodilatation and natriuresis in renal transplant patients. Furthermore, the observed increase in sodium excretion could indicate that L-arginine counteracts the antinatriuretic effect of cyclosporin.