Central Nervous System Origin Research Articles

Neuropathogenesis of SARS-CoV-2 in human neuronal, microglial and glial cells.

Neurological complications, both acute and chronic, are reported commonly in COVID-19 affected individuals. In this context, the understanding of pathogenesis of SARS-CoV-2 in specific cells of central nervous system (CNS) origin is relevant. The present study explores infection biology of a clinical isolate of SARS-CoV-2 in human cell lines of neural origin such as the glioblastoma (U87-MG), neuroblastoma (SHSY5Y) and microglia (C20). Despite showing clear evidence of infection by immunofluorescence with an anti-spike protein antibody, all the three neural cell lines were observed to be highly restrictive to the replication of the infecting virus. While the U87-MG glioblastoma cells demonstrated no cytopathic effects and a low viral titre with no signs of replication, the SHSY5Y neuroblastoma cells exhibited cytopathic effects with bleb formation but no evidence of viable virus. The C20 microglial cells showed neither signs of cytopathic effects nor viable virus. Ultrastructural studies demonstrated intracellular virions in infected neural cells. The presence of lipid droplets in infected SHSY5Y cells suggested an impact on host cell metabolism. The decrease in viral RNA levels over time in all the neural cell lines suggested restricted viral replication. In conclusion, this study highlights the limited susceptibility of neural cells to SARS-CoV-2 infection. This reduced permissibility of neural cell lines to SARS-CoV-2 may point to their inherent lower expression of receptors that support viral entry in addition to the intracellular factors that potently inhibit viral replication. The study findings prompt further investigation into the mechanisms of SARS-CoV-2 infection of neural cells.

Association of Serum Brain-Derived Tau With Clinical Outcome and Longitudinal Change in Patients With Severe Traumatic Brain Injury

Blood-based measurements of total tau (T-tau) are commonly used to examine neuronal injury in patients with traumatic brain injury (TBI), but current assays do not differentiate between brain-derived tau (BD-tau) and tau produced in peripheral tissues. A novel assay for BD-tau has recently been reported that selectively quantifies nonphosphorylated tau of central nervous system origin in blood samples. To examine the association of serum BD-tau with clinical outcomes in patients with severe TBI (sTBI) and its longitudinal changes over 1 year. This prospective cohort study was conducted at the neurointensive unit at the Sahlgrenska University Hospital, Gothenburg, Sweden, between September 1, 2006, and July 1, 2015. The study included 39 patients with sTBI followed up for up to 1 year. Statistical analysis was performed between October and November 2021. Serum BD-tau, T-tau, phosphorylated tau231 (p-tau231), and neurofilament light chain (NfL) measured on days 0, 7, and 365 after injury. Associations of serum biomarkers with clinical outcome and longitudinal change in sTBI. Severity of sTBI was evaluated using the Glasgow Coma Scale at hospital admission, while clinical outcome was assessed with the Glasgow Outcome Scale (GOS) at 1-year follow-up. Participants were classified as having a favorable outcome (GOS score, 4-5) or unfavorable outcome (GOS score, 1-3). Among the 39 patients (median age at admission, 36 years [IQR, 22-54 years]; 26 men [66.7%]) in the study on day 0, the mean (SD) serum BD-tau level was higher among patients with unfavorable outcomes vs those with favorable outcomes (191.4 [190.8] pg/mL vs 75.6 [60.3] pg/mL; mean difference, 115.9 pg/mL [95% CI, 25.7-206.1 pg/mL]), while the other markers had smaller between-group mean differences (serum T-tau, 60.3 pg/mL [95% CI, -22.0 to 142.7 pg/mL]; serum p-tau231, 8.3 pg/mL [95% CI, -6.4 to 23.0 pg/mL]; serum NfL, -5.4 pg/mL [95% CI, -99.0 to 88.3 pg/mL]). Similar results were recorded on day 7. Longitudinally, baseline serum BD-tau concentrations showed slower decreases in the whole cohort (42.2% on day 7 [from 138.6 to 80.1 pg/mL] and 93.0% on day 365 [from 138.6 to 9.7 pg/mL]) compared with serum T-tau (81.5% on day 7 [from 57.3 to 10.6 pg/mL] and 99.0% on day 365 [from 57.3 to 0.6 pg/mL]) and p-tau231 (92.5% on day 7 [from 20.1 to 1.5 pg/mL] and 95.0% on day 365 [from 20.1 to 1.0 pg/mL]). These results did not change when considering clinical outcome, where T-tau decreased twice as fast as BD-tau in both groups. Similar results were obtained for p-tau231. Furthermore, the biomarker levels on day 365 were lower, compared with day 7, for BD-tau but not T-tau or p-tau231. Serum NfL had a different trajectory to the tau biomarkers, with levels increasing by 255.9% on day 7 compared with day 0 (from 86.8 to 308.9 pg/mL) but decreasing by 97.0% by day 365 vs day 7 (from 308.9 to 9.2 pg/mL). This study suggests that serum BD-tau, T-tau, and p-tau231 have differential associations with clinical outcome and 1-year longitudinal change in patients with sTBI. Serum BD-tau demonstrated utility as a biomarker to monitor outcomes in sTBI and can provide valuable information regarding acute neuronal damage.

