[Small tidal volume hyperventilation relieves intraocular and intracranial pressure elevation in prone spinal surgery: a randomized controlled trial].

OBJECTIVE: To investigate the effects of different ventilation strategies on intraocular pressure (IOP) and intracranial pressure in patients undergoing spinal surgery in the prone position under general anesthesia. METHODS: Seventy-two patients undergoing prone spinal surgery under general anesthesia between November, 2022 and June, 2023 were equally randomized into two groups to receive routine ventilation (with Vt of 8mL/kg, Fr of 12-15/min, and etCO2 maintained at 35-40 mmHg) or small tidal volume hyperventilation (Vt of 6 mL/kg, Fr of18-20/min, and etCO2 maintained at 30-35 mmHg) during the surgery. IOP of both eyes (measured with a handheld tonometer), optic nerve sheath diameter (ONSD; measured at 3 mm behind the eyeball with bedside real-time ultrasound), circulatory and respiratory parameters of the patients were recorded before anesthesia (T0), immediately after anesthesia induction (T1), immediately after prone positioning (T2), at 2 h during operation (T3), immediately after supine positioning after surgery (T4) and 30 min after the operation (T5). RESULTS: Compared with those at T1, IOP and ONSD in both groups increased significantly at T3 and T4(P < 0.05). IOP was significantly lower in hyperventilation group than in routine ventilation group at T3 and T4(P < 0.05), and ONSD was significantly lower in hyperventilation group at T4(P < 0.05). IOP was positively correlated with the length of operative time (r=0.779, P < 0.001) and inversely with intraoperative etCO2 at T3(r=-0.248, P < 0.001) and T4(r=-0.251, P < 0.001).ONSD was correlated only with operation time (r=0.561, P < 0.05) and not with IOP (r=0.178, P>0.05 at T3; r=0.165, P>0.05 at T4). CONCLUSION: Small tidal volume hyperventilation can relieve the increase of IOP and ONSD during prone spinal surgery under general anesthesia.

Expanding the phenotype in Pitt-Hopkins syndrome; description of new oral finding and dental management considerations.

BACKGROUND: Pitt-Hopkins syndrome (PTHS) is a rare neurodevelopmental disorder with physical, cognitive, and behavioral characteristics that is caused by heterozygous mutations in the TCF4 gene. Patients with PTHS might present a unique challenge for oral healthcare professionals because of the associated comorbidities. CASE REPORT: Here we describe a new case of PTHS in a 13-year-old girl with particular emphasis on oro-dental findings and oral healthcare management. Observed oro-dental findings in our case included shallow palate, absence of lingual frenum, gingival enlargement, thick lips and relative microdontia. The patient was unable to tolerate dental care under local anesthesia. Therefore, comprehensive dental treatment was performed under general anesthesia after a careful pre-anesthetic cardio-respiratory, neurological, and hematological evaluation. The patient was closely monitored intra-operatively for breathing rhythm, O2 saturation, and signs of respiratory distress. The patient was observed for 24 h post-op for respiratory distress and was discharged then uneventfully. CONCLUSION: Dental treatment under general anesthesia in these patients might be complicated by the abnormal breathing rhythm, and close monitoring and follow up for signs of respiratory distress after general anesthesia is necessary. Recognition of oral and dental findings might help to expand the phenotype and better characterize rare syndromes.

Tcf4 dysfunction alters dorsal and ventral cortical neurogenesis in Pitt-Hopkins syndrome mouse model showing sexual dimorphism.

Pitt-Hopkins syndrome (PTHS) is a neurodevelopmental disorder caused by haploinsufficiency of transcription factor 4 (TCF4). In this work, we focused on the cerebral cortex and investigated in detail the progenitor cell dynamics and the outcome of neurogenesis in a PTHS mouse model. Labeling and quantification of progenitors and newly generated neurons at various time points during embryonic development revealed alterations affecting the dynamic of cortical progenitors since the earliest stages of cortex formation in PTHS mice. Consequently, establishment of neuronal populations and layering of the cortex were found to be altered in heterozygotes subjects at birth. Interestingly, defective layering process of pyramidal neurons was partially rescued by reintroducing TCF4 expression using focal in utero electroporation in the cerebral cortex. Coincidentally with a defective dorsal neurogenesis, we found that ventral generation of interneurons was also defective in this model, which may lead to an excitation/inhibition imbalance in PTHS. Overall, sex-dependent differences were detected with more marked effects evidenced in males compared with females. All of this contributes to expand our understanding of PTHS, paralleling the advances of research in autism spectrum disorder and further validating the PTHS mouse model as an important tool to advance preclinical studies.

