Systemic 8-OH-DPAT challenge causes hyperventilation largely via activating pre-botzinger complex 5-HT1A receptors.

Systemic 8-OH-DPAT (a 5-HT1A receptor agonist) challenge evokes hyperventilation independent of peripheral 5-HT1A receptors. Though the pre-Botzinger Complex (PBC) is critical in generating respiratory rhythm and activation of local 5-HT1A receptors induces tachypnea via disinhibition of local GABAA neurons, its role in the respiratory response to systemic 8-OH-DPAT challenge is still unclear. In anesthetized rats, 8-OH-DPAT (100 µg/kg, iv) was injected twice to confirm the reproducibility of the evoked responses. The same challenges were performed after bilateral microinjections of (S)-WAY-100135 (a 5-HT1A receptor antagonist) or gabazine (a GABAA receptor antagonist) into the PBC. Our results showed that: 1) 8-OH-DPAT caused reproducible hyperventilation associated with hypotension and bradycardia; 2) microinjections of (S)-WAY-100135 into the PBC attenuated the hyperventilation by ˜60 % without effect on the evoked hypotension and bradycardia; and 3) the same hyperventilatory attenuation was also observed after microinjections of gabazine into the PBC. Our data suggest that PBC 5-HT1A receptors play a key role in the respiratory response to systemic 8-OH-DPAT challenge likely via disinhibiting local GABAergic neurons.

Two types of early epileptic encephalopathy in a Pitt-Hopkins syndrome patient with a novel TCF4 mutation.

INTRODUCTION: Pitt-Hopkins syndrome (PTHS) is a neurodevelopmental disorder caused by mutations in TCF4. Seizures have been found to vary among patients with PTHS. We report the case of a PTHS patient with a novel missense mutation in the gene TCF4, presenting with two types of early epileptic encephalopathy. CASE REPORT: The patient was a Japanese boy. His first seizure was reported at 17 days of age, with twitching of the left eyelid and tonic-clonic seizures on either side of his body. An ictal electroencephalogram (EEG) showed epileptic discharges arising independently from both hemispheres, occasionally resembling migrating partial seizures of infancy (MPSI) that migrated from one side to the other. Brain magnetic resonance imaging revealed agenesis of the corpus callosum. His facial characteristics included a distinctive upper lip and thickened helices. His seizures were refractory, and psychomotor development was severely delayed. At the age of 10 months, he developed West syndrome with spasms and hypsarrhythmia. After being prescribed topiramate (TPM), his seizures and EEG abnormalities dramatically improved. Also, psychomotor development progressed. Whole-exome sequencing revealed a novel de novo missense mutation in exon 18 (NM_001083962.2:c.1718A > T, p.(Asn573Ile)), corresponding to the basic region of the basic helix-loop-helix domain, which may be a causative gene for epileptic encephalopathy. CONCLUSIONS: To our knowledge, this is the first report of a patient with PTHS treated with TPM, who presented with both MPSI as well as West syndrome. This may help provide new insights regarding the phenotypes caused by mutations in TCF4.

Disordered breathing in a Pitt-Hopkins syndrome model involves Phox2b-expressing parafacial neurons and aberrant Nav1.8 expression.

Pitt-Hopkins syndrome (PTHS) is a rare autism spectrum-like disorder characterized by intellectual disability, developmental delays, and breathing problems involving episodes of hyperventilation followed by apnea. PTHS is caused by functional haploinsufficiency of the gene encoding transcription factor 4 (Tcf4). Despite the severity of this disease, mechanisms contributing to PTHS behavioral abnormalities are not well understood. Here, we show that a Tcf4 truncation (Tcf4tr/+) mouse model of PTHS exhibits breathing problems similar to PTHS patients. This behavioral deficit is associated with selective loss of putative expiratory parafacial neurons and compromised function of neurons in the retrotrapezoid nucleus that regulate breathing in response to tissue CO2/H+. We also show that central Nav1.8 channels can be targeted pharmacologically to improve respiratory function at the cellular and behavioral levels in Tcf4tr/+ mice, thus establishing Nav1.8 as a high priority target with therapeutic potential in PTHS.

Caffeine Exacerbates Hyperventilation and Reductions in Cerebral Blood Flow in Physically Fit Men Exercising in the Heat.