Vasculogenic Myoclonus of Peripheral Origin after Whiplash Injury: A Case Report

Based on the neuroanatomical origin of the electrical discharge, myoclonus could be classified in terms of its etiology as cortical, subcortical, spinal, or peripheral. A 29-year-old female patient experienced a continuous involuntary rhythmic twitching movement of the right elbow for 6 months. This myoclonus occurred immediately after a whiplash injury caused by a rear-end car accident. The patient had no radiological, clinical, or electrophysiological evidence for central nervous system origin. Concentric needle electromyography recordings of the right biceps, brachioradialis, and triceps muscles presented bursts of spontaneous rhythmic activity synchronous to the clinical myoclonus. Doppler ultrasound on the right arm revealed that the biceps and triceps contraction coincided with the vascular pulsation of the brachial artery and vein. This result suggested that myoclonus was caused by vascular stimulation, similar to the pathophysiology of hemifacial spasms. A whiplash injury around the neck or arm may have affected the vascular structures in the upper and middle trunks, resulting in vasculogenic myoclonus. Electromyography can be used to determine the classification and distribution of myoclonic jerks.

Solid malignancies during the first year of life: A 20-year review at Red Cross War Memorial Children’s Hospital, Cape Town, South Africa

Background. Among paediatric tumours, two groups stand out: neonatal and infantile tumours, which respectively represent 2% and 10% of paediatric tumours. The distribution of tumours in these age groups is different from that in older children. Objectives. Descriptive analysis of a cohort of patients treated for a solid malignancy at Red Cross War Memorial Children’s Hospital (RCWMCH), Cape Town, South Africa. Methods. A 20-year retrospective case series review of patients aged <1 year at diagnosis was performed on data extracted from the RCWMCH oncology database. Results. Of 243 cases extracted from the database, 198 were solid tumours, of which 122 (61.1%) were included in the analysis; the 76 excluded were benign or of eye, bone or central nervous system origin and therefore did not meet the inclusion criteria. There were 38 renal malignancies (31.2%), 30 neuroblastomas (24.6%), 25 soft-tissue sarcomas (20.5%), 17 germ cell tumours/gonadal tumours (13.9%) and 12 liver tumours (9.8%). Of the patients, 119 (97.5%) had surgery, 91 (74.6%) had chemotherapy and 10 (8.2%) had radiotherapy. Tumour group 5-year survival was 78.5% for neuroblastic tumours, 79.0% for nephroblastomas, 81.5% for hepatoblastomas, 62.5% and 54.2% for rhabdomyosarcoma and non-rhabdomyosarcoma soft-tissue sarcomas, respectively, and 79.5% for malignant extracranial and extragonadal germ cell tumours. For the entire cohort, the mean follow-up was 46 months, with an estimated 5-year overall survival of 74.6%. Mortality was 21.5% and loss to follow-up 6.6%. Conclusion. The distribution of tumours differs slightly from the literature, with a predominance of renal tumours over neuroblastomas. The overall mortality rate of 21.5%, the surgical complication rate of 10.9% and the 5-year overall survival of 74.6% correspond with the literature, supporting the view that a paediatric hospital in a middle-income country can achieve results similar to those in higher-income countries when international protocols are applied by a dedicated multidisciplinary team.

Primary sellar melanocytoma.

We present an up-to-date review of all published cases of sellar melanocytoma, a benign melanocytic neoplasm arising from melanocytes present in the leptomeninges surrounding the pituitary. Both the Medline and Embase databases were searched for case reports or case series of patients with a sellar mass consisting of melanocytes. All 14 identified patients developed symptoms due to compression of the surrounding structures. Symptoms included pituitary dysfunction and visual impairment. All patients received a transsphenoidal resection as first-line treatment. The diagnosis is made on pathological examination but deciding whether a sellar melanocytic tumor is best classified as a melanocytoma or a melanoma is not straightforward. Genetic analyses can help differentiate between central nervous system origin and metastasis of a cutaneous melanoma with the presence of a GNAQ and GNA11 mutations or a BRAF mutation, respectively. First choice treatment is complete resection, and in case of incomplete resection or recurrence additional radiotherapy is advised.

A tale of two tinnituses: Does hearing status influence central tinnitus localization?

Tinnitus is a complex symptom that manifests as the perception of sound in the absence of external stimuli. There are various patient-related factors and co-morbidities associated with tinnitus, however, the impact of hearing status on tinnitus is poorly understood. Various works suggest that tinnitus may originate in the central nervous system (CNS). Reports of tinnitus resolution following central insult provide further support for this concept. Based on these reports of tinnitus resolution, a line of research evaluating deep brain stimulation (DBS) of the caudate as a therapy for tinnitus has emerged. The emerging data show early promise and independent evaluation of this work suggests that hearing status may influence localization of tinnitus within the caudate. We closely review the available reports of tinnitus resolution following central insult and tinnitus outcomes in DBS to hypothesize that the CNS origins of tinnitus may vary based on hearing status. Our interpretation of the available literature suggests that the anterior aspect of the caudate may be a location for tinnitus intervention in patients with normal hearing or mild hearing loss (HL) and more posterior locations in the caudate may be a region of intervention in patients with moderate/ severe HL. Ultimately, this concept may shift the paradigm of thought on tinnitus to offer clinically and anatomically relevant information with targeted therapeutic options.

Differentiation of Outcomes by Treatment Regimen and Histology in Central Nervous System Primary Embryonal Tumors