Temporal association of ventricular arrhythmias and respiratory events in heart failure patients with central sleep apnoea.

In contrast to obstructive sleep apnoea, the peak of sympathetic tone in central sleep apnoea occurs during the hyperventilation phase. To explore the temporal association of premature ventricular complex (PVC) burden in the context of the apnoea/hypopnoea-hyperpnoea cycle, the duration of apnoea/hypopnoea was defined as 100 %. We assessed the PVC burden throughout the apnoea/hypopnoea-hyperpnoea cycle during the periods of ±150 % in 50 % increments before and after the apnoea/hypopnoea phase. In this subanalysis of 54 SERVE-HF patients, PVC burden was 32 % higher in the late hyperventilation period (50-100 % after apnoea/hypopnoea) compared to the apnoea/hypopnoea phase.

[Genetic analysis of a fetus with Pitt-Hopkins syndrome due to a 18q21.2q21.31 microdeletion].

OBJECTIVE: To carry out invasive prenatal diagnosis for a fetus with ultrasound-indicated agenesis of corpus callosum and explore its genetic etiology. METHODS: A pregnant woman presented at the Affiliated Hospital of Putian College on December 16, 2022 was selected as the study subject. Amniotic fluid and peripheral blood samples from the fetus and the couple were collected. Conventional G-banded chromosomal karyotyping was carried out, and whole-genome copy number variation analysis was performed using single nucleotide polymorphism microarray (SNP-array). RESULTS: The karyotypes of the fetus and the couple were normal by the G-banding analysis. SNP-array analysis of the amniotic fluid sample revealed a 4.5 Mb microdeletion in the 18q21.2q21.31 region of the fetus. SNP-array analysis of peripheral blood samples from the couple did not find any abnormality. CONCLUSION: Through G-banded chromosomal karyotyping and SNP-array analysis, a fetus with 18q21.2q21.31 microdeletion was identified, which has conformed to the diagnosis of Pitt-Hopkins syndrome. Above finding has provided a basis for genetic counseling for the couple.

Surge of Sympathetic Activity during Hyperventilation at the End of Apnea for Patients with Obstructive Sleep Apnea.

Background and Objectives: The mechanisms connecting obstructive sleep apnea (OSA) and cardiovascular disease are multifactorial, involving intermittent hypoxia, hypercapnia, and sympathetic activation. The aim of this study was to explore the oscillations of sympathetic activity during the sleep apnea episodes throughout the entire night in patients with OSA. Materials and Methods: The participants received whole-night polysomnography (PSG), and electrocardiogram (EKG) data from the PSG were collected for heart rate variability (HRV) analysis. HRV measurements were conducted in the time and frequency domains. The root mean square of successive differences between normal heartbeats (RMSSD), which reflects parasympathetic activity, and the ratio of the absolute power of the low-frequency band (0.04-0.15 Hz) to the absolute power of the high-frequency band (0.015-0.4 Hz) (LF/HF ratio), which indicates sympathetic activity, were computed. Results: A total of 43 participants (35 men and 8 women) were included in the analysis. The mean age of the participants was 44.1 ± 11.3 years old, and the mean BMI was 28.6 ± 5.4 kg/m2. The sleep apnea episodes throughout the entire night in patients with OSA were selected randomly and occurred most frequently during the non-REM stages (39, 90.7%). The selected sleep apnea episodes typically exhibited multiple apneas, often interrupted by snoring respiration and followed by hyperventilation at the end of the episode (HE). Our findings indicate that the centers of the 5 min HRV window for the lowest and highest LF/HF ratios, at 111.8 ± 88.2 and 117.4 ± 88.6 min after sleep onset, respectively, showed a statistically significant difference (p < 0.001). Similarly, the ratios of the lowest and highest LF/HF, at 0.82 ± 0.56 and 3.53 ± 2.94, respectively, exhibited a statistically significant difference (p < 0.001). Conclusions: In the current study, the selected sleep apnea episodes throughout the entire night in patients with OSA occurred primarily during the non-REM stages. Additionally, we observed that sympathetic activity reached its peak in the window that includes hyperventilation at the end stage of apnea, potentially posing a cardiovascular risk. However, additional studies are needed to validate these results.

