Simultaneous administration of cocaine and caffeine dysregulates HCN and T-type channels.

RATIONALE: The abuse of psychostimulants has adverse consequences on the physiology of the central nervous system. In Argentina, and other South American countries, coca paste or "PACO" (cocaine and caffeine are its major components) is massively consumed with deleterious clinical consequences for the health and well-being of the general population. A scant number of studies have addressed the consequences of stimulant combination of cocaine and caffeine on the physiology of the somatosensory thalamocortical (ThCo) system. OBJECTIVES: Our aim was to study ion conductances that have important implications regulating sleep-wake states 24-h after an acute or chronic binge-like administration of a cocaine and caffeine mixture following previously analyzed pasta base samples ("PACO"-like binge") using mice. METHODS: We randomly injected (i.p.) male C57BL/6JFcen mice with a binge-like psychostimulants regimen during either 1 day (acute) or 1 day on/1 day off during 13 days for a total of 7 binges (chronic). Single-cell patch-clamp recordings of VB neurons were performed in thalamocortical slices 24 h after the last psychostimulant injection. We also recorded EEG/EMG from mice 24 h after being systemically treated with chronic administration of cocaine + caffeine versus saline, vehicle. RESULTS: Our results showed notorious changes in the intrinsic properties of the VB nucleus neurons that persist after 24-h of either acute or chronic binge administrations of combined cocaine and caffeine ("PACO"-like binge). Functional dysregulation of HCN (hyperpolarization-activated cyclic nucleotide-gated) and T-type VGC (voltage-gated calcium) channels was described 24-h after acute/chronic "PACO"-like administrations. Furthermore, intracellular basal [Ca2+] disturbances resulted a key factor that modulated the availability and the activation of T-type channels, altering T-type "window currents." As a result, all these changes ultimately shaped the low-threshold spikes (LTS)-associated Ca2+ transients, regulated the membrane excitability, and altered sleep-wake transitions. CONCLUSION: Our results suggest that deleterious consequences of stimulants cocaine and caffeine combination on the thalamocortical physiology as a whole might be related to potential neurotoxic effects of soaring intracellular [Ca2+].

Is time elapsed between cannabis use and sleep start time associated with sleep continuity? An experience sampling method.

BACKGROUND: A substantial proportion of people using cannabis report using it to improve sleep. Yet, little research exists on the associations between the timing of cannabis use and sleep. This study examines the time elapsed between cannabis use and sleep start time and its association with two of the main indicators of sleep continuity: (1) sleep onset latency (SOL) and (2) number of awakenings (NOA) throughout the night. METHODS: Each morning, for 7 consecutive days, daily cannabis users (n = 54) reported on the timing of previous night's cannabis use and sleep indicators on their smartphones. Mixed effects models examined the relations of within- and between-subjects' time elapsed between previous night cannabis use and sleep start time, with (1) SOL and (2) NOA. RESULTS: Within subjects, shorter time elapsed between cannabis use and sleep start time was associated with shorter SOL (ß = 0.519, p = 0.010), but not NOA (ß = -0.030, p = 0.535). Furthermore, between individuals, the time gap between the previous night cannabis use and sleep start time was not associated with SOL or NOA (p > 0.05). CONCLUSIONS: It is possible that cannabis use proximal to bedtime is associated with shorted sleep onset latency but not nighttime awakenings. Cannabis users should be informed about both the potential sleep aid effects of cannabis and its limitations. Pending further evidence of the effects of cannabis on sleep, cannabis users experiencing sleep problems should be provided with evidence-based alternatives to improve sleep, e.g., pharmacological and behavioral treatments.

Nocturnal leg cramps.

