Supersensitivity Psychosis with Acute Dystonia.

Introduction: Supersensitivity psychosis is a phenomenon that occurs with chronic usage of antipsychotics secondary to treatment resistance. At this time, there are no standardized guidelines regarding the management of supersensitivity psychosis. Case Presentation: We present a case of a patient with schizoaffective disorder who developed supersensitivity psychosis and acute dystonia in response to discontinuing psychotropic medications, including high-dose quetiapine and olanzapine. The patient presented with excessive anxiety, paranoia, bizarre thoughts, and generalized dystonia affecting the face, trunk, and extremities. We treated the patient with olanzapine, valproic acid, and diazepam, which alleviated the psychosis back to baseline and significantly improved the dystonia. Despite compliance, the patient returned for inpatient stabilization due to depressive symptoms and worsening of the dystonia. During the second admission, the patient required further modification of psychotropics and supplemental electroconvulsive therapy. Conclusion: In this paper, we discuss the proposed treatment of supersensitivity psychosis, including the role that electroconvulsive therapy may play in alleviating supersensitivity psychosis and associated movement disorders. We hope to expand the knowledge of additional neuromotor manifestations in supersensitivity psychosis and the management of this unique presentation.

Mismatched opioid prescription in patients discharged after neurological surgeries: a retrospective cohort study.

ABSTRACT: Although postsurgical overprescription has been well-studied, postsurgical opioid underprescription remains largely overlooked. This retrospective cohort study was to investigate the extent of discharge opioid overprescription and underprescription in patients after neurological surgeries. Six thousand nine hundred forty-nine adult opioid-naive patients who underwent inpatient neurosurgical procedures at the University of California San Francisco were included. The primary outcome was the discrepancy between individual patient's prescribed daily oral morphine milligram equivalent (MME) at discharge and patient's own inpatient daily MME consumed within 24 hours of discharge. Analyses include Wilcoxon, Mann-Whitney, Kruskal-Wallis, and χ 2 tests, and linear or multivariable logistic regression. 64.3% and 19.5% of patients were opioid overprescribed and underprescribed, respectively, with median prescribed daily MME 360% and 55.2% of median inpatient daily MME in opioid overprescribed and underprescribed patients, respectively. 54.6% of patients with no inpatient opioid the day before discharge were opioid overprescribed. Opioid underprescription dose-dependently increased the rate of opioid refill 1 to 30 days after discharge. From 2016 to 2019, the percentage of patients with opioid overprescription decreased by 24.8%, but the percentage of patients with opioid underprescription increased by 51.2%. Thus, the mismatched discharge opioid prescription in patients after neurological surgeries presented as both opioid overprescription and underprescription, with a dose-dependent increased rate of opioid refill 1 to 30 days after discharge in opioid underprescription. Although we are fighting against opioid overprescription to postsurgical patients, we should not ignore postsurgical opioid underprescription.

Does surgery for metastatic spinal tumors improve functional outcomes in patients without spinal cord compression but with potentially unstable spines (SINS 7-12)?

OBJECTIVE: In the absence of spinal cord compression, it is unclear if surgery is more effective than radiation treatment for improving functional outcomes in metastatic spinal tumor patients with potentially unstable spines. The authors compared functional status outcomes assessed with Karnofsky Performance Status (KPS) and Eastern Cooperative Oncology Group (ECOG) scores after surgery or radiation in patients without spinal cord compression with Spine Instability Neoplastic Score (SINS) values of 7-12 indicating possible instability (SINS 7-12). METHODS: A retrospective review was performed of patients with metastatic spinal tumor SINS values of 7-12 at a single institution between 2004 and 2014. Patients were divided into two different groups: 1) those treated with surgery and 2) those treated with radiation. Baseline clinical characteristics were measured, and KPS and ECOG scores were obtained pre- and postradiation or postsurgery. The paired, nonparametric Wilcoxon signed-rank test and ordinal logistic regression analysis were used for statistical analysis. RESULTS: A total of 162 patients met inclusion criteria; 63 patients were treated operatively and 99 patients were treated with radiation. The mean follow-up was 1.9 years, with a median of 1.1 years for the surgical cohort (ranging from 2.5 months to 13.8 years) and a mean of 2 years with a median of 0.8 years for the radiation cohort (ranging from 2 months to 9.3 years). After covariates were accounted for, the average posttreatment changes in KPS scores in the surgical cohort were 7.46 ± 17.3 and in the radiation cohort were -2 ± 13.6 (p = 0.045). No significant difference was observed in ECOG scores. KPS scores improved postoperatively in 60.3% of patients in the surgical group and postradiation in 32.3% of patients in the radiation cohort (p < 0.001). Subanalysis within the radiation cohort revealed no differences in fracture rates or local control between patients treated with external-beam radiation therapy versus stereotactic body radiation therapy. In patients initially treated with radiation, 21.2% eventually developed compression fractures at a treated level. Five of the 99 patients in the radiation cohort-all of whom had a fracture-eventually underwent either methyl methacrylate augmentation or instrumented fusion. CONCLUSIONS: Patients with SINS values of 7-12 who underwent surgery had greater improvement in KPS scores-but not in ECOG scores-than patients undergoing radiation alone. In patients treated with radiation, treatment was converted to a procedural intervention such as surgery only in patients who sustained fractures. Of the patients with fractures after radiation (21 of 99), 5 patients underwent an invasive procedure and 16 did not.