Complex visceral hyperalgesia in an adolescent with Pitt-Hopkins syndrome.

An early-adolescent boy with a background of Pitt-Hopkins syndrome was transferred to a tertiary paediatric hospital with symptoms of a functional large bowel obstruction. He required extensive surgical intervention including a transverse colectomy, drainage of an abdominal abscess, laparotomy and adhesionolysis, and insertion of a gastrostomy and jejunostomy. He had significant ongoing issues with visceral hyperalgesia that was refractory to a wide range of pharmacological treatments and required admission to the intensive care unit on multiple occasions, and consultations with international experts in Pitt-Hopkins syndrome and pain specialists. An individualised pain plan was created and adjusted over time, with eventual good effect, and he was transferred back to his regional hospital and subsequently discharged home.

Hyperventilation testing in the diagnosis of vasospastic angina: A clinical review and meta-analysis.

BACKGROUND: Given the limited access to invasive vasospastic reactivity testing in Western Countries, there is a need to further develop alternative non-invasive diagnostic methods for vasospastic angina (VSA). Hyperventilation testing (HVT) is defined as a class IIa recommendation to diagnose VSA by the Japanese Society of Cardiology. METHODS: In this systematic review and meta-analysis reported according to the PRISMA statement, we review the mechanisms, methods, modalities and diagnostic accuracy of non-invasive HVT for the diagnostic of VSA. RESULTS: A total of 106 articles published between 1980 and 2022 about VSA and HVT were included in the systematic review, among which 16 were included in the meta-analysis for diagnostic accuracy. Twelve electrocardiogram-HVT studies including 804 patients showed a pooled sensitivity of 54% (95% confidence intervals [CI]; 30%-76%) and a pooled specificity of 99% (95% CI; 88%-100%). Four transthoracic echocardiography-HVT studies including 197 patients revealed a pooled sensitivity of 90% (95% CI; 82%-94%) and a pooled specificity of 98% (95% CI; 86%-100%). Six myocardial perfusion imaging-HVT studies including 112 patients yielded a pooled sensitivity of 95% (95% CI; 63%-100%) and a pooled specificity of 78% (95% CI; 19%-98%). Non-invasive HVT resulted in a low rate of adverse events, ventricular arrhythmias being the most frequently reported, and were resolved with the administration of nitroglycerin. CONCLUSIONS: Non-invasive HVT offers a safe alternative with high diagnostic accuracy to diagnose VSA in patients with otherwise undiagnosed causes of chest pain.

Effects of hyperventilation on repeated breath-holding while in a fasting state: do risks outweigh the benefits?

