The Association between Proton Pump Inhibitors and the Effectiveness of CDK Inhibitors in HR+/HER- Advanced Breast Cancer Patients: A Systematic Review and Meta-Analysis.

There have been many clinical questions regarding whether the use of proton pump inhibitors (PPIs) could deteriorate the effects of cyclin-dependent kinase inhibitors (CDKIs) in HR+/HER2- advanced breast cancer patients. We performed a systematic review and meta-analysis of this clinical question, including studies enrolling HR+/HER2- metastatic breast cancer patients treated with CDKIs (Palbociclib or Ribociclib) and reporting at least one comparative survival outcome, either overall survival (OS) or progression-free survival (PFS), between concomitant PPI users and non-users. Eight studies met the eligibility criteria, with a total of 2584 patients included (PPI users: 830, PPI non-users: 1754), demonstrating that concomitant PPI use was associated with significantly higher risks of all-cause mortality (HR = 2.03; 95% CI, 1.49 to 2.77; I2 = 0%) and disease progression (HR = 1.75; 95% CI, 1.26 to 2.43; I2 = 59%) in breast cancer patients taking Palbociclib. In contrast, there were no significant survival impacts of PPIs on Ribociclib (HR = 1.46; 95% CI, 0.91 to 2.34; I2 = 36%). Additionally, there was no significant difference in the risk associated with CDKI dose reduction due to drug toxicity (RR = 1.12; 95% CI, 0.97 to 1.29). Therefore, when HR+/HER2- advanced breast cancer patients require the use of PPIs, it may be reasonable to consider using Ribociclib.

Minimally Invasive Surgical Treatment of Extensive Spinal Epidural Abscess With Unilateral Laminotomy for Bilateral Decompression Using an Ultrasonic Bone Curette: A Technique Note.

BACKGROUND: An extensive spinal epidural abscess is a devasting infection of the multiple-level epidural space. Emergent surgical decompression is required to remove the abscess and decompress the affected spinal cord. This study evaluated the efficacy of unilateral laminotomy for bilateral decompression (ULBD) in the treatment of extensive spinal epidural abscesses. METHODS: Three patients with extensive spinal epidural abscesses (epidural abscess involving more than 5 vertebral levels) were treated with the ULBD technique between September 2019 and August 2020. An ultrasonic curette was used for over-the-top decompression. Surgical drainage of the epidural abscess was performed concurrently with sublaminar drilling on top of the dura sac by using cold saline to automatically maintain the effluent in the ultrasonic curettage device. RESULTS: The 3 patients were men, with a mean age of 65.7 years. Diabetes mellitus, fever, and paraplegia were reported in all 3 patients. Escherichia coli, Staphylococcus aureus, and Streptococcus intermedius were cultured separately. The mean operative time was 163 minutes, and the mean estimated blood loss was 160 mL. All patients fully recovered from neurologic deficits and returned to preinjury levels of functioning at the final follow-up. CONCLUSIONS: As a minimally invasive technique, ULBD is a safe and effective treatment for extensive spinal epidural abscesses in critically ill patients. Moreover, the use of an ultrasonic bone curette not only safely accelerates over-the-top decompression but also flushes the epidural abscess with copious amount of cold saline.

The Accuracy of Artificial Intelligence in the Endoscopic Diagnosis of Early Gastric Cancer: Pooled Analysis Study.

BACKGROUND: Artificial intelligence (AI) for gastric cancer diagnosis has been discussed in recent years. The role of AI in early gastric cancer is more important than in advanced gastric cancer since early gastric cancer is not easily identified in clinical practice. However, to our knowledge, past syntheses appear to have limited focus on the populations with early gastric cancer. OBJECTIVE: The purpose of this study is to evaluate the diagnostic accuracy of AI in the diagnosis of early gastric cancer from endoscopic images. METHODS: We conducted a systematic review from database inception to June 2020 of all studies assessing the performance of AI in the endoscopic diagnosis of early gastric cancer. Studies not concerning early gastric cancer were excluded. The outcome of interest was the diagnostic accuracy (comprising sensitivity, specificity, and accuracy) of AI systems. Study quality was assessed on the basis of the revised Quality Assessment of Diagnostic Accuracy Studies. Meta-analysis was primarily based on a bivariate mixed-effects model. A summary receiver operating curve and a hierarchical summary receiver operating curve were constructed, and the area under the curve was computed. RESULTS: We analyzed 12 retrospective case control studies (n=11,685) in which AI identified early gastric cancer from endoscopic images. The pooled sensitivity and specificity of AI for early gastric cancer diagnosis were 0.86 (95% CI 0.75-0.92) and 0.90 (95% CI 0.84-0.93), respectively. The area under the curve was 0.94. Sensitivity analysis of studies using support vector machines and narrow-band imaging demonstrated more consistent results. CONCLUSIONS: For early gastric cancer, to our knowledge, this was the first synthesis study on the use of endoscopic images in AI in diagnosis. AI may support the diagnosis of early gastric cancer. However, the collocation of imaging techniques and optimal algorithms remain unclear. Competing models of AI for the diagnosis of early gastric cancer are worthy of future investigation. TRIAL REGISTRATION: PROSPERO CRD42020193223; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=193223.

