Patterns of Tumor Necrosis Factor Inhibitor (TNFi) Biosimilar Use Across United States Rheumatology Practices.

Objective: It is unclear if biosimilars of biologics for inflammatory arthritis are realizing their promise to increase competition and improve accessibility. This study evaluates biosimilar tumor necrosis factor inhibitor (TNFi) utilization across rheumatology practices in the United States and compares whether patients initiating biosimilars remain on these treatments at least as long as new initiators of bio-originators.

Methods: We identified a cohort of patients initiating a TNFi biosimilar between January 2017 and September 2018 from an electronic health record registry containing data from 218 rheumatology practices and over 1 million rheumatology patients in the United States.

Entrainment of temperature and activity rhythms to restricted feeding in orexin knock out mice.

Ablation of the SCN, an established circadian clock, does not abolish food entrainment, suggesting that the food-entrainable oscillator (FEO) must lie outside the SCN. Typically, animals show anticipatory locomotor activity and rise in core body temperature under the influence of the FEO. Signals from the FEO would, therefore, converge onto arousal neurons so that the animal might forage for food.

Effects of hypocretin-1 in 192-IgG-saporin-lesioned rats.

Hypocretin, also known as orexin, is a neuropeptide located in the perifornical region of the lateral hypothalamus; this region projects to all the major arousal centres including the basal forebrain. The basal forebrain contains a mixed population of neurons, some of which are cholinergic. To identify the relative contribution of the noncholinergic neurons to arousal, here we utilized 192-IgG-saporin to lesion the basal forebrain cholinergic neurons and determine whether microinjection of hypocretin-1 to the basal forebrain is still effective in inducing arousal.

Transplantation of hypocretin neurons into the pontine reticular formation: preliminary results.

Study Objectives: The sleep disorder narcolepsy is now considered a neurodegenerative disease because there is a massive loss of neurons containing the neuropeptide, hypocretin, and because narcoleptic patients have very low cerebrospinal fluid levels of hypocretin. Transplants of various cell types have been used to induce recovery in a variety of neurodegenerative animal models. In models such as Parkinson disease, cell survival has been shown to be small but satisfactory.

Effects of inflammation produced by chronic lipopolysaccharide administration on the survival of hypocretin neurons and sleep.

The number of hypocretin-containing neurons is markedly decreased in most patients with the sleep disorder narcolepsy. It is presently not known why the loss of hypocretin neurons occurs in these patients. In the present study, we tested the role of inflammation in the degeneration of hypocretin neurons.

Effects of hypocretin2-saporin and antidopamine-beta-hydroxylase-saporin neurotoxic lesions of the dorsolateral pons on sleep and muscle tone.

The hypocretin neurons have been implicated in regulating sleep-wake states as they are lost in patients with the sleep disorder narcolepsy. Hypocretin (HCRT) neurons are located only in the perifornical region of the posterior hypothalamus and heavily innervate pontine brainstem neurons, such as the locus coeruleus (LC), which have traditionally been implicated in promoting arousal. It is not known how the hypocretin innervation of the pons regulates sleep-wake states as pontine lesions have never been shown to increase sleep.

Different neuronal phenotypes in the lateral hypothalamus and their role in sleep and wakefulness.

The sleep disorder narcolepsy is now linked with a loss of neurons containing the neuropeptide hypocretin (also known as orexin). The hypocretin neurons are located exclusively in the lateral hypothalamus, a brain region that has been implicated in arousal based on observations made by von Economo during the viral encephalitic epidemic of 1916-1926. There are other neuronal phenotypes located in the lateral hypothalamus that are distinct and separate from the hypocretin neurons.

Relationship between CSF hypocretin levels and hypocretin neuronal loss.

The sleep disorder narcolepsy may now be considered a neurodegenerative disease, as there is a massive reduction in the number of neurons containing the neuropeptide, hypocretin (HCRT). Most narcoleptic patients have low to negligible levels of HCRT in the cerebrospinal fluid (CSF), and such measurements serve as an important diagnostic tool. However, the relationship between HCRT neurons and HCRT levels in CSF in human narcoleptics is not known and cannot be directly assessed.

The diurnal rhythm of adenosine levels in the basal forebrain of young and old rats.

There are significant decrements in sleep with age. These include fragmentation of sleep, increased wake time, decrease in the length of sleep bouts, decrease in the amplitude of the diurnal rhythm of sleep, decrease in rapid eye movement sleep and a profound decrease in electroencephalogram Delta power (0.3-4 Hz).

Effects of lateral hypothalamic lesion with the neurotoxin hypocretin-2-saporin on sleep in Long-Evans rats.

Narcolepsy, a disabling neurological disorder characterized by excessive daytime sleepiness, sleep attacks, sleep fragmentation, cataplexy, sleep-onset rapid eye movement sleep periods and hypnagogic hallucinations was recently linked to a loss of neurons containing the neuropeptide hypocretin. There is considerable variability in the severity of symptoms between narcoleptic patients, which could be related to the extent of neuronal loss in the lateral hypothalamus. To investigate this possibility, we administered two concentrations (90 ng or 490 ng in a volume of 0.

Effects of hypocaloric diet on sleep in young and old rats.

Aging produces a loss in a number of behavioral and cognitive functions, including sleep. Hypocaloric diet is one of the few methods that have been shown to retard the effects due to age. However, the effects of such a diet on sleep have never been investigated.