Breath-holding preceded by either an overnight fast or hyperventilation has been shown to potentiate the risk of a hypoxic blackout. However, no study has explored the combined effects of fasting and hyperventilation on apneic performance and associated physiological responses. Nine nondivers (8 males) attended the laboratory on two separate occasions (≥48 h apart), both after a 12-h overnight fast. During each visit, a hyperoxic rebreathing trial was performed followed by three repeated maximal static apneas preceded by either normal breathing (NORM) or a 30-s hyperventilation (HYPER). Splenic volume, hematology, cardiovascular, and respiratory variables were monitored. There were no interprotocol differences at rest or during hyperoxic rebreathing for any variable (P ≥ 0.09). On nine occasions (8 in HYPER), the subjects reached our safety threshold (oxygen saturation 65%) and were asked to abort their apneas, with the preponderance of these incidents (6 of 9) occurring during the third repetition. Across the sequential attempts, longer apneas were recorded in HYPER [median(range), 220(123-324) s vs. 185(78-296) s, P ≤ 0.001], with involuntary breathing movements occurring later [134(65-234) s vs. 97(42-200) s, P ≤ 0.001] and end-apneic partial end-tidal pressures of oxygen (PETO2) being lower (P ≤ 0.02). During the final repetition, partial end-tidal pressure of carbon dioxide [(PETCO2), 6.53 ± 0.46 kPa vs. 6.01 ± 0.45 kPa, P = 0.005] was lower in HYPER. Over the serial attempts, preapneic tidal volume was gradually elevated [from apnea 1 to 3, by 0.26 ± 0.24 L (HYPER) and 0.28 ± 0.30 L (NORM), P ≤ 0.025], with a correlation noted with preapneic PETCO2 (r = -0.57, P < 0.001) and PETO2 (r = 0.76, P < 0.001), respectively. In a fasted state, preapnea hyperventilation compared with normal breathing leads to longer apneas but may increase the susceptibility to a hypoxic blackout.NEW & NOTEWORTHY This study shows that breath-holds (apneas) preceded by a 12-h overnight fast coupled with a 30-s hyperventilation as opposed to normal breathing may increase the likelihood of a hypoxic blackout through delaying the excitation of hypercapnic ventilatory sensory chemoreflexes. Evidently, this risk is exacerbated over a series of repeated maximal attempts, possibly due to a shift in preapneic gas tensions facilitated by an unintentional increase in tidal volume breathing.

Ultra-rapid, Free-breathing, Real-time Cardiac Cine MRI Using GRASP Amplified with View Sharing and KWIC Filtering.

Purpose To achieve ultra-high temporal resolution (approximately 20 msec) in free-breathing, real-time cardiac cine MRI using golden-angle radial sparse parallel (GRASP) reconstruction amplified with view sharing (VS) and k-space-weighted image contrast (KWIC) filtering. Materials and Methods Fourteen pediatric patients with congenital heart disease (mean age [SD], 9 years ± 2; 13 male) and 10 adult patients with arrhythmia (mean age, 62 years ± 8; nine male) who underwent both standard breath-hold cine and free-breathing real-time cine using GRASP were retrospectively identified. To achieve high temporal resolution, each time frame was reconstructed using six radial spokes, corresponding to acceleration factors ranging from 24 to 32. To compensate for loss in spatial resolution resulting from over-regularization in GRASP, VS and KWIC filtering were incorporated. The blur metric, visual image quality scores, and biventricular parameters were compared between clinical and real-time cine images. Results In pediatric patients, the incorporation of VS and KWIC into GRASP (ie, GRASP + VS + KWIC) produced significantly (P < .05) sharper x-y-t (blur metric: 0.36 ± 0.03, 0.41 ± 0.03, 0.48 ± 0.03, respectively) and x-y-f (blur metric: 0.28 ± 0.02, 0.31 ± 0.03, 0.37 ± 0.03, respectively) component images compared with GRASP + VS and conventional GRASP. Only the noise score differed significantly between GRASP + VS + KWIC and clinical cine; all visual scores were above the clinically acceptable (3.0) cutoff point. Biventricular volumetric parameters strongly correlated (R2 > 0.85) between clinical and real-time cine images reconstructed with GRASP + VS + KWIC and were in good agreement (relative error < 6% for all parameters). In adult patients, the visual scores of all categories were significantly lower (P < .05) for clinical cine compared with real-time cine with GRASP + VS + KWIC, except for noise (P = .08). Conclusion Incorporating VS and KWIC filtering into GRASP reconstruction enables ultra-high temporal resolution (approximately 20 msec) without significant loss in spatial resolution. Keywords: Cine, View Sharing, k-Space-weighted Image Contrast Filtering, Radial k-Space, Pediatrics, Arrhythmia, GRASP, Compressed Sensing, Real-Time, Free-Breathing Supplemental material is available for this article. © RSNA, 2024.

Clinical and genetic characterization of 47 Chinese pediatric patients with Pitt-Hopkins syndrome: a retrospective study.