The anti-inflammatory properties of ethyl acetate fraction in ethanol extract from Sarcodia suiae sp. alleviates atopic dermatitis-like lesion in mice.

Atopic dermatitis (AD) is a chronic inflammatory and pruritic disease; it can be treated by inhibiting inflammation. Sarcodia suiae sp. is an edible, artificially cultivable red algae with multiple bioactivities. We assessed the anti-inflammatory activity of the ethyl acetate fraction of S. suiae sp. ethanol extract (PD1) on 1-chloro-2,4-dinitrochlorobenzene (DNCB)-induced AD-like lesions. Results show that PD1 alleviated symptoms and significantly decreased clinical dermatitis score. PD1 inhibited serum immunoglobulin E expression and alleviated swelling in the spleen and subiliac lymph nodes. In skin tissues, PD1 alleviated aberrant hyperplasia, decreased epidermal thickness, and decreased the accumulation of mast cells. PD1 mediated the recovery of skin barrier-related proteins, such as claudin-1 and filaggrin. Our study demonstrated that PD1 has anti-inflammatory effects, alleviates AD symptoms, inhibits inflammatory responses in skin tissues, and restores barrier function in DNCB-induced AD mice. These findings reveal that S. suiae sp. extract provides an alternative protective option against AD.

The Potential Effects of Oxidative Stress-Related Plasma Abnormal Protein Aggregate Levels on Brain Volume and Its Neuropsychiatric Consequences in Parkinson's Disease.

BACKGROUND: Oxidative stress has been implicated in the pathogenesis of many diseases, including Parkinson's disease. Large protein aggregates may be produced after the breakdown of the proteostasis network due to overt oxidative stress. Meanwhile, brain volume loss and neuropsychiatric deficits are common comorbidities in Parkinson's disease patients. In this study, we applied a mediation model to determine the potential influences of oxidative stress-related plasma abnormal protein aggregate levels on brain volume and neuropsychiatric consequences in Parkinson's disease. METHOD: 31 patients with PD and 24 healthy controls participated in this study. The PD patients were further grouped according to the presentation of cognitive decline or not. All participants received complete examinations to determine plasma abnormal protein aggregates levels, brain volume, and neuropsychiatric performance. The results were collected and analyzed in a single-level three-variable mediation model. RESULTS: Patients with PD cognitive decline exhibited higher plasma NfL levels, decreased regional brain volume, and poor neuropsychiatric subtest results compared with PD patients with normal cognition, with several correlations among these clinical presentations. The mediation model showed that the superior temporal gyrus completely mediated the effects of elevated plasma NfL levels due to the poor psychiatric performance of picture completion and digit span. CONCLUSION: This study provides insight into the effects of oxidative stress-related plasma abnormal protein aggregate levels on regional brain volume and neuropsychiatric consequences in Parkinson's disease patients.

A resorbable hyaluronic acid hydrogel to prevent adhesion in porcine model under laparotomy pelvic surgery.

Surgical post-operative adhesions can lead to serious clinical complications. Barrier agent is the broad usage for the prevention of post-operative adhesions. This study aimed to evaluate the reducing adhesion efficacy of non-animal hyaluronic acid (HA) hydrogel in pigs undergoing conventional laparotomy pelvic surgery. HA hydrogel was applied to eighteen female pigs who underwent conventional laparotomy. The adhesion degrees and histopathology were evaluated in bilateral uterine horns as well as peritoneal sidewall excision. In the present study, all animals survived and had no complications after the surgery. The histopathological observations were demonstrated that HA obviously improved laparotomy pelvic surgery-induced adhesion in peritoneal sidewall and uterine horn. The anastomotic healing score of injury + HA group was significantly lower than the injury alone group. We conclude HA hydrogel can attenuate the post-operative adhesions in porcine.