Wound complications in metastatic spine tumor patients with and without preoperative radiation.

OBJECTIVE: Wound complications are a common adverse event following metastatic spine tumor surgery. Some patients with spinal metastases may first undergo radiation but eventually require spinal surgery because of either cord compression or instability. The authors compared wound complication rates in patients who had undergone surgery for metastatic disease and received preoperative radiation treatments, postoperative radiation, or no radiation. METHODS: Records from patients treated at the University of California, San Francisco, for metastatic spine disease between 2005 and 2017 were retrospectively reviewed. Baseline characteristics were collected, including preoperative Karnofsky Performance Status (KPS), Spine Instability Neoplastic Score, total radiation dose, indication for surgery, diabetes status, time between radiation and surgery, use of perioperative chemotherapy or steroids, estimated blood loss, extent of fusion, and preoperative albumin level. Wound complication was defined as poor healing, dehiscence, or infection per the Centers for Disease Control and Prevention guidelines, within 6 months of surgery. One-way ANOVA was used to compare means across groups. Cumulative incidence analysis with competing risk methodology was used to adjust for risk of death during follow-up. Statistical analysis was performed using R software. RESULTS: Two hundred five patients with adequate medical records were identified. Seventy patients had received preoperative radiation, 74 had received postoperative radiation within 6 months after surgery, and 61 had received no radiation at the surgical site. Wound complication rates were similar across the 3 cohorts: 14.3% (n = 10) in the group with preoperative radiation, 10.8% (n = 8) in the group that received postoperative radiation, and 11.5% (n = 7) in the group with no radiation (p = 0.773). Competing risk analysis showed a higher cumulative incidence of wound complications for the preoperative cohort, though this difference was not significant (p = 0.46). Overall, 89 patients were treated with external beam radiation therapy (EBRT), whereas 55 received stereotactic body radiation therapy (SBRT). There was no significant difference in wound complications for patients treated with EBRT (11.2%, n = 10) versus SBRT (14.5%, n = 8; p = 0.825). KPS was the only factor correlated with wound complications on univariate analysis (p = 0.03). CONCLUSIONS: Wound complication rates did not differ across the 3 cohorts: patients treated with preoperative radiation, postoperative radiation within 6 months of surgery, or no radiation. The effect size was small for KPS and likely does not represent a clinically significant predictor of wound complications.

Psychometric properties of the CEMA-A questionnaire: motives for lying.

Previous research on the motives for lying lacks factorial models that allow grouping of motives into specific categories. The objective of this study is to confirm the factorial structure of the questionnaire of motives for lying (CEMA-A). Participants were 1,722 adults residing in the Canary Islands (Spain) who completed the CEMA-A and the Eysenck Personality Questionnaire (EPQ-R). The four-dimensional structure of the questionnaire was confirmed (χ2 = 1460.97, df = 325, p = 0.001; CFI = 0.94; TLI = 0.93; NFI = 0.93; NNFI = 0.93; RMSEA = 0.05, CI = 0.051-0.057; SRMR = 0.04). The four factors of the CEMA-A were Intrapersonal Motivation-Emotionality, Interpersonal Motivation-Sociability, Egoism/Hardness Motivation, and Malicious Motivation, with an internal consistency between 0.79 and 0.91. Invariance analyses confirmed the equivalence of the instrument for men and women. The CEMA-A factors positively correlated with Neuroticism and Psychoticism, and negatively with Dissimulation. Extraversion was not related to any of the factors, and only displayed a low negative correlation with Intrapersonal Motivation-Emotionality. Analysis of variance showed that men scored higher in Egoism/Hardness and Malicious Motivation. The CEMA-A has proven capable of apprehending the motives for lying and has adequate psychometric criteria for use in various populations.

