The parafascicular nucleus relays spinal inputs to the striatum: an electron microscope study in the rat.

A disynaptic projection from the spinal cord to the striatum was observed in the rat light and electron microscopically. An anterograde tracer, wheat germ agglutinin conjugated to horseradish peroxidase was injected into the ventral gray matter of the upper cervical spinal cord, and a retrograde tracer, biotinylated dextran amine was injected into the striatum of a rat. Then the parafascicular nucleus was examined. Some anterogradely labeled axon terminals originating in the spinal cord were observed to synapse with retrogradely labeled dendrites of parafascicular nucleus neurons which sent axons to the striatum. We concluded that information from the spinal cord was transmitted to the striatum, being relayed by parafascicular nucleus neurons.

Potassium-competitive acid blockers: Advanced therapeutic option for acid-related diseases.

Acid-related diseases (ARDs), such as peptic ulcers and gastroesophageal reflux disease, represent a major health-care concern. Some major milestones in our understanding of gastric acid secretion and ARD treatment reached during the last 50years include 1) discovery of histamine H2-receptors and development of H2-receptor antagonists, 2) identification of H+,K+-ATPase as the parietal cell proton pump and development of proton pump inhibitors (PPIs), and 3) identification of Helicobacter pylori (H. pylori) as the major cause of peptic ulcers and development of effective eradication regimens. Although PPI treatments have been effective and successful, there are limitations to their efficacy and usage, i.e. short half-life, insufficient acid suppression, slow onset of action, and large variation in efficacy among patients due to CYP2C19 metabolism. Potassium-competitive acid blockers (P-CABs) inhibit H+,K+-ATPase in a reversible and K+-competitive manner, and exhibit almost complete inhibition of gastric acid secretion from the first dose. Many pharmaceutical companies have tried to develop P-CABs, but most of their clinical development has been discontinued due to safety concerns or a similar efficacy to PPIs. Revaprazan was developed in Korea and was the first P-CAB approved for sale. Vonoprazan, approved in 2014 in Japan, has a completely different chemical structure and higher pKa value compared to other P-CABs, and exhibits rapid onset of action and prolonged control of intragastric acidity. Vonoprazan is an effective treatment for ARDs that is especially effective in healing reflux esophagitis and for H. pylori eradication. P-CABs, such as vonoprazan, promise to further improve the management of ARDs.

Current treatment status and medical cost for multiple sclerosis based on analysis of a Japanese claims database.

OBJECTIVE: To assist policymakers as they reflect on treatment protocols and approaches for the efficient delivery of medical care for multiple sclerosis (MS) patients in Japan. METHODS: We analyzed data from a large Japanese health insurance claims database. Using an algorithm based on diagnosis codes, all patients with a diagnosis of MS were identified; patients having a non-MS demyelinating disease were excluded from the population. MS patient data were used for cross-sectional analysis carried out on the data collected at a certain period. We identified a total of 1808 MS patients, and we analyzed data for 1133 patients with an observation period of ≥6 months from October 2013 to September 2014. Newly diagnosed MS patients were identified within the MS patients, and their data were used for longitudinal analysis, tracking each patient over a period of time. RESULTS: The total per patient per month cost for MS was ¥93 542 (US$781, €695 as of October 2015). Disease-modifying therapy drugs costs constituted half of the overall medical costs. For newly diagnosed MS patients, hospitalization costs were the largest component in the initial month, while drug costs were the largest component more than several months after the initial visit. There was a positive correlation between relapse frequency and medical cost. CONCLUSIONS: These results provide up-to-date information on the demographics, medical treatment and cost status of MS in almost real-time by using a claims database. They suggest that claims data analysis can effectively support medical policymaking.

Characteristics of the Novel Potassium-Competitive Acid Blocker Vonoprazan Fumarate (TAK-438).

UNLABELLED: Proton pump inhibitors (PPIs) are widely prescribed as first-line therapy for the treatment of acid-related diseases, such as peptic ulcers and gastro-esophageal reflux disease, and for the eradication of Helicobacter pylori. However, the therapeutic efficacy of conventional PPIs is considered limited because: (1) they are unstable under acidic conditions and require an enteric-coated formulation in clinical use; (2) they show high interindividual variability in pharmacokinetics due to genetic polymorphisms of cytochrome P450 (CYP) 2C19 metabolism; (3) they have a relatively slow onset of pharmacological action and may require several doses to achieve optimal acid suppression and symptom relief; and (4) they often do not provide stable suppression of gastric acid secretion over 24 h. Vonoprazan fumarate (TAK-438, hereinafter referred to as "vonoprazan") is a new potassium-competitive acid blocker (P-CAB) developed to resolve the above limitations of conventional PPIs. Various physicochemical data have shown that vonoprazan has a high solubility and stability over a broad pH range in aqueous conditions. In addition, vonoprazan has a more potent and longer-lasting acid suppression effect than the conventional PPI, lansoprazole. Preclinical pharmacokinetic studies have shown that vonoprazan is accumulated and retained in the stomach for more than 24 h, even after it is eliminated from the plasma. From these findings, we propose that vonoprazan, which possesses a novel mode of action, can improve on the outcomes seen with conventional PPI-based treatments for acid-related diseases. FUNDING: This review project, including the publication of this article, was funded by Takeda Pharmaceutical Company Limited.