Associations among Cognitive Functions, Plasma DNA, and Diffusion Tensor Image along the Perivascular Space (DTI-ALPS) in Patients with Parkinson's Disease.

BACKGROUND: Parkinson's disease (PD) is a common neurodegenerative disease associated with accumulation of misfolding proteins and increased neuroinflammation, which may further impair the glymphatic system. The purpose of this study was to utilize diffusion tensor image analysis along the perivascular space (DTI-ALPS) to evaluate glymphatic system activity and its relationship with systemic oxidative stress status in PD patients. METHODS: Magnetic resonance imaging and neuropsychological tests were conducted on 25 PD patients with normal cognition (PDN), 25 PD patients with mild cognitive impairment (PD-MCI), 38 PD patients with dementia (PDD), and 47 normal controls (NC). Oxidative stress status was assessed by plasma DNA level. Differences in ALPS-index among the subgroups were assessed and further correlated with cognitive functions and plasma DNA levels. RESULTS: The PD-MCI and PDD groups showed significantly lower ALPS-index compared to normal controls. The ALPS-index was inversely correlated with plasma nuclear DNA, mitochondrial DNA levels, and cognitive scores. CONCLUSIONS: Lower diffusivity along the perivascular space, represented by lower ALPS-index, indicates impairment of the glymphatic system in PD patients. The correlation between elevated plasma nuclear DNA levels and lower ALPS-index supports the notion that PD patients may exhibit increased oxidative stress associated with glymphatic system microstructural alterations.

Effects of Streptococcus thermophilus on anterior cruciate ligament transection-induced early osteoarthritis in rats.

Osteoarthritis (OA) is the most common joint disorder and is classically defined as a progressively degenerative disease of articular cartilage. It manifests as joint pain and disability and currently has no comprehensive treatments. The primary purpose of the present study was to test the effects of probiotics, Streptococcus thermophilus (TCI633), on anterior cruciate ligament transection (ACLT)-induced experimental osteoarthritis (OA) in rats. In the current study, the experimental groups were given TCI633 (5x109, 5x1010 and 5x1011 CFU/kg/day) and glucosamine sulfate (250 mg/kg) between week 8 and 20 following ACLT. The results showed that oral administration of TCI633 and glucosamine had significant therapeutic effects on pain behaviors and knee swelling. Dose-dependent effects of TCI633 were also observed in ACLT-treated rats. Histopathological analysis demonstrated that ACLT+TCI633 (5x109, 5x1010 and 5x1011 CFU/kg/day) improved the synovial inflammation and cartilage damage of ACLT rats. Histology evaluation using the Osteoarthritis Research Society International system and synovial inflammatory score analysis showed the dose-dependent inhibition of TCI633 on synovial inflammation and cartilage damage. Immunohistochemical staining and TUNEL apoptosis staining showed that TCI633 could effectively increase the expression of type II collagen and reduce the amount of chondrocyte apoptosis in cartilage. Therefore, the present study demonstrated that oral intake of TCI633 could significantly suppressing pain behavior, reduce joint swelling and synovial tissue inflammation and increase type II collagen expression in cartilage. There was also a reduction in chondrocyte apoptosis and decreased progression of OA in ACLT-treated rats.

White matter alteration and autonomic impairment in obstructive sleep apnea.

STUDY OBJECTIVES: Autonomic impairment and white matter (WM) alterations have been noted as effects of obstructive sleep apnea (OSA). This study sought to evaluate the change of WM integrity in patients with OSA using diffusion tensor imaging (DTI) and to determine its relationship with autonomic impairment. METHODS: A total of 30 patients with moderate and severe OSA and 19 healthy volunteers were recruited. A cardiovascular autonomic survey was performed and the baroreflex sensitivity (BRS) for each participant was derived from changes in heart rate and blood pressure during the early part of phase II of the Valsalva maneuver. DTI-related indices were derived from DTI. The fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) maps were compared using voxel-based statistics to determine differences between the patients with OSA and the healthy controls. The correlations among DTI indices, clinical severity, and autonomic parameters were investigated. RESULTS: The BRS values were significantly worse in the OSA group than in the control patients. An exploratory group-wise comparison between the two groups revealed that the patients with OSA exhibited low FA, increased MD, AD, and RD in several brain locations. The declined DTI indices in autonomic-related areas were significantly correlated with increased clinical disease severity and baroreflex impairment. CONCLUSIONS: OSA alters WM integrity in the cingulum and temporal lobe, and this impairment might play some role in autonomic dysfunction. The possible interaction between autonomic dysfunction and central nervous system microstructural alterations may represent variant hypoxic patterns, sympathetic activation, and their consequent processes in OSA.