INTRODUCTION: Caffeine is an exercise performance enhancer widely used by individuals engaged in training or competition under heat-stressed conditions. Caffeine ingestion during exercise in the heat is believed to be safe because it does not greatly affect body temperature responses, heart rate, or body fluid status. However, it remains unknown whether caffeine affects hyperthermia-induced hyperventilation or reductions in the cerebral blood flow index. We tested the hypothesis that under conditions inducing severe hyperthermia, caffeine exacerbates hyperthermia-induced hyperventilation and reduces the cerebral blood flow index during exercise. METHODS: Using a randomized, single-blind, crossover design, 12 physically active healthy young men (23 ± 2 yr) consumed a moderate dose of caffeine (5 mg·kg-1) or placebo in the heat (37°C). Approximately 60 min after the ingestion, they cycled for ~45 min at a workload equal to ~55% of their predetermined peak oxygen uptake (moderate intensity) until their core temperature increased to 2.0°C above its preexercise baseline level. RESULTS: In both trials, ventilation increased and the cerebral blood flow index assessed by middle cerebral artery mean blood velocity decreased as core temperature rose during exercise (P < 0.05), indicating that hyperthermia-induced hyperventilation and lowering of the cerebral blood flow occurred. When core temperature was elevated by 1.5°C or more (P < 0.05), ventilation was higher and the cerebral blood flow was lower throughout the caffeine trial than the placebo trial (P < 0.05). CONCLUSIONS: A moderate dose of caffeine exacerbates hyperthermia-induced hyperventilation and reductions in the cerebral blood flow index during exercise in the heat with severe hyperthermia.

Repurposing the Dihydropyridine Calcium Channel Inhibitor Nicardipine as a Nav1.8 Inhibitor In Vivo for Pitt Hopkins Syndrome.

PURPOSE: Individuals with the rare genetic disorder Pitt Hopkins Syndrome (PTHS) do not have sufficient expression of the transcription factor 4 (TCF4) which is located on chromosome 18. TCF4 is a basic helix-loop-helix E protein that is critical for the normal development of the nervous system and the brain in humans. PTHS patients lacking sufficient TCF4 frequently display gastrointestinal issues, intellectual disability and breathing problems. PTHS patients also commonly do not speak and display distinctive facial features and seizures. Recent research has proposed that decreased TCF4 expression can lead to the increased translation of the sodium channel Nav1.8. This in turn results in increased after-hyperpolarization as well as altered firing properties. We have recently identified through a drug repurposing screen an FDA approved dihydropyridine calcium antagonist nicardipine used to treat angina, which inhibited Nav1.8. METHODS: We have now performed behavioral testing in groups of 10 male Tcf4(± ) PTHS mice dosing by oral gavage at 3 mg/kg once a day for 3 weeks using standard methods to assess sociability, nesting, fear conditioning, self-grooming, open field and test of force. RESULTS: Nicardipine returned this spectrum of behavioral deficits in the Tcf4(± ) PTHS mouse model to WT levels and resulted in statistically significant results. CONCLUSIONS: These in vivo results in the well characterized Tcf4(± ) PTHS mice may suggest the potential to test this already approved drug further in a clinical study with PTHS patients or suggest the potential for use off label under compassionate use with their physician.

Repurposing Approved Drugs as Inhibitors of Kv7.1 and Nav1.8 to Treat Pitt Hopkins Syndrome.

PURPOSE: Pitt Hopkins Syndrome (PTHS) is a rare genetic disorder caused by mutations of a specific gene, transcription factor 4 (TCF4), located on chromosome 18. PTHS results in individuals that have moderate to severe intellectual disability, with most exhibiting psychomotor delay. PTHS also exhibits features of autistic spectrum disorders, which are characterized by the impaired ability to communicate and socialize. PTHS is comorbid with a higher prevalence of epileptic seizures which can be present from birth or which commonly develop in childhood. Attenuated or absent TCF4 expression results in increased translation of peripheral ion channels Kv7.1 and Nav1.8 which triggers an increase in after-hyperpolarization and altered firing properties. METHODS: We now describe a high throughput screen (HTS) of 1280 approved drugs and machine learning models developed from this data. The ion channels were expressed in either CHO (KV7.1) or HEK293 (Nav1.8) cells and the HTS used either 86Rb+ efflux (KV7.1) or a FLIPR assay (Nav1.8). RESULTS: The HTS delivered 55 inhibitors of Kv7.1 (4.2% hit rate) and 93 inhibitors of Nav1.8 (7.2% hit rate) at a screening concentration of 10 µM. These datasets also enabled us to generate and validate Bayesian machine learning models for these ion channels. We also describe a structure activity relationship for several dihydropyridine compounds as inhibitors of Nav1.8. CONCLUSIONS: This work could lead to the potential repurposing of nicardipine or other dihydropyridine calcium channel antagonists as potential treatments for PTHS acting via Nav1.8, as there are currently no approved treatments for this rare disorder.