BACKGROUND: Pitt-Hopkins syndrome (PTHS) is a neurodevelopmental disorder that remains underdiagnosed and its clinical presentations and mutation profiles in a diverse population are yet to be evaluated. This retrospective study aims to investigate the clinical and genetic characteristics of Chinese patients with PTHS. METHODS: The clinical, biochemical, genetic, therapeutic, and follow-up data of 47 pediatric patients diagnosed with PTHS between 2018 and 2021 were retrospectively analyzed. RESULTS: The Chinese PTHS patients presented with specific facial features and exhibited global developmental delay of wide severity range. The locus heterogeneity of the TCF4 gene in the patients was highlighted, emphasizing the significance of genetic studies for accurate diagnosis, albeit no significant correlations between genotype and phenotype were observed in this cohort. The study also reports the outcomes of patients who underwent therapeutic interventions, such as ketogenic diets and biomedical interventions. CONCLUSIONS: The findings of this retrospective analysis expand the phenotypic and molecular spectra of PTHS patients. The study underscores the need for a long-term prospective follow-up study to assess potential therapeutic interventions.

Impact of ambient temperature, diurnal temperature range on hyperventilation syndrome emergency admission: a time-series analysis in Beijing, China.

OBJECTIVES: To assess the association between ambient temperature and diurnal temperature range (DTR) on emergency admissions for hyperventilation syndrome (HVS). DESIGN: Distributed lag non-linear model design was used with a lag time to 5 days. SETTING: Emergency admission data used were from the Beijing Red Cross Emergency Centre (2017-2018). PARTICIPANTS AND EXPOSURE: Cases were those with emergency visits to the Beijing Emergency Center during the period 2017-2018 and who were given the primary outcome indicator defined as HVS according to the International Classification of Diseases, 10th edition code F45.303. Ambient temperature and DTR were used as exposure factors with adjustments for relative humidity, wind speed, precipitation, seasonality long-term trend and day of the week. MAIN OUTCOME MEASURE: We used the minimum emergency visits temperature as a reference to indicate the relative risk with 95% CI of exposure-response for the risk of HVS visits at different temperatures. RESULTS: A u-shape was described between ambient temperature and HVS visits, with a minimum risk at 12°C. Moderate heat (23°C) at lag (0-3) days, extreme heat at lag 0 days, had greatest relative risks on HVS visits, with 2.021 (95% CI 1.101 to 3.71) and 1.995 (95% CI 1.016 to 3.915), respectively. A stronger association between HVS visits and temperature was found in women and aged ≤44 years. Notably, the relationship between DTR and HVS visits appeared a reverse u-shaped. Low DTR (4°C) effect appeared at lag (0-1) days with 0.589 (95% CI 0.395 to 0.878), lasting until lag (0-3) days with 0.535 (95% CI 0.319 to 0.897) and was associated with a reduced risk of HVS visits in women and those aged ≤44 years. CONCLUSIONS: Ambient temperature and DTR were associated with HVS visits, appearing a differentiation in gender and age groups. Timely prevention strategies during high temperatures and control mild changes in temperature might reduce the risk of HVS.

A patient with Pitt-Hopkins syndrome with concomitant common variable immunodeficiency.

In patients with 18q deletion syndrome (18q-), immunodeficiency, autoimmunity, and allergies have been described in a subset. Pitt-Hopkins syndrome represents a specific subset of patients with 18q- who have a proximal deletion involving the TCF4 gene or a TCF4 variant. Immunodeficiency has been reported in the overall 18q- population; however, immunodeficiency with Pitt-Hopkins syndrome has not been highlighted. This case report details the immunologic evaluations and the associated infections seen in a young adult with Pitt-Hopkins syndrome to underscore the challenges of managing adults with a complex phenotype who develop frequent infections. This patient with Pitt-Hopkins syndrome ultimately fulfilled the diagnostic criteria for common variable immunodeficiency. Immunoglobulin replacement has led to a somewhat improved infection pattern, although she continues to have aspiration events leading to pneumonia. This case highlights the clinical evolution of Pitt-Hopkins syndrome and serves as a reminder that immunodeficiency can occur in this syndrome.

The acute influence of amateur boxing on dynamic cerebral autoregulation and cerebrovascular reactivity to carbon dioxide.