Niche Modulation of IGF-1R Signaling: Its Role in Stem Cell Pluripotency, Cancer Reprogramming, and Therapeutic Applications.

Stem cells work with their niches harmoniously during development. This concept has been extended to cancer pathology for cancer stem cells (CSCs) or cancer reprogramming. IGF-1R, a classical survival signaling, has been shown to regulate stem cell pluripotency, CSCs, or cancer reprogramming. The mechanism underlying such cell fate determination is unclear. We propose the determination is due to different niches in embryo development and tumor malignancy which modulate the consequences of IGF-1R signaling. Here we highlight the modulations of these niche parameters (hypoxia, inflammation, extracellular matrix), and the targeted stem cells (embryonic stem cells, germline stem cells, and mesenchymal stem cells) and CSCs, with relevance to cancer reprogramming. We organize known interaction between IGF-1R signaling and distinct niches in the double-sided cell fate with emerging trends highlighted. Based on these new insights, we propose that, through targeting IGF-1R signaling modulation, stem cell therapy and cancer stemness treatment can be further explored.

Correlation between Executive Network Integrity and Sarcopenia in Patients with Parkinson's Disease.

Background: Sarcopenia is critically associated with morbidity and mortality in the progression of Parkinson's disease (PD). However, analyses of clinical severity and brain changes, such as white matter (WM) alterations in PD patients with sarcopenia are limited. Further understanding of the factors associated with sarcopenia may provide a focused screen and potential for early intervention in PD patients. Methods: 52 PD patients and 19 healthy participants accepted dual-energy X-ray absorptiometry to measure the body composition. Using diffusion tensor imaging, the difference of WM integrity was measured between PD patients with sarcopenia (PDSa) and without sarcopenia (PDNSa). Multivariate analysis was performed to explore the relationships between clinical factors, WM integrity, and sarcopenia in PD patients. Results: 21 PD patients (40.4%) had sarcopenia. PDSa had a higher Unified Parkinson's Disease Rating Scale (UPDRS III) score, lower body mass index (BMI) and lower fat weight compared with the PDNSa. Additionally, PDSa patients exhibited lower fractional anisotropy accompanied by higher radial diffusivity and/or higher mean diffusivity in the fronto-striato-thalamic circuits, including bilateral cingulum, left superior longitudinal fasciculus, left genu of corpus callosum, and right anterior thalamic radiation, which participate in the executive function. In addition, decreased muscle mass was associated with worse WM integrity in these regions. Multiple linear regression analysis revealed that WM integrity in the left cingulum, right anterior thalamic radiation, together with gender (male) significantly predicted muscle mass in PD patients. Conclusions: WM alterations in the executive network, such as the fronto-striato-thalamic circuits, may indicate a risk factor for ongoing sarcopenia in PD patients. The effectiveness of using executive function to serve as a prodromal marker of sarcopenia in PD patients should be evaluated in future studies.

New 1,4-Dienonesteroids from the Octocoral Dendronephthya sp.

Two new steroids, dendronesterones D (1) and E (2), featuring with 1,4-dienone moiety, along with three known steroids, methyl 3-oxochola-4,22-diene-24-oate (3), 5α,8α-epidioxy-24(S)- methylcholesta-6,22-dien-3ß-ol (4), and 5α,8α-epidioxy-24(S)-methylcholesta-6,9(11),22-trien-3ß-ol (5), were isolated from an octocoral Dendronephthya sp. The structures of steroids 1 and 2 were elucidated by using spectroscopic methods and steroid 1 was found to exhibit significant in vitro anti-inflammatory activity in lipopolysaccharides (LPS)-induced RAW264.7 macrophage cells by inhibiting the expression of the iNOS protein.