Ultrasound tagged near infrared spectroscopy does not detect hyperventilation-induced reduction in cerebral blood flow.

INTRODUCTION: Continuous non-invasive monitoring of cerebral blood flow (CBF) may be important during anaesthesia and several options are available. We evaluated the CerOx monitor that employs ultrasound tagged near infrared spectroscopy to estimate changes in a CBF index (CFI). METHODS: Seven healthy males (age 21-26 years) hyperventilated and were administered phenylephrine to increase mean arterial pressure by 20-30 mmHg. Frontal lobe tissue oxygenation (ScO2) and CFI were obtained using the CerOx and mean blood flow velocity in the middle cerebral artery (MCAv mean) was determined by transcranial Doppler. Blood flow in the internal and external carotid artery (ICAf and ECAf) was determined using duplex ultrasonography and forehead skin blood flow (SkBF) and oxygenation (S skin O2) by laser Doppler and white light spectroscopy. RESULTS: During hyperventilation MCAv mean and ICAf decreased by 44% (median; interquartile range 40-49; p = 0.016) and 46% (40-53; p = 0.03), respectively. Conversely, CFI increased by 9% (2-31; p = 0.016), while no significant change was observed in ScO2. SkBF increased by 19% (9-53; p = 0.016) and S skin O2 by 6% (1-7; p = 0.047), although ECAf was unchanged. Administration of phenylephrine was not associated with any changes in MCAv mean, ICAf, ECAf, ScO2, SkBF, S skin O2, or CFI. CONCLUSION: The CerOx was able to detect a stable CBF during administration of phenylephrine. However, during hyperventilation MCAv mean and ICAf decreased while CFI increased, likely due to an increase in superficial tissue oxygenation. Thus, CFI does not provide an unbiased evaluation of changes in CBF.

Treatment of cardiac arrhythmias in a mouse model of Rett syndrome with Na+-channel-blocking antiepileptic drugs.

One quarter of deaths associated with Rett syndrome (RTT), an X-linked neurodevelopmental disorder, are sudden and unexpected. RTT is associated with prolonged QTc interval (LQT), and LQT-associated cardiac arrhythmias are a potential cause of unexpected death. The standard of care for LQT in RTT is treatment with ß-adrenergic antagonists; however, recent work indicates that acute treatment of mice with RTT with a ß-antagonist, propranolol, does not prevent lethal arrhythmias. In contrast, acute treatment with the Na(+) channel blocker phenytoin prevented arrhythmias. Chronic dosing of propranolol may be required for efficacy; therefore, we tested the efficacy of chronic treatment with either propranolol or phenytoin on RTT mice. Phenytoin completely abolished arrhythmias, whereas propranolol showed no benefit. Surprisingly, phenytoin also normalized weight and activity, but worsened breathing patterns. To explore the role of Na(+) channel blockers on QT in people with RTT, we performed a retrospective analysis of QT status before and after Na(+) channel blocker antiepileptic therapies. Individuals with RTT and LQT significantly improved their QT interval status after being started on Na(+) channel blocker antiepileptic therapies. Thus, Na(+) channel blockers should be considered for the clinical management of LQT in individuals with RTT.

Inhaled salbutamol does not affect athletic performance in asthmatic and non-asthmatic cyclists.

RATIONALE: Salbutamol may affect lung function and exercise performance differently in individuals with and without asthma. OBJECTIVES: To compare the effects of inhaled salbutamol on lung function, exercise performance and respiratory parameters during cycling exercise in athletes with a positive response to a eucapnic voluntary hyperpnoea (EVH+) and negative (EVH-) challenge, indicative of exercise-induced bronchoconstriction. METHODS: In a randomised controlled trial with a crossover design, a total of 49 well-trained male athletes (14 EVH+ and 35 EVH-) performed two simulated 10 km time-trials on a cycle ergometer 60 min after the inhalation of either 400 µg of salbutamol or a placebo. Lung function, assessed by forced expiratory volume in 1 s, was measured immediately before and 30 min after inhalation. Performance was measured by mean power output. MEASUREMENTS & MAIN RESULTS: Despite a significant increase in lung function after the inhalation of salbutamol compared to the placebo (p<0.001), salbutamol did not affect athletes' perceptions of dyspnoea (p>0.05) or leg exertion (p>0.05) during exercise. Salbutamol did not affect mean power output: EVH+ and EVH- athletes averaged 4.0 (0.5) and 4.1 (0.5) W/kg after salbutamol and 4.0 (0.5) W/kg and 4.0 (0.4) W/kg after placebo, respectively (p>0.05 for each comparison). CONCLUSIONS: The inhalation of salbutamol induced a significant increase in resting lung function in EVH+ and EVH- athletes but this improvement in lung function did not translate to improved exercise performance. Salbutamol had no discernible effect on key ventilatory and exercise parameters regardless of EVH challenge outcome.