PURPOSE: The purpose of this study was to investigate the acute effect of head impacts, sustained over the course of three rounds of amateur boxing, on indices of cerebrovascular function. METHODS: Eighteen university amateur boxers (six female) completed three experimental trials in a randomised order; (1) three rounds of boxing (BOX), (2) an equivalent bout of pad boxing (where no blows to the head were sustained; PAD), and (3) a time-matched seated control trial (CON). Indices of cerebrovascular function were determined immediately before and 45 min after each trial. Specifically, dynamic cerebral autoregulation (dCA) was determined by considering the relationship between changes in cerebral blood velocity and mean arterial pressure during 5 min of squat-stand manoeuvres at 0.05 and 0.10 Hz. Cerebrovascular reactivity was determined using serial breath holding and hyperventilation attempts. RESULTS: Participants received an average of 40 ± 16 punches to the head during the BOX trial. Diastolic, mean and systolic dCA phase during squat stand manoeuvres at 0.05 Hz was lower after BOX compared to pre BOX (P ≤ 0.02, effect size (d) ≥ 0.74). No other alterations in dCA outcomes were observed at 0.05 or 0.10 Hz. The number of head impacts received during the BOX trial was associated with the change in systolic phase (r = 0.50, P = 0.03). No differences in cerebrovascular reactivity to breath holding or hyperventilation were observed. CONCLUSIONS: A typical bout of amateur boxing (i.e., three rounds) can subtly alter cerebral pressure-flow dynamics, and the magnitude of this change may be related to head impact exposure.

Exposure to passive heat and cold stress differentially modulates cerebrovascular-CO2 responsiveness.

Heat and cold stress influence cerebral blood flow (CBF) regulatory factors (e.g., arterial CO2 partial pressure). However, it is unclear whether the CBF response to a CO2 stimulus (i.e., cerebrovascular-CO2 responsiveness) is maintained under different thermal conditions. This study aimed to compare cerebrovascular-CO2 responsiveness between normothermia, passive heat, and cold stress conditions. Sixteen participants (8 females; 25 ± 7 yr) completed two experimental sessions (randomized) comprising normothermic and either passive heat or cold stress conditions. Middle and posterior cerebral artery velocity (MCAv, PCAv) were measured during rest, hypercapnia (5% CO2 inhalation), and hypocapnia (voluntary hyperventilation to an end-tidal CO2 of 30 mmHg). The linear slope of the cerebral blood velocity (CBv) response to changing end-tidal CO2 was calculated to measure cerebrovascular-CO2 responsiveness, and cerebrovascular conductance (CVC) was used to examine responsiveness independent of blood pressure. CBv-CVC-CO2 responsiveness to hypocapnia was greater during heat stress compared with cold stress (MCA: +0.05 ± 0.08 cm/s/mmHg/mmHg, P = 0.04; PCA: +0.02 ± 0.02 cm/s/mmHg/mmHg, P = 0.002). CBv-CO2 responsiveness to hypercapnia decreased during heat stress (MCA: -0.67 ± 0.89 cm/s/mmHg, P = 0.02; PCA: -0.64 ± 0.62 cm/s/mmHg; P = 0.01) and increased during cold stress (MCA: +0.98 ± 1.33 cm/s/mmHg, P = 0.03; PCA: +1.00 ± 0.82 cm/s/mmHg; P = 0.01) compared with normothermia. However, CBv-CVC-CO2 responsiveness to hypercapnia was not different between thermal conditions (P > 0.08). Overall, passive heat, but not cold, stress challenges the maintenance of cerebral perfusion. A greater cerebrovascular responsiveness to hypocapnia during heat stress likely reduces an already impaired cerebrovascular reserve capacity and may contribute to adverse events (e.g., syncope).NEW & NOTEWORTHY This study demonstrates that thermoregulatory-driven perfusion pressure changes, from either cold or heat stress, impact cerebrovascular responsiveness to hypercapnia. Compared with cold stress, heat stress poses a greater challenge to the maintenance of cerebral perfusion during hypocapnia, challenging cerebrovascular reserve capacity while increasing cerebrovascular-CO2 responsiveness. This likely exacerbates cerebral hypoperfusion during heat stress since hyperthermia-induced hyperventilation results in hypocapnia. No regional differences in middle and posterior cerebral artery responsiveness were found with thermal stress.

Pathogenic variants in SOX11 mimicking Pitt-Hopkins syndrome phenotype.