BA6 Induces Apoptosis via Stimulation of Reactive Oxygen Species and Inhibition of Oxidative Phosphorylation in Human Lung Cancer Cells.

Lung cancer is the leading cause of cancer deaths in the world, with a five-year survival rate of less than 30%. Clinically effective chemotherapeutic treatments at the initial stage may eventually face the dilemma of no drug being effective due to drug resistance; therefore, finding new effective drugs for lung cancer treatment is a necessary and important issue. Compounds capable of further increasing the oxidative stress of cancer cells are considered to have anticancer potential because they possessed the ability to induce apoptosis. This study mainly investigated the effects of BA6 (heteronemin), the marine sponge sesterterpene, on lung cancer cell apoptosis, via modulation of mitochondrial reactive oxygen species (mtROS) and oxidative phosphorylation (OXPHOS). BA6 has cellular cytotoxic activities against a variety of cancer cell lines, but it has no effect on nontumor cells. The BA6-treated lung cancer cells show a significant increase in both cellular ROS and mtROS, which in turn caused the loss of mitochondrial membrane potential (MMP). The increase of oxidative stress in lung cancer cells treated with BA6 was accompanied by a decrease in the expression of antioxidant enzymes Cu/Zn SOD, MnSOD, and catalase. In addition, OXPHOS performed in the mitochondria and glycolysis in the cytoplasm were inhibited, which subsequently reduced downstream ATP production. Pretreatment with mitochondria-targeted antioxidant MitoTEMPO reduced BA6-induced apoptosis through the mitochondria-dependent apoptotic pathway, which was accompanied by increased cell viability, decreased mtROS, enhanced MMP, and suppressed expression of cleaved caspase-3 and caspase-9 proteins. In conclusion, the results of this study clarify the mechanism of BA6-induced apoptosis in lung cancer cells via the mitochondrial apoptotic pathway, suggesting that it is a potentially innovative alternative to the treatment of human lung cancer.

Rhodoptilometrin, a Crinoid-Derived Anthraquinone, Induces Cell Regeneration by Promoting Wound Healing and Oxidative Phosphorylation in Human Gingival Fibroblast Cells.

Gingival recession (GR) potentially leads to the exposure of tooth root to the oral cavity microenvironment and increases susceptibility to dental caries, dentin hypersensitivity, and other dental diseases. Even though many etiological factors were reported, the specific mechanism of GR is yet to be elucidated. Given the species richness concerning marine biodiversity, it could be a treasure trove for drug discovery. In this study, we demonstrate the effects of a marine compound, (+)-rhodoptilometrin from crinoid, on gingival cell migration, wound healing, and oxidative phosphorylation (OXPHOS). Experimental results showed that (+)-rhodoptilometrin can significantly increase wound healing, migration, and proliferation of human gingival fibroblast cells, and it does not have effects on oral mucosa fibroblast cells. In addition, (+)-rhodoptilometrin increases the gene and protein expression levels of focal adhesion kinase (FAK), fibronectin, and type I collagen, changes the intracellular distribution of FAK and F-actin, and increases OXPHOS and the expression levels of complexes I~V in the mitochondria. Based on our results, we believe that (+)-rhodoptilometrin might increase FAK expression and promote mitochondrial function to affect cell migration and promote gingival regeneration. Therefore, (+)-rhodoptilometrin may be a promising therapeutic agent for GR.

Decreased cerebral blood flow and improved cognitive function in patients with end-stage renal disease after peritoneal dialysis: An arterial spin-labelling study.