Endogenous hydrogen sulfide in the rostral ventrolateral medulla/Bötzinger complex downregulates ventilatory responses to hypoxia.

Hydrogen sulfide (H2S) is now recognized as a new gaseous transmitter involved in several brain-mediated responses. The rostral ventrolateral medulla (RVLM)/Bötzinger complex is a region in the brainstem that is involved in cardiovascular and respiratory functions. Recently, it has been shown that exogenous H2S in the RVLM modulates autonomic function and thus blood pressure. In the present study, we investigated whether H2S, endogenously produced in the RVLM/Bötzinger complex, plays a role in the control of hypoxia-induced hyperventilation. Ventilation (VE) was measured before and after bilateral microinjection of Na2S (H2S donor, 0.04, 1 and 2 pmol/100 nl) or aminooxyacetate (AOA, 0.2, 1 and 2 pmol/100 nl, a cystathionine ß-synthase, CBS, inhibitor) into the RVLM/Bötzinger complex followed by a 60-min period of hypoxia (7% inspired O2) or normoxia exposure. Control rats received microinjection of vehicle. Microinjection of vehicle, AOA or Na2S did not change VE in normoxic conditions. Exposure to hypoxia evoked a typical increase in VE. Microinjection of Na2S (2 pmol) followed by hypoxia exposure attenuated the hyperventilation. Conversely, microinjection of AOA (2 pmol) into the RVLM/Bötzinger complex caused an increase in the hypoxia-induced hyperventilation. Thus, endogenous H2S in the RVLM/Bötzinger complex seems to play no role in the maintenance of basal pulmonary ventilation during normoxia whereas during hypoxia H2S has a downmodulatory function. Homogenates of RVLM/Bötzinger complex of animals previously exposed to hypoxia for 60 min exhibited a decreased rate of H2S production. Our data are consistent with the notion that the gaseous messenger H2S synthesis is downregulated in the RVLM/Bötzinger complex during hypoxia favoring hyperventilation.

5% CO2 inhalation suppresses hyperventilation-induced absence seizures in children.

Hyperventilation can cause respiratory alkalosis by exhaling CO2, and is often used to confirm diagnosis of absence epilepsy. CO2 has long been known for its anticonvulsant properties since the 1920s. In this pilot study, we aimed to determine whether inhaling medical carbogen containing 5% CO2 and 95% O2 can suppress hyperventilation-induced absence seizures and spike-and-wave discharges (SWDs). We examined 12 patients whose absence seizures were induced by hyperventilation using video electroencephalographic recording for at least 4h. The patients were asked to hyperventilate for 3 min while breathing the following gases: (1) room air (12 patients); (2) carbogen (12 patients); and (3) 100% O2 (8 patients). Eight out of twelve patients were also examined in room air through pretreatment with carbogen for 3 min before the 3 min hyperventilation. Compared with hyperventilation in room air, hyperventilation supplemented with 5% CO2 had the following effects: (a) decrease in the number and duration of seizures; (b) prolonged appearance of epileptic discharges; and (c) reduction in the number and duration of SWDs (P<0.001). However, pretreatment with 5% CO2 and 100% O2 supplement did not yield similar effects. We demonstrated that 5% CO2 could suppress hyperventilation-induced absence seizures and SWDs, supporting the claim that 5% CO2 is an effective anticonvulsant agent. Our pilot study provides clinical basis that 5% CO2 inhalation could be a therapeutic approach for hyperventilation-related seizures.

Effects of the recombinant form of the natural human B-type natriuretic peptide and levosimendan on pulmonary hyperventilation and chemosensivity in heart failure.