Simultaneous Schlieren-Shadowgraph Visualization and Temperature Measurement Fields of Fluid Flow Using One Color CCD Camera.

Visualizing two variables in the fluid flow requires a complex optical system to fulfill such a purpose. Furthermore, in these applications, measuring the temperature fields of the fluid is sometimes necessary. In this work, we use a color digital camera to record in one snapshot shadowgraph and two direction sensitivity Schlieren images. Furthermore, the Schlieren images obtained are used to measure temperature fields. The optical system, as main components, employs an rgb Light Emitting Diode (LED), two knife edges represented by shortpass and longpass ultra-thin filters, and a color digital camera. The results of this study show that shadowgraph images are contaminated with the crosstalk effect, and correction against it was applied. On the other hand, the reached resolution of the optical system to measure temperature values is approximately one degree.

Adjacent Segment Vertebral Body Bone Density Changes as Measured By Hounsfield Units After Lumbar Spine Fusion.

OBJECTIVE: We sought to evaluate Hounsfield units (HU) at the adjacent segment after single-level transforaminal lumbar interbody fusion (TLIF) with preoperative and postoperative computed tomography scans. METHODS: We performed a retrospective study on a series of patients who underwent L4-5 TLIF, from 2007 to 2017, by 3 spine surgeons at our institution. One-hundred and forty-three total patients were identified, and 41 patients with minimum 1-year follow-up met inclusion criteria. HU values were measured on preoperative and postoperative computed tomography at the adjacent L3 segment and at L1 as a control arm. Lumbar lordosis, pelvic tilt, pelvic incidence, sacral slope, and sagittal vertical axis were also collected preoperatively and postoperatively. RESULTS: Mean preoperative HU value at L3 did not differ from the postoperative value (134.11 ± 47.14 mg/cm3 vs. 141.21 ± 55.14 mg/cm3, P = 0.34). Similarly, the mean preoperative HU value at the L1 control level region of interest did not differ from the postoperative value (150.17 ± 53.91 mg/cm3 vs. 145.78 ± 58.34 mg/cm3, P = 0.634). The interrater reliability of HU measurements was satisfactory with a resulting intraclass correlation coefficient of 0.76. CONCLUSIONS: As measured by HU, we did not observe a change in bone density or other signs of adjacent segment disease at the L3 vertebral body 12 months after L4-5 TLIF. Spinopelvic parameters were not shown to be correlated with HU changes.

Evaluación de estrategias para la indicación de instrucciones postoperatorias en exodoncia: Estudio clínico aleatorizado. Primera etapa / An evaluation of strategies for postoperative indications in tooth extraction: A randomised clinical trial. First Stage

Introducción: la exodoncia presenta diversos factores que influyen en el éxito del período postoperatorio. El aprendizaje de las indicaciones postoperatorias ha evidenciado influir en la morbilidad, complicaciones y calidad de vida del paciente durante sus cuidados postoperatorios. Sin embargo, la estrategia de aprendizaje convencional para entregar las instrucciones postoperatorias verbal-escrita (VE) no toma en cuenta el posible compromiso cognitivo, psicológico y emocional del individuo, realizando una entrega de instrucciones indiferente al estado del paciente. Materiales y métodos: los pacientes serán asignados aleatoriamente a grupos divididos según estrategia de aprendizaje utilizada: convencional VE y psicopedagógica visual, auditiva y kinésica (VAK). Inmediatamente posterior al procedimiento se realizará la explicación de los cuidados postoperatorios según grupo. Se realizará una encuesta inmediatamente posterior a la entrega de instrucciones, luego a las 24 horas y a los 7 días luego de la cirugía, con el objetivo de evaluar el grado de retención. Finalmente, para comparar, se contrastaron las medias de cada grupo en los tres tiempos de aplicación. Resultados: se observa una media mayor en el grupo VAK, visible en todos los tiempos de aplicación, donde observamos una tendencia a presentar mejores niveles de retención. Diferencias aun no estadísticamente significativas, ya que la muestra aún no representa el total del muestreo calculado. Discusión: los resultados preliminares nos muestran que la estrategia visual-kinésica-auditiva es superior a la convencional en cuanto a nivel de retención, lo cual podría convertirla en un método de elección al momento de entregar indicaciones post exodoncia, para tener un resultado postoperatorio óptimo.