OBJECTIVES: The aim of this study was to evaluate the relationship between cognitive impairment and brain perfusion using arterial spin labelling (ASL) in end-stage renal disease (ESRD) patients undergoing PD. METHODS: ESRD patients undergoing PD were recruited. Laboratory screening, neuropsychological tests and ASL magnetic resonance imaging (MRI) were conducted prior to and after 6 months of PD. Age- and sex-matched normal subjects without ESRD served as the control group. Comparisons of regional CBF between ESRD patients before or after undergoing PD and normal controls were performed. Correlations between biochemical, neuropsychological and CBF data were also conducted to evaluate the relationships. RESULTS: ESRD patients showed poor performance in many of the neuropsychological tests; PD improved cognition in some domains. Pre-PD patients had higher mean CBF than post-PD patients and normal controls, but no significant difference was found between the normal controls and post-PD patients. Negative correlations were observed pre-PD (regional CBF in left hippocampus vs. perseverative responses, r = -0.662, p = 0.014), post-PD (mean CBF vs. haemoglobin level, r = -0.766, p = 0.002), and before and after PD (change in CBF in the left putamen vs. change in haematocrit percentage, r = -0.808, p = 0.001). CONCLUSION: Before PD, ESRD patients had increased cerebral perfusion that was related to poorer executive function, especially in the left hippocampus. Post-PD patients performed better in some cognitive test domains than pre-PD patients. The degree of anaemia, i.e., haemoglobin level or haematocrit percentage, might predict cognitive impairment in PD patients. KEY POINTS: • In this study, ESRD patients before PD had cerebral hyperperfusion that was related to poorer executive function. • Post-PD patients performed better in some cognitive test domains than pre-PD patients did. • The degree of anaemia might predict cognitive impairment in PD patients.

Anti-Inflammatory and Antinociceptive Effects of Ethyl Acetate Fraction of an Edible Red Macroalgae Sarcodia ceylanica.

Research so far has only shown that edible red macroalgae, Sarcodia ceylanica has the ability to eliminate free radicals and anti-diabetic, anti-bacterial properties. This study was conducted both in vitro and in vivo on the ethyl acetate extract (PD1) of farmed red macroalgae in order to explore its anti-inflammatory properties. In order to study the in vitro anti-inflammatory effects of PD1, we used lipopolysaccharide (LPS) to induce inflammatory responses in murine macrophages. For evaluating the potential in vivo anti-inflammatory and antinociceptive effects of PD1, we used carrageenan-induced rat paw edema to produce inflammatory pain. The in vitro results indicated that PD1 inhibited the LPS-induced pro-inflammatory protein, inducible nitric oxide synthase (iNOS) in macrophages. Oral PD1 can reduce carrageenan-induced paw edema and inflammatory nociception. PD1 can significantly inhibit carrageenan-induced leukocyte infiltration, as well as the protein expression of inflammatory mediators (iNOS, interleukin-1ß, and myeloperoxidase) in inflammatory tissue. The above results indicated that PD1 has great potential to be turned into a functional food or used in the development of new anti-inflammatory and antinociceptive agents. The results from this study are expected to help scientists in the continued development of Sarcodia ceylanica for other biomedical applications.

White matter damage and systemic inflammation in Parkinson's disease.

BACKGROUND: Systemic inflammation and white matter (WM) alterations have been noted as effects of Parkinson's disease (PD). This study sought to evaluate WM integrity in PD patients using diffusion tensor imaging (DTI) and to assess its relationship with systemic inflammation. METHODS: Sixty-six patients with PD (23 men and 43 women) and 67 healthy volunteers (29 men and 38 women) underwent blood sampling to quantify inflammatory markers and DTI scans to determine fiber integrity. The inflammatory markers included leukocyte apoptosis, as well as cellular and serum adhesion molecules, in each peripheral blood sample. DTI-related indices [including fractional anisotropy (FA), axial diffusivity (AD), radial diffusivity (RD), and mean diffusivity (MD)] were derived from DTI scans. The resulting FA maps were compared using voxel-based statistics to determine differences between the PD and control groups. The differences in the DTI indices, clinical severity, and inflammatory markers were correlated. RESULTS: Exploratory group-wise comparison between the two groups revealed that the PD patients exhibited extensive DTI index differences. Low FA accompanied by high RD and MD, without significant differences in AD, suggesting a demyelination process, were found in the parietal, occipital, cerebellar, and insular WM of the PD patients. The declined DTI indices were significantly correlated with increased clinical disease severity, adhesion molecules, and leukocyte apoptosis. CONCLUSIONS: Patients with PD experience WM integrity damage in vulnerable regions, and these impairments are associated with increased disease severity and systemic inflammation. The possible interactions among them may represent variant neuronal injuries and their consequent processes in PD.

Autonomic Function Impairment and Brain Perfusion Deficit in Parkinson's Disease.