Cholecystokinin and substance P immunoreactive projections to the paraventricular thalamic nucleus in the rat.

Cholecystokinin (CCK) and substance P (SP) are thought to play an important role in a variety of stress responses. Both CCK- and SP-positive fibers innervating the thalamus are found principally in the midline nuclei, including the paraventricular thalamic nucleus (PVT), which has strong reciprocal connections with the medial prefrontal cortex. In the present study, we determined the source of the CCK- and SP-immunoreactive fibers to the PVT, employing combination of retrograde neuronal tracing and immunohistochemistry in the rat. The PVT-projecting neurons showing CCK immunoreactivity were detected in the dorsomedial nucleus of the hypothalamus, and ventral mesencephalic periaqueductal gray, including the Edinger-Westphal nucleus and the dorsal raphe nucleus. Sources of SP afferents to the PVT were detected in the Edinger-Westphal nucleus, the mesopontine tegmentum and the medullary raphe nucleus. CCK- and SP-immunoreactive fibers may exert modulatory influence on the prefrontal cortical activity via the PVT and regulate behavioral components of stress-adaptation responses.

Axonal projections of pulmonary slowly adapting receptor relay neurons in the rat.

We elucidated efferent projections of second-order relay neurons (P-cells) activated by afferents originating from slowly adapting pulmonary receptors (SARs) to determine the central pathway of the SAR-evoked reflexes. Special attention was paid to visualizing the P-cell projections within the nucleus tractus solitarii (NTS), which may correspond to the inhibitory pathway from P-cells to second-order relay neurons (RAR-cells) of rapidly adapting pulmonary receptors. P-cells were recorded from the NTS in Nembutal-anesthetized, paralyzed, and artificially ventilated rats. First, we used electrophysiological methods of antidromic mapping and showed that the majority of the P-cells examined projected their axons to the caudal NTS and to the dorsolateral pons corresponding to the parabrachial complex. Second, a mixture of HRP and Neurobiotin was injected intracellularly or juxtramembranously into P-cells. (1) Stained P-cells (n = 7) were located laterally to the solitary tract and had dendrites extending characteristically along the lateral border of the solitary tract. (2) All P-cells had stem axons projecting to the ipsilateral medulla. Of these, the axons from five P-cells projected to the nucleus ambiguus and its vicinity with distributing boutons. Some of these axons further ascended in the ventrolateral medulla, and distributed boutons in the areas ventral or ventrolateral to the nucleus ambiguus. (3) All the P-cells had axonal branches with boutons in the NTS area. In particular, axons from three P-cells projected bilaterally to the medial NTS caudal to the obex, i.e., to the area of RAR-cells. These results show anatomic substrates for the connections implicated in the P-cell inhibition of RAR-cells as well as the SAR-induced respiratory reflexes.

Fos expression in afferents to the rat midline thalamus following immobilization stress.

The paraventricular thalamic nucleus (PVT), the most dorsal component of the thalamic midline, is known to be strongly activated following a variety of stressors and thus might be suggested to play a role as a relay for stress-related information targeted for viscerolimbic areas in the brain. This thalamic midline nucleus, however, lacks significant direct connections with the paraventricular hypothalamic nucleus (PVH), which is a key player in the hypothalamic-pituitary-adrenal (HPA) axis whose activation and subsequent glucocorticoid secretion are clearly crucial for homeostasis under 'stressful' conditions. The present study was designed to identify afferents of the PVT, which are activated by an immobilization stress, one type of the 'neurogenic' stress paradigms, using combined Fos immunohistochemistry and retrograde tracing experiments with cholera toxin B subunit. Dual immunohistochemistry revealed that immobilization stress induced expression of Fos immunoreactive nuclei was constantly observed in many regions of the neuraxis. Dually-labeled neurons in the cerebral cortex were mainly observed in the hippocampus, exclusively in the pyramidal layer of the caudal part of the ventral subiculum. In diencephalons a small number of dually labeled neurons was observed in the rostromedial zona incerta. In the midbrain, many of the retrogradely labeled neurons in the dorsal raphe nucleus were also immunoreactive for Fos protein. Mesencephalic periaqueductal gray contained a substantial number of dually labeled neurons. In the pons, the parabrachial nuclei, locus ceruleus, Barrington's nucleus and raphe nucleus contained only small numbers of dually labeled neurons. Within the medulla, nearly all of the retrogradely labeled neurons in the caudal part of the ventrolateral medulla were also immunoreactive for Fos antigen. Dually labeled neurons in the medulla were also observed in the nucleus of the solitary tract, exclusively in its commissural part. Given the known fact that most of the regions mentioned above provide important inputs to the HPA axis, our results suggest that a diencephalic network, presumably implicated in behavioral responses to given stress, might be activated by the parallel projection system that activate the HPA axis and might add some important insights to the understanding of animal and human stress-related HPA pathology.