Introduction: Tooth extractions present several factors that affect the success of the postoperative period. The correct learning of the postoperative instructions has shown to affect the morbidity, complications, and quality of life of the patient after the surgery. Neverthe-less, the conventional verbal-written (VW) learning strategy to give the postoperative indications doesn't consider the possible cognitive, psychological and emotional compromise of the patient. Methods: The patients were assigned randomly into two groups, according to the learning strategy used: conventional (VW) and a psycho-pedagogical visual, auditive, and kinesic learning strategy (VAK). After extraction, the patients were explained about the postoperative care, according to the group they belonged to. A survey was conducted immediately, one day, and seven days after the procedure to record the grade of retention of the information. The means of each group were compared. Results: A higher mean was observed in the VAK group, which is visible in all the application times, determining a tendency to present better levels of retention of the information. The differences are not yet statistically significant, as the sample does not represent the total of patients previously considered. Discussion: The preliminary results show that the VAK strategy is superior to the conventional one regarding the level of retention of the information, becoming the method of choice when giving postoperative indications after dental extractions to develop a more optimal postoperative result

Omeprazole-induced Visual Hallucinations: A Case Report.

Proton pump inhibitors (PPIs) are medications that are frequently prescribed for gastroesophageal reflux disease. However, a few case reports have described neuropsychiatric symptoms following PPI use. In this report, we present a case of visual hallucinations secondary to PPI usage and propose possible mechanisms. In this case, a 65-year-old man with no psychiatric history developed acute visual hallucinations following initiation of omeprazole, in the absence of delusions, paranoia, and other psychotic symptoms. The visual hallucinations began after the patient started treatment with omeprazole and resolved almost immediately upon discontinuation of omeprazole. To treat symptoms of gastroesophageal reflux disease, omeprazole was replaced with famotidine, and the visual hallucinations did not recur after the omeprazole had been discontinued. No other psychotic signs or symptoms were present in this patient throughout the duration of his hospitalization. Although the scientific literature provides limited information on psychosis related to PPI use, a growing number of case reports and studies in recent years have suggested that neuropsychiatric symptoms may occur after PPI use. It is our hope that this case report adds to the scientific and medical knowledge in this area.

An analysis of tumor-related potential spinal column instability (Spine Instability Neoplastic Scores 7-12) eventually requiring surgery with a 1-year follow-up.

OBJECTIVE: Within the Spine Instability Neoplastic Score (SINS) classification, tumor-related potential spinal instability (SINS 7-12) may not have a clear treatment approach. The authors aimed to examine the proportion of patients in this indeterminate zone who later required surgical stabilization after initial nonoperative management. By studying this patient population, they sought to determine if a clear SINS cutoff existed whereby the spine is potentially unstable due to a lesion and would be more likely to require stabilization. METHODS: Records from patients treated at the University of California, San Francisco, for metastatic spine disease from 2005 to 2019 were retrospectively reviewed. Seventy-five patients with tumor-related potential spinal instability (SINS 7-12) who were initially treated nonoperatively were included. All patients had at least a 1-year follow-up with complete medical records. A univariate chi-square test and Student t-test were used to compare categorical and continuous outcomes, respectively, between patients who ultimately underwent surgery and those who did not. A backward likelihood multivariate binary logistic regression model was used to investigate the relationship between clinical characteristics and surgical intervention. Recursive partitioning analysis (RPA) and single-variable logistic regression were performed as a function of SINS. RESULTS: Seventy-five patients with a total of 292 spinal metastatic sites were included in this study; 26 (34.7%) patients underwent surgical intervention, and 49 (65.3%) did not. There was no difference in age, sex, comorbidities, or lesion location between the groups. However, there were more patients with a SINS of 12 in the surgery group (55.2%) than in the no surgery group (44.8%) (p = 0.003). On multivariate analysis, SINS > 11 (OR 8.09, CI 1.96-33.4, p = 0.004) and Karnofsky Performance Scale (KPS) score < 60 (OR 0.94, CI 0.89-0.98, p = 0.008) were associated with an increased risk of surgery. KPS score was not correlated with SINS (p = 0.4). RPA by each spinal lesion identified an optimal cutoff value of SINS > 10, which were associated with an increased risk of surgical intervention. Patients with a surgical intervention had a higher incidence of complications on multivariable analysis (OR 2.96, CI 1.01-8.71, p = 0.048). CONCLUSIONS: Patients with a mean SINS of 11 or greater may be at increased risk of mechanical instability requiring surgery after initial nonoperative management. RPA showed that patients with a KPS score of 60 or lower and a SINS of greater than 10 had increased surgery rates.