INTRODUCTION: Autonomic disorders have been recognized as important Parkinson's disease (PD) components. Some vulnerable structures are related to the central autonomic network and have also been linked to autonomic function alterations. The aims of the study are to evaluate the severity of the autonomic dysfunction and the cortical hypoperfusion using arterial spin labeling (ASL) MRI. And then, possible relationships of significant between-group differences in perfusion pattern to clinical variables and autonomic functions were examined to determine the pharmaceutical effects of dopaminergic treatment on cerebral blood flow (CBF) in patients with PD. METHODS: Brain ASL MRI was carried out in 20 patients with PD (6 men and 14 women, mean age: 63.3 ± 6.4 years) and 22 sex- and age-matched healthy volunteers to assess whole-brain CBF and the effects of dopaminergic therapy on perfusion. All subjects underwent a standardized evaluation of cardiovagal and adrenergic function including a deep breathing, Valsalva maneuver, and 5-min head-up tilt test. Perfusion MRI data were acquired on a 3.0 T scanner with a pulsed continuous ASL technique. The CBF, autonomic parameters, and clinical data were analyzed after adjusting for age and sex. RESULTS: Patients exhibited a decline in autonomic function (rapid heart rate in response to deep breathing, low baroreflex sensitivity, high systolic and diastolic pressure, and altered tilting test response), widespread low CBF, and robust response to dopaminergic therapy. Lower perfusion in the middle frontal gyrus was associated with increased clinical disease severity (Unified Parkinson's Disease Rating Scale I score, P < 0.001). Lower perfusion in autonomic control areas, such as the frontal lobe and insula, were significantly associated with autonomic impairment (P < 0.001). CONCLUSIONS: Our study indicates that PD is a progressive neurodegenerative disorder that changes the perfusion of central nervous system and is associated with variable autonomic dysfunctions. Neuronal loss and sympathetic activation may explain the interaction between cortical autonomic region perfusion and cardiovascular autonomic function.

Systemic inflammation and alterations to cerebral blood flow in obstructive sleep apnea.

Systemic inflammation and alterations to regional cerebral blood flow (CBF) have been reported previously in obstructive sleep apnea (OSA). This study utilized arterial spin labelling (ASL) perfusion magnetic resonance imaging (MRI) to evaluate CBF in OSA patients and determine its relationship with systemic inflammation. Twenty male patients with moderate and severe OSA [apnea-hypopnea index (AHI) >15] and 16 healthy male volunteers (AHI <5) were recruited. Early- or late-phase changes in leucocyte apoptosis and its subsets were determined by flow cytometry. Perfusion MRI data were acquired with a pulsed continuous ASL technique. The CBF maps were compared using voxel-based statistics to determine differences between the OSA and control groups. The differences in CBF, clinical severity and leucocyte apoptosis were correlated. Exploratory groupwise comparison between the two groups revealed that the OSA patients exhibited low CBF values in the vulnerable regions. The lower regional CBF values were correlated with higher clinical disease severity and leucocyte apoptosis. OSA impairs cerebral perfusion in vulnerable regions, and this deficit is associated with increased disease severity. The apparent correlation between systemic inflammation and cerebral perfusion may be indicative of haemodynamic alterations and their consequences in OSA.

Plasma DNA Mediate Autonomic Dysfunctions and White Matter Injuries in Patients with Parkinson's Disease.

Background. Cardiovascular autonomic dysfunction is well known in Parkinson's disease (PD) presentation and it produces hypoperfusion of vital organs. The association between cardiovascular autonomic dysfunction and oxidative stress was examined in previous animal models. Oxidative stress and neuroinflammation were thought to have roles in PD pathogenesis. Owing to the relative low intrinsic antioxidative properties, brain white matter (WM) is vulnerable to the oxidative stress. This study is conducted to examine possible relationships by using a hypothesis-driven mediation model. Methods. Twenty-nine patients with PD and 26 healthy controls participated in this study, with complete examinations of cardiac autonomic parameters, plasma DNA level, and WM integrity. A single-level three-variable mediation model was used to investigate the possible relationships. Results. The elevated serum oxidative stress biomarkers include plasma nuclear DNA and mitochondrial DNA, and poorer cardiac autonomic parameters and multiple regional microstructural WM changes are demonstrated. Further mediation analysis shows that plasma nuclear DNA served as the mediators between poorer baroreflex sensitivity and mean diffusivity changes in cingulum. Conclusions. These results provide a possible pathophysiology for how the poor baroreflex sensitivity and higher oxidative stress adversely impacted the WM integrity. This model could provide us with a piece of the puzzle of the entire PD pathogenesis.