BACKGROUND: The origin of dyspnea in chronic heart failure (HF) is multifactorial, and excessive ventilation is thought to play a role in inducing this symptom. Chemosensivity is augmented in HF, correlates with increased pulmonary ventilation (VE), and is an adverse prognostic marker. Despite increased blood levels of natriuretic peptides in clinical conditions associated with dyspnea, their effect on pulmonary VE and chemoreceptor activity remains unexplored. METHODS: We tested in a prospective, placebo-controlled, three-way cross-over, double-blind randomized study the effects of the recombinant form of the natural human B-type natriuretic peptide (R-BNP) in comparison with placebo and levosimendan on chemoreflex sensitivity at rest, as well as their effects on pulmonary VE, systemic blood pressure, heart rate and sympathetic serum activity both at rest and during exercise. RESULTS: Eleven stable chronic HF patients were randomized to sessions of 6-min treadmill-walking tests during placebo, or levosimendan or R-BNP intravenous infusion in the following conditions: room air, hypoxia, and hypercapnia. R-BNP administration determined higher pulmonary ventilatory response at rest and during exercise (P < 0.001) consequent to a boost of respiratory rate (P < 0.001) under room air and hypoxia conditions. Norepinephrine blood levels increased from rest to exercise in all conditions without differences among placebo, levosimendan, and R-BNP effects. BNP blood levels remained unchanged. CONCLUSIONS: The novelty of the present findings is that R-BNP infusion in HF patients can boost pulmonary ventilatory response at rest and during exercise.

Immune-mediated mechanisms in the pathogenesis of Hopkins syndrome.

Hopkins syndrome occurs after an acute asthma attack. An immune-mediated mechanism has been suggested. Immunoglobulin or methylprednisone pulse therapies comprise the most useful treatment. We describe a 3-year-old girl who developed severe weakness in her left arm, 7 days after an acute asthma attack. A complete blood count with autoimmune biomarkers, immunoglobulin profile, and virology study and magnetic resonance of the brain, spine, and brachial plexus produced normal results. In the cerebrospinal fluid, T lymphocytes comprised the predominant leukocyte population, and oligoclonal bands were positive. An electromyogram revealed a partial axonal lesion (normal motor nerve conduction velocity with low amplitude) of the axillary, musculocutaneus, and interosseous nerves of the left arm, with normal sensory nerve conduction and partial denervation. We began therapy with intravenous immunoglobulin for 5 consecutive days, repeated every 4 weeks for 2 months. Afterward, our patient recovered. This report contributes to understanding the role of immune-mediated mechanisms in the pathogenesis of this disease, and the importance of immunotherapy in its treatment.

[Device diagnosis and combined treatment of hyperventilation syndrome].

Hyperventilation syndrome is a separate disease and a symptom of other psychosomatic diseases. A variant of device diagnosis of the disease is proposed--integral rheoplethysmography by M. I. Tischenko and cardiointervalography by R. M. Baevsky. Hyper- and asthenic courses of the disease are described, the pathological psychoemotional pattern is recognized. The proposed treatment combines physiohemotherapy (laser treatment) and pharmacotherapy.

Use of buspirone and fluoxetine for breathing problems in Rett syndrome.

Rett syndrome is a severe neurodevelopmental disease with a prevalence of 0.88 per 10,000 girls aged 5-18 years, and is often caused by mutations in methyl-cytosine-phosphate-guanine (CpG)-binding protein 2. Disorder of respiratory control is a prominent feature of Rett syndrome. Brainstem serotoninergic neurons are known to play an important role in the arrangement of breathing rhythm and pattern. We present a patient whose severe hyperventilation and apneic attacks resolved with the concomitant treatment of fluoxetine and buspirone. To our knowledge, we describe the first patient with Rett syndrome to receive fluoxetine for respiratory problems.

Fibromialgia. Consideraciones etiopatogénicas / No disponible

La fibromialgia es una enfermedad que cursa con dolor espontáneo generalizado, fatiga crónica, rigidez muscular, trastornos del sueño y alteraciones neuroinmunológicas, endocrinológicas y afectivas. Esta condición dificulta el diagnóstico y frustra al médico y al paciente, ya que la diversidad y lo cambiante de la sintomatología a menudo se escapan a la justificación etiopatogénica. Con objeto de clarificar de una manera esquemática los factores que pueden subyacer bajo el desarrollo de la enfermedad, para así facilitar su comprensión clínica, exponemos someramente las distintas hipótesis descritas al respecto (AU)

Fibromialgia is a disease that is accompanied with generalized spontaneous pain, chronic fatigue, muscular rigidity, disruptive sleep and neuroinmunological, endocrinological and affective alterations. This condition makes the diagnosis difficult and frustrates the doctor and the patient, since the diversity and the swings in the symptoms often escape the etiopatogenic justification. With the objective to clarify in a schematic way the factors that can exist due to the development of the disease, to be able to facilitate its clinical understanding, we expose briefly the different hypotheses on this matter (AU)