Pitt-Hopkins syndrome (PTHS) is a rare neurodevelopmental disorder characterised by severe intellectual disability (ID), distinctive facial features and autonomic nervous system dysfunction, caused by TCF4 haploinsufficiency. We clinically diagnosed with PTHS a 14 6/12 -year-old female, who had a normal status of TCF4. The pathogenic c.667del (p.Asp223MetfsTer45) variant in SOX11 was identified through whole exome sequencing (WES). SOX11 variants were initially reported to cause Coffin-Siris syndrome (CSS), characterised by growth restriction, moderate ID, coarse face, hypertrichosis and hypoplastic nails. However, recent studies have provided evidence that they give rise to a distinct neurodevelopmental disorder. To date, SOX11 variants are associated with a variable phenotype, which has been described to resemble CSS in some cases, but never PTHS. By reviewing both clinically and genetically 32 out of 82 subjects reported in the literature with SOX11 variants, for whom detailed information are provided, we found that 7/32 (22%) had a clinical presentation overlapping PTHS. Furthermore, we made a confirmation that overall SOX11 abnormalities feature a distinctive disorder characterised by severe ID, high incidence of microcephaly and low frequency of congenital malformations. Purpose of the present report is to enhance the role of clinical genetics in assessing the individual diagnosis after WES results.

Effects of caffeine on cerebral blood flow.

OBJECTIVE: The objective of the present study is to evaluate whether, after caffeine ingestion, there are variations in blood velocity of the middle cerebral arteries in clinically healthy young people as well as to evaluate whether this variation is dependent on the administered dose. METHODS: We used transcranial Doppler ultrasonography to record blood velocities of the middle cerebral arteries in three groups of 15 clinically healthy young adults each: no caffeine, a45 mg, and 120 mg of caffeine groups. Transcranial Doppler ultrasonography provided simultaneous bilateral velocity of the middle cerebral arteries measurements while participants performed functional tests (hyperventilation and hypoventilation orders) and three cognitive activities (test 1, short-term memory; test 2, solving a vocabulary problem; and test 3, solving a math problem) each in 31-s tests with 1-min rests between them. Participants were assessed before and 30 min after caffeine ingestion. RESULTS: There was a significant decrease in mean velocity, peak systolic velocity, end-diastolic velocity, and heart rate after high caffeine intake, except in hyperventilation, which was only observed in peak systolic velocity. With the intake of a lower dose, significant decreases were seen with hypoventilation and with test 1. In hyperventilation, there was only a significant decrease in end-diastolic velocity and heart rate; in test 2, it was found in mean velocity and peak systolic velocity; and in test 3, only in heart rate. CONCLUSION: With this study, we conclude that caffeine influences the cardiovascular system acutely, interfering with the velocity of the middle cerebral arteries, causing its decrease. We also conclude that this acute effect causes vasodilation of the cerebral arteries, more accentuated with higher doses of caffeine.

The reproducibility of breathing maneuvers as a vasoactive stimulus in the heart: an oxygenation-sensitive resonance imaging study.

BACKGROUND: Endothelial dysfunction and impaired oxygenation of the heart is a hallmark of several diseases, including coronary artery disease, hypertension, diabetes, and sleep apnea. Recent studies indicate that oxygenation-sensitive cardiovascular magnetic resonance (OS-CMR) imaging combined with breathing maneuvers may allow for assessing coronary vascular responsiveness as a marker for coronary vascular function in various clinical settings. However, despite the use of OS-CMR in evaluating tissue oxygenation, the reproducibility of these standardized, combined breathing maneuvers as a vasoactive stimulus has yet to be systematically assessed or validated. In this study, we aimed to assess the reproducibility of vasoactive breathing maneuvers to assess vascular function in a population of healthy volunteers. METHODS: Eighteen healthy volunteers were recruited for the study. Inclusion criteria were an age over 18 years and absence of any evidence or knowledge of cardiovascular, neurological, or pulmonary disease. MRI was performed on a clinical 3 T MRI system (MAGNETOM Skyra, Siemens Healthineers, Erlangen, Germany). The OS-CMR acquisition was performed as previously described (1 min hyperventilation followed by a maximal, voluntary breath-hold). Standard statistical tests were performed as appropriate. RESULTS: Data from 18 healthy subjects was analyzed. The healthy volunteers had a mean age of 42 ± 15 years and a mean BMI of 25.4 ± 2.8 kg/m2, with an average heart rate of 72 ± 11 beats per minute, and ten of whom (56%) were female. There were no significant differences between global myocardial oxygenation (%[Formula: see text] SI) after hyperventilation (HV1: - 7.82 [Formula: see text] 5.2; HV2: - 7.89 [Formula: see text] 6.4, p = 0.9) or breath-hold (BH1: 5.34 [Formula: see text] 3.1; BH2: 6.0 [Formula: see text] 3.3, p = 0.5) between the repeated breathing maneuvers. The Bland-Altman analysis showed good agreement (bias: 0.074, SD of bias: 2.93). CONCLUSION: We conclude that in healthy individuals, the myocardial oxygenation response to a standardized breathing maneuver with hyperventilation and a voluntary breath-hold is consistent and highly reproducible. These results corroborate previous evidence for breathing-enhanced OS-CMR as a robust test for coronary vascular function.