Up to 60 percent of adults report that they have had nocturnal leg cramps. The recurrent, painful tightening usually occurs in the calf muscles and can cause severe insomnia. The exact mechanism is unknown, but the cramps are probably caused by muscle fatigue and nerve dysfunction rather than electrolyte or other abnormalities. Nocturnal leg cramps are associated with vascular disease, lumbar canal stenosis, cirrhosis, hemodialysis, pregnancy, and other medical conditions. Medications that are strongly associated with leg cramps include intravenous iron sucrose, conjugated estrogens, raloxifene, naproxen, and teriparatide. A history and physical examination are usually sufficient to differentiate nocturnal leg cramps from other conditions, such as restless legs syndrome, claudication, myositis, and peripheral neuropathy. Laboratory evaluation and specialized testing usually are unnecessary to confirm the diagnosis. Limited evidence supports treating nocturnal leg cramps with exercise and stretching, or with medications such as magnesium, calcium channel blockers, carisoprodol, or vitamin B(12). Quinine is no longer recommended to treat leg cramps.

Menopausal-type symptoms among breast cancer patients on aromatase inhibitor therapy.

OBJECTIVES: To examine self-reported menopausal-type symptoms among breast cancer patients on aromatase inhibitors (AIs) compared to women of the same age who had not been diagnosed with cancer, and to determine whether the percentage of breast cancer patients experiencing these symptoms changed over the first 6 months of AI treatment. METHODS: Data from a 6-month cohort study of 100 breast cancer patients initiating AI therapy and of 200 women of a similar age without a history of cancer were analyzed. At baseline (prior to the initiation of AI therapy among the breast cancer patients), 3 months, and 6 months, a comprehensive questionnaire was administered to participants that ascertained data on the experiencing of specific menopausal-type symptoms. RESULTS: The data showed statistically significant increases in the prevalence of certain symptoms from baseline to either follow-up point among the breast cancer patients; these symptoms included hot flushes, night sweats, pain during intercourse, hair loss, forgetfulness, depression, difficulty falling asleep, and interrupted sleep. Additionally, breast cancer patients were more likely than the women in the comparison group to report the new onset of many of these same symptoms during the follow-up time period. CONCLUSIONS: Because bothersome symptoms and side-effects are a major reason for discontinuation and non-adherence to treatment, symptoms should be monitored and addressed by oncologists so that the breast cancer patient can maintain her quality of life and remain adherent to the treatment schedule.

Nocturnal leg cramps and prescription use that precedes them: a sequence symmetry analysis.

BACKGROUND: The use of diuretics, statins, and inhaled long-acting ß2-agonists (LABAs) is linked to muscle cramps but largely by anecdotal evidence. This study sought population-level data to better evaluate these associations. METHODS: Linked health care databases containing prescribing information (December 1, 2000, to November 30, 2008) about 4.2 million residents of British Columbia, Canada, were evaluated using sequence symmetry analysis to determine in adults 50 years or older whether new quinine prescriptions (initiations of cramp treatment) increase in the year following diuretic, statin, or LABA starts. The statistic of interest was the sequence ratio: the number of quinine starts in the year following index drug introduction compared with the number of quinine starts in the preceding year (adjusted for age and time trends in population prescribing). RESULTS: Adjusted sequence ratios (95% CIs) for the 3 drug classes were 1.47 (1.33-1.63 [P < .001]) for diuretics, 1.16 (1.04-1.29 [P = .004]) for statins, and 2.42 (2.02-2.89 [P < .001]) for LABAs. For diuretic subclasses, adjusted sequence ratios (95% CIs) were 2.12 (1.61-2.78 [P < .001]) for potassium sparing, 1.48 (1.29-1.68 [P < .001]) for thiazidelike, and 1.20 (1.00-1.44 [P = .07]) for loop. For LABA subclasses, adjusted sequence ratios (95% CIs) were 2.17 (1.56-3.02) for LABAs alone and 2.55 (2.06-3.12) for LABAs-corticosteroids (P < .001 for both). CONCLUSIONS: Cramp treatment was substantially more likely in the year following introduction of LABAs, potassium-sparing diuretics, or thiazidelike diuretics, and 60.3% of quinine users (individuals experiencing cramp) received at least 1 of these medications during a 13-year period. In contrast, statin and loop diuretic associations were small. Physicians should be mindful that the use of these medications may worsen symptoms in patients experiencing nocturnal leg cramps.

Cortico-pontine theta synchronization phase shift following monoaminergic lesion in rat.

The experiments were performed in 14 adult, male Sprague Dawley rats chronically instrumented for sleep recording and recorded during baseline condition, following sham injection (saline i.p. 1 ml/kg), and every week for 5 weeks following injection of the systemic neurotoxins (DSP-4 or PCA; 1 ml/kg, i.p.) for chemical axotomy of the locus coeruleus (LC) and dorsal raphe (DR) axon terminals. In our former study we demonstrated that the systemically induced lesion of the noradrenergic or serotonergic axon terminals did not affect the sleep-wake distribution from control condition. In this study, by using spectral analysis and phase shift spectra of the cortical and pontine EEG we analyzed cortico-pontine theta oscillation synchronization phase shift on 6-hour recordings in control condition and 28 days following the monoaminergic lesions, as a time for permanently established DR or LC chemical axotomy. Our results demonstrated for the first time that chronically decreased brain monoamines in freely moving rats changed cortico-pontine theta synchronization phase shift. Pons became a leading theta oscillator. We assume that deficit of monoamines induced predominance of the NREM/REM transitions, characterized with phasic theta oscillations (the increased density of clustered P waves which intrinsic frequency corresponds to theta frequency oscillations), and may produced preceding phasic theta versus tonic theta oscillation drive.

REM sleep behavior disorder in patients with guadeloupean parkinsonism, a tauopathy.

STUDY OBJECTIVE: To describe sleep characteristics and rapid eye movement (REM) sleep behavior disorder in patients with Guadeloupean atypical parkinsonism (Gd-PSP), a tauopathy resembling progressive supranuclear palsy that mainly affects the midbrain. It is possibly caused by the ingestion of sour sop (corossol), a tropical fruit containing acetogenins, which are mitochondrial poisons. DESIGN: Sleep interview, motor and cognitive tests, and overnight videopolysomnography. PATIENTS: Thirty-six age-, sex-, disease-duration- and disability-matched patients with Gd-PSP (n = 9), progressive supranuclear palsy (a tauopathy, n = 9), Parkinson disease (a synucleinopathy, n = 9) and controls (n = 9). SETTINGS: Tertiary-care academic hospital. RESULTS: REM sleep behavior disorder was found in 78% patients with Gd-PSP (43% of patients reported having this disorder several years before the onset of parkinsonism), 44% of patients with idiopathic Parkinson disease, 33% of patients with progressive supranuclear palsy, and no controls. The percentage of muscle activity during REM sleep was greater in patients with Gd-PSP than in controls (limb muscle activity, 8.3%+/-8.7% vs 0.1%+/- 0.2%; chin muscle activity, 24.3%+/- 23.7% vs 0.7%+/-2.0%) but similar to that of other patient groups. The latency and percentage of REM sleep were similar in patients with Gd-PSP, patients with Parkinson disease, and controls, whereas patients with progressive supranuclear palsy had delayed and shortened REM sleep. CONCLUSION: Although Gd-PSP is a tauopathy, most patients experience REM sleep behavior disorder. This suggests that the location of neuronal loss or dysfunction in the midbrain, rather than the protein comprising the histologic lesions (synuclein versus tau aggregation), is responsible for suppressing muscle atonia during REM sleep. Subjects with idiopathic REM sleep behavior disorder should avoid eating sour sop.

Herbal supplement PC-Spes for prostate cancer.

OBJECTIVE: To determine the efficacy and toxicity of the herbal supplement PC-Spes in prostate cancer patients. METHODS: Literature search through MEDLINE (1966-October 2001), PubMed, and abstracts from the Annual Meeting of the American Society of Clinical Oncology (1995-2001). RESULTS: PC-Spes was associated with biochemical and clinical response in some prostate cancer patients. The mechanisms of action of PC-Spes appeared to be related to its estrogenic activity. CONCLUSIONS: PC-Spes is associated with some efficacy in prostate cancer patients. Due to the limited data available, it should not be used to replace standard androgen suppression therapy in androgen-dependent patients. PC-Spes may have a role for patients who have failed standard treatments for androgen-independent disease and have no history of thromboembolism or abnormal bleeding. PC-Spes has a toxicity profile similar to those of androgen suppression and estrogen therapy.