Are preoperative chlorhexidine gluconate showers associated with a reduction in surgical site infection following craniotomy? A retrospective cohort analysis of 3126 surgical procedures.

OBJECTIVE: Surgical site infection (SSI) is a complication linked to increased costs and length of hospital stay. Prevention of SSI is important to reduce its burden on individual patients and the healthcare system. The authors aimed to assess the efficacy of preoperative chlorhexidine gluconate (CHG) showers on SSI rates following cranial surgery. METHODS: In November 2013, a preoperative CHG shower protocol was implemented at the authors' institution. A total of 3126 surgical procedures were analyzed, encompassing a time frame from April 2012 to April 2016. Cohorts before and after implementation of the CHG shower protocol were evaluated for differences in SSI rates. RESULTS: The overall SSI rate was 0.6%. No significant differences (p = 0.11) were observed between the rate of SSI of the 892 patients in the preimplementation cohort (0.2%) and that of the 2234 patients in the postimplementation cohort (0.8%). Following multivariable analysis, implementation of preoperative CHG showers was not associated with decreased SSI (adjusted OR 2.96, 95% CI 0.67-13.1; p = 0.15). CONCLUSIONS: This is the largest study, according to sample size, to examine the association between CHG showers and SSI following craniotomy. CHG showers did not significantly alter the risk of SSI after a cranial procedure.

Vertebral body fracture rates after stereotactic body radiation therapy compared with external-beam radiation therapy for metastatic spine tumors.

OBJECTIVE: Stereotactic body radiation therapy (SBRT) is utilized to deliver highly conformal, dose-escalated radiation to a target while sparing surrounding normal structures. Spinal SBRT can allow for durable local control and palliation of disease while minimizing the risk of damage to the spinal cord; however, spinal SBRT has been associated with an increased risk of vertebral body fractures. This study sought to compare the fracture rates between SBRT and conventionally fractionated external-beam radiation therapy (EBRT) in patients with metastatic spine tumors. METHODS: Records from patients treated at the University of California, San Francisco, with radiation therapy for metastatic spine tumors were retrospectively reviewed. Vertebral body fracture and local control rates were compared between SBRT and EBRT. Ninety-six and 213 patients were identified in the SBRT and EBRT groups, respectively. Multivariate analysis identified the need to control for primary tumor histology (p = 0.003 for prostate cancer, p = 0.0496 for renal cell carcinoma). The patient-matched EBRT comparison group was created by matching SBRT cases using propensity scores for potential confounders, including the Spinal Instability Neoplastic Score (SINS), the number and location of spine levels treated, sex, age at treatment, duration of follow-up (in months) after treatment, and primary tumor histology. Covariate balance following group matching was confirmed using the Student t-test for unequal variance. Statistical analysis, including propensity score matching and multivariate analysis, was performed using R software and related packages. RESULTS: A total of 90 patients met inclusion criteria, with 45 SBRT and 45 EBRT matched cases. Balance of the covariates, SINS, age, follow-up time, and primary tumor histology after the matching process was confirmed between groups (p = 0.062, p = 0.174, and 0.991, respectively, along with matched tumor histology). The SBRT group had a higher 5-year rate of vertebral body fracture at 22.22% (n = 10) compared with 6.67% (n = 3) in the EBRT group (p = 0.044). Survival analysis was used to adjust for uneven follow-up time and showed a significant difference in fracture rates between the two groups (p = 0.044). SBRT also was associated with a higher rate of local control (86.67% vs 77.78%). CONCLUSIONS: Patients with metastatic cancer undergoing SBRT had higher rates of vertebral body fractures compared with patients undergoing EBRT, and this difference held up after survival analysis. SBRT also had higher rates of initial local control than EBRT but this difference did not hold up after survival analysis, most likely because of a high percentage of radiosensitive tumors in the EBRT cohort.

Preliminary results of anterior lumbar interbody fusion, anterior column realignment for the treatment of sagittal malalignment.

OBJECTIVE Sagittal malalignment decreases patients' quality of life and may require surgical correction to achieve realignment goals. High-risk posterior-based osteotomy techniques are the current standard treatment for addressing sagittal malalignment. More recently, anterior lumbar interbody fusion, anterior column realignment (ALIF ACR) has been introduced as an alternative for correction of sagittal deformity. The objective of this paper was to report clinical and radiographic results for patients treated using the ALIF-ACR technique. METHODS A retrospective study of 39 patients treated with ALIF ACR was performed. Patient demographics, operative details, radiographic parameters, neurological assessments, outcome measures, and preoperative, postoperative, and mean 1-year follow-up complications were studied. RESULTS The patient population comprised 39 patients (27 females and 12 males) with a mean follow-up of 13.3 ± 4.7 months, mean age of 66.1 ± 11.6 years, and mean body mass index of 27.3 ± 6.2 kg/m2. The mean number of ALIF levels treated was 1.5 ± 0.5. Thirty-three (84.6%) of 39 patients underwent posterior spinal fixation and 33 (84.6%) of 39 underwent posterior column osteotomy, of which 20 (60.6%) of 33 procedures were performed at the level of the ALIF ACR. Pelvic tilt, sacral slope, and pelvic incidence were not statistically significantly different between the preoperative and postoperative periods and between the preoperative and 1-year follow-up periods (except for PT between the preoperative and 1-year follow-up, p = 0.018). Sagittal vertical axis, T-1 spinopelvic inclination, lumbar lordosis, pelvic incidence-lumbar lordosis mismatch, intradiscal angle, and motion segment angle all improved from the preoperative to postoperative period and the preoperative to 1-year follow-up (p < 0.05). The changes in motion segment angle and intradiscal angle achieved in the ALIF-ACR group without osteotomy compared with the ALIF-ACR group with osteotomy at the level of ACR were not statistically significant. Total visual analog score, Oswestry Disability Index, and Scoliosis Research Society-22 scores all improved from preoperative to postoperative and preoperative to 1-year follow-up. Fourteen patients (35.9%) experienced 26 complications (15 major and 11 minor). Eleven patients required reoperation. The most common complication was proximal junctional kyphosis (6/26 complications, 23%) followed by vertebral body/endplate fracture (3/26, 12%). CONCLUSIONS This study showed satisfactory radiographic and clinical outcomes at the 1-year follow-up. Proximal junctional kyphosis was the most common complication followed by fracture, complications that are commonly associated with sagittal realignment surgery and may not be mitigated by the anterior approach.

Beneficial neurocognitive effects of transcranial laser in older adults.

Transcranial infrared laser stimulation (TILS) at 1064 nm, 250 mW/cm2 has been proven safe and effective for increasing neurocognitive functions in young adults in controlled studies using photobiomodulation of the right prefrontal cortex. The objective of this pilot study was to determine whether there is any effect from TILS on neurocognitive function in older adults with subjective memory complaint at risk for cognitive decline (e.g., increased carotid artery intima-media thickness or mild traumatic brain injury). We investigated the cognitive effects of TILS in older adults (ages 49-90, n = 12) using prefrontal cortex measures of attention (psychomotor vigilance task (PVT)) and memory (delayed match to sample (DMS)), carotid artery intima-media thickness (measured by ultrasound), and evaluated the potential neural mechanisms mediating the cognitive effects of TILS using exploratory brain studies of electroencephalography (EEG, n = 6) and functional magnetic resonance imaging (fMRI, n = 6). Cognitive performance, age, and carotid artery intima-media thickness were highly correlated, but all participants improved in all cognitive measures after TILS treatments. Baseline vs. chronic (five weekly sessions, 8 min each) comparisons of mean cognitive scores all showed improvements, significant for PVT reaction time (p < 0.001), PVT lapses (p < 0.001), and DMS correct responses (p < 0.05). The neural studies also showed for the first time that TILS increases resting-state EEG alpha, beta, and gamma power and promotes more efficient prefrontal blood-oxygen-level-dependent (BOLD)-fMRI response. Importantly, no adverse effects were found. These preliminary findings support the use of TILS for larger randomized clinical trials with this non-invasive approach to augment neurocognitive function in older people to combat aging-related and vascular disease-related cognitive decline.

Erythropoietin and Soluble Erythropoietin Receptor: A Role for Maternal Vascular Adaptation to High-Altitude Pregnancy.

Context: An imbalance of proangiogenic and antiangiogenic factors is thought to induce the widespread vascular dysfunction characteristic of preeclampsia (PreE). Erythropoietin (Epo), a pleiotropic cytokine, has important angiogenic and vasoactive properties; however, its contribution to maternal vascular dysfunction in PreE is unknown. Objectives: Because high altitude (HA) raises the incidence of PreE, we asked whether HA increased maternal Epo and soluble Epo receptor (sEpoR) levels and whether such effects differed between PreE and normotensive controls at HA. Design, Setting, and Participants: Longitudinal studies were conducted in pregnant Andean residents at HA (n = 28; 3600 m) or sea level (SL; n = 16; 300 m). Cross-sectional studies included 34 gestational age‒matched Andean PreE cases (n = 17) and controls (n = 17) in La Paz-El Alto, Bolivia (3600 to 4100 m). Results: HA augmented the pregnancy-associated rise in Epo relative to SL (P = 0.002), despite similar reductions in hemoglobin (Hb) across pregnancy at each altitude (7% to 9%, P < 0.001 for both). HA PreE cases had circulating Epo levels equivalent to those of controls but greater sEpoR (P < 0.05) and reduced Hb (P = 0.06, trend). Conclusion(s): Our findings suggest that an augmented pregnancy-associated rise in Epo may be important for successful vascular adaptation to pregnancy at HA. We further speculate that the elevated sEpoR observed in PreE vs controls at HA impedes the effect of Epo to maintain endothelial function and may, in turn, be of pathological relevance for PreE at HA.

Unique DNA Methylation Patterns in Offspring of Hypertensive Pregnancy.

Epigenomic processes are believed to play a pivotal role for the effect of environmental exposures in early life to modify disease risk throughout the lifespan. Offspring of women with hypertensive complications of pregnancy (HTNPREG ) have an increased risk of developing systemic and pulmonary vascular dysfunction in adulthood. In this preliminary report, we sought to determine whether epigenetic modifications of genes involved in the regulation of vascular function were present in HTNPREG offspring. We contrasted DNA methylation and gene expression patterns of peripheral blood mononuclear cells obtained from young male offspring of HTNPREG (n = 5) to those of normotensive controls (n = 19). In HTNPREG offspring we identified six differentially methylated regions (DMRs) including three genes (SMOC2, ARID1B and CTRHC1) relevant to vascular function. The transcriptional activity of ARID1B and CTRCH1 was inversely related to methylation status. HTNPREG offspring had higher systolic pulmonary artery pressure (sPPA ) versus controls. Our findings demonstrate that epigenetic marks are altered in offspring of HTNPREG with a modest elevation of sPPA and introduce novel epigenomic targets for further study. On the basis of these findings we speculate that epigenomic mechanisms may be involved in mediating the effect of HTNPREG to raise the risk of vascular disease later in life.

Perinatal hypoxia increases susceptibility to high-altitude polycythemia and attendant pulmonary vascular dysfunction.

Perinatal exposures exert a profound influence on physiological function, including developmental processes vital for efficient pulmonary gas transfer throughout the lifespan. We extend the concept of developmental programming to chronic mountain sickness (CMS), a debilitating syndrome marked by polycythemia, ventilatory impairment, and pulmonary hypertension that affects ∼10% of male high-altitude residents. We hypothesized that adverse perinatal oxygenation caused abnormalities of ventilatory and/or pulmonary vascular function that increased susceptibility to CMS in adulthood. Subjects were 67 male high-altitude (3,600-4,100 m) residents aged 18-25 yr with excessive erythrocytosis (EE, Hb concentration ≥18.3 g/dl), a preclinical form of CMS, and 66 controls identified from a community-based survey (n = 981). EE subjects not only had higher Hb concentrations and erythrocyte counts, but also lower alveolar ventilation, impaired pulmonary diffusion capacity, higher systolic pulmonary artery pressure, lower pulmonary artery acceleration time, and more frequent right ventricular hypertrophy, than controls. Compared with controls, EE subjects were more often born to mothers experiencing hypertensive complications of pregnancy and hypoxia during the perinatal period, with each increasing the risk of developing EE (odds ratio = 5.25, P = 0.05 and odds ratio = 6.44, P = 0.04, respectively) after other factors known to influence EE status were taken into account. Adverse perinatal oxygenation is associated with increased susceptibility to EE accompanied by modest abnormalities of the pulmonary circulation that are independent of increased blood viscosity. The association between perinatal hypoxia and EE may be due to disrupted alveolarization and microvascular development, leading to impaired gas exchange and/or pulmonary hypertension.

Neonatal oxygenation, pulmonary hypertension, and evolutionary adaptation to high altitude (2013 Grover Conference series).

Andeans and Tibetans have less altitude reduction in birth weight than do shorter-resident groups, but only Tibetans are protected from pulmonary hypertension and chronic mountain sickness (CMS). We hypothesized that differences in neonatal oxygenation were involved, with arterial O2 saturation (SaO2) being highest in Tibetans, intermediate in Andeans, and lowest in Han or Europeans, and that improved oxygenation in Andeans relative to Europeans was accompanied by a greater postnatal decline in systolic pulmonary arterial pressures (Ppasys ). We studied 41 healthy (36 Andeans, 5 Europeans) and 9 sick infants at 3,600 m in Bolivia. The SaO2 in healthy babies was highest at 6-24 hours of postnatal age and then declined, whereas sick babies showed the opposite pattern. Compared to that of 30 Tibetan or Han infants studied previously at 3,600 m, SaO2 was higher in Tibetans than in Han or Andeans during wakefulness and active or quiet sleep. Tibetans, as well as Andeans, had higher values than Han while feeding. The SaO2's of healthy Andeans and Europeans were similar and, like those of Tibetans, remained at 85% or above, whereas Han values dipped below 70%. Andean and European Ppasys values were above sea-level norms and higher in sick than in healthy babies, but right heart pressure decreased across 4-6 months in all groups. We concluded that Tibetans had better neonatal oxygenation than Andeans at 3,600 m but that, counter to our hypothesis, neither was SaO2 higher nor Ppa lower in Andean than in European infants. Further, longitudinal studies in these 4 groups are warranted to determine whether neonatal oxygenation influences susceptibility to high-altitude pulmonary hypertension and CMS later in life.

Uterine artery blood flow, fetal hypoxia and fetal growth.

Evolutionary trade-offs required for bipedalism and brain expansion influence the pregnancy rise in uterine artery (UtA) blood flow and, in turn, reproductive success. We consider the importance of UtA blood flow by reviewing its determinants and presenting data from 191 normotensive (normal, n = 125) or hypertensive (preeclampsia (PE) or gestational hypertension (GH), n = 29) Andean residents of very high (4100-4300 m) or low altitude (400 m, n = 37). Prior studies show that UtA blood flow is reduced in pregnancies with intrauterine growth restriction (IUGR) but whether the IUGR is due to resultant fetal hypoxia is unclear. We found higher UtA blood flow and Doppler indices of fetal hypoxia in normotensive women at high versus low altitude but similar fetal growth. UtA blood flow was markedly lower in early-onset PE versus normal high-altitude women, and their fetuses more hypoxic as indicated by lower fetal heart rate, Doppler indices and greater IUGR. We concluded that, despite greater fetal hypoxia, fetal growth was well defended by higher UtA blood flows in normal Andeans at high altitude but when compounded by lower UtA blood flow in early-onset PE, exaggerated fetal hypoxia caused the fetus to respond by decreasing cardiac output and redistributing blood flow to help maintain brain development at the expense of growth elsewhere. We speculate that UtA blood flow is not only an important supply line but also a trigger for stimulating the metabolic and other processes regulating feto-placental metabolism and growth. Studies using the natural laboratory of high altitude are valuable for identifying the physiological and genetic mechanisms involved in human reproductive success.