The ventilatory response to modified rebreathing is unchanged by hyperoxic severity: implications for the hyperoxic hyperventilation paradox.

Normobaric hyperoxia stimulates ventilation (V̇e) in a time- and dose-dependent manner. Whether this occurs via an oxygen (O2)-specific mechanism or secondary to carbon dioxide (CO2) retention at the central chemoreceptors remains unclear. We measured the ventilatory response to hyperoxic CO2 rebreathing with O2 clamped at increasingly higher pressures. We hypothesized that the V̇e versus Pco2 relationship is fixed and independent of Po2. On four occasions, 20 participants (10 F; mean ± SD age: 24 ± 4 yr) performed three repetitions of modified rebreathing in four, randomized, isoxic-hyperoxic conditions: mild: Po2 = 150 mmHg; moderate: Po2 = 200 mmHg; high: Po2 = 300 mmHg; and extreme: Po2 ≈ 700 mmHg. Breath-by-breath V̇e, end-tidal CO2 ([Formula: see text]), and O2 ([Formula: see text]) were measured by pneumotach and gas analyzer. For each rebreathing trial, the [Formula: see text] at which V̇e rose was identified as the ventilatory recruitment threshold (VRT, mmHg), data before VRT provided baseline V̇e (V̇eBSL, L·min-1) and the slope of the response above VRT gave central chemoreflex sensitivity (V̇eS, L·min-1·mmHg-1). For each condition, VRT, V̇eBSL, and V̇eS from like-trials were averaged, and repeated measures ANOVA assessed between-condition differences. There were no effects of [Formula: see text] on V̇eBSL (mild: 7.4 ± 4.2 L·min-1; moderate: 6.9 ± 4.2 L·min-1; high: 6.5 ± 3.7 L·min-1; extreme: 7.5 ± 2.7 L·min-1; P = 0.24), VRT (mild: 42.8 ± 3.2 mmHg; moderate: 42.5 ± 2.7 mmHg; high: 42.3 ± 2.7 mmHg; extreme: 41.8 ± 2.7 mmHg; P = 0.07), or V̇eS (mild: 4.88 ± 2.6 L·min-1·mmHg-1; moderate: 4.76 ± 2.2 L·min-1·mmHg-1; high: 4.81 ± 2.3 L·min-1·mmHg-1; extreme: 4.39 ± 1.9 L·min-1·mmHg-1; P = 0.41). The V̇e-Pco2 relationship is unaltered across a range of mild to extreme Po2. Brief exposure to normobaric hyperoxia may not independently stimulate breathing nor does it alter central chemoreflex sensitivity.NEW & NOTEWORTHY Normobaric hyperoxia stimulates ventilation (V̇e) in a time- and dose-dependent manner. Whether this occurs directly or indirectly through heightened central carbon dioxide pressure (Pco2) or via central chemoreflex sensitization is unclear. Participants who performed modified rebreathing at high oxygen pressures (Po2) of 150, 200, 300, and ≈700 mmHg exhibited no changes to their ventilatory responses to Pco2. Brief exposure to normobaric hyperoxia may not independently stimulate breathing nor does it alter central chemoreflex sensitivity.