Hypothalamic regulation of sleep.

The recent discovery linking narcolepsy, a sleep disorder characterized by very short REM sleep latency, with a neuropeptide that regulates feeding and energy metabolism, provides a way to understand how several behaviors may be disrupted as a result of a defect in this peptide. In this chapter we review the evidence linking hypocretin and sleep, including our own studies, and propose that a defect in the lateral hypothalamus that also involves the hypocretin neurons is likely to produce a disturbance in sleep, mood, appetite, and rhythms.

Effects of hypocretin-saporin injections into the medial septum on sleep and hippocampal theta.

Neurons containing the peptide hypocretin, also known as orexin, were recently implicated in the human sleep disorder narcolepsy. Hypocretin neurons are located only in the lateral hypothalamus from where they innervate virtually the entire brain and spinal cord. This peptide is believed to be involved in regulating feeding and wakefulness.

Distribution of hypocretin-containing neurons in the lateral hypothalamus and C-fos-immunoreactive neurons in the VLPO.

The present study investigated the distribution of neurons implicated in the regulation of sleep in three species generally used in sleep research, i.e., mice, rats and cats.

Effects of prolonged wakefulness on c-fos and AP1 activity in young and old rats.

Recent studies have demonstrated that the immediate-early gene c-fos is induced in neuronal populations responsible for specific sleep-wake states. The induction of this gene may be functionally relevant to sleep homeostasis since without the gene mice (c-fos null) take longer to fall asleep and have a selective reduction in slow-wave sleep. This suggests that a build-up of c-fos during wakefulness increases the drive to sleep and lack of c-fos is associated with reduced sleep.

Prefrontal gray matter volume reduction in first episode schizophrenia.

Functional measures have consistently shown prefrontal abnormalities in schizophrenia. However, structural magnetic resonance imaging (MRI) findings of prefrontal volume reduction have been less consistent. In this study, we evaluated prefrontal gray matter volume in first episode (first hospitalized) patients diagnosed with schizophrenia, compared with first episode patients diagnosed with affective psychosis and normal comparison subjects, to determine the presence in and specificity of prefrontal abnormalities to schizophrenia.

Sleep and wakefulness in c-fos and fos B gene knockout mice.

G-protein coupled receptor (GPCR) stimulation has been implicated in the regulation of sleep. Upon stimulation of a GPCR an intracellular cascade involving second and third messengers is initiated. The latter include the fos-family of immediate early genes (IEGs).

Brain site-specificity of extracellular adenosine concentration changes during sleep deprivation and spontaneous sleep: an in vivo microdialysis study.

Previous data suggested that increases in extracellular adenosine in the basal forebrain mediated the sleep-inducing effects of prolonged wakefulness. The present study sought to determine if the state-related changes found in basal forebrain adenosine levels occurred uniformly throughout the brain. In vivo microdialysis sample collection coupled to microbore high-performance liquid chromatography measured extracellular adenosine levels in six brain regions of the cat: basal forebrain, cerebral cortex, thalamus, preoptic area of hypothalamus, dorsal raphe nucleus and pedunculopontine tegmental nucleus.

Adenosinergic modulation of basal forebrain and preoptic/anterior hypothalamic neuronal activity in the control of behavioral state.

This review describes a series of animal experiments that investigate the role of endogenous adenosine (AD) in sleep. We propose that AD is a modulator of the sleepiness associated with prolonged wakefulness. More specifically, we suggest that, during prolonged wakefulness, extracellular AD accumulates selectively in the basal forebrain (BF) and cortex and promotes the transition from wakefulness to slow wave sleep (SWS) by inhibiting cholinergic and non-cholinergic wakefulness-promoting BF neurons at the AD A1 receptor.

REM sleep deprivation increases the levels of tyrosine hydroxylase and norepinephrine transporter mRNA in the locus coeruleus.

The present study was conducted to determine the effects of REM sleep deprivation on the levels of tyrosine hydroxylase (TH) and norepinephrine transporter (NET) mRNA in the locus coeruleus (LC) of rats. The animals were deprived of REM sleep for 1, 3 or 5 days, then killed and changes in the mRNA levels were determined using in situ hybridization. The levels of both TH and NET mRNA increased in animals deprived of REM sleep for 3 days or longer whereas no change in these messages were observed in the LC of control animals.

An intermediate conductance K+ channel in the cell membrane of mouse intestinal smooth muscle.

Single channel currents were recorded from cell-attached and inside-out patches in smooth muscle cells of the mouse ileum in order to identify TEA-sensitive Ca2+-dependent K+ channels. Cells were bathed in high-K+ (150 mM) solution with [Ca2+] buffered to 80-150 nM with EGTA and patch pipettes were filled with low-K+ (2.5 mM) physiological solution.

Effects of sleep on wake-induced c-fos expression.

We investigated the effects of sleep on wake-induced c-fos expression in the cerebral cortex of rats and c-fos-lacZ transgenic mice. In the cortex of rats, the levels of c-Fos, detected both by immunocytochemistry and Western blot, remained high during 6 or 12 hr of enforced wakefulness but declined rapidly (within 1 hr) with increasing time of recovery sleep. Similarly, in the transgenic mice in which lacZ expression is driven from the c-fos promoter, beta-galactosidase activity was high after enforced wakefulness and declined with increasing amounts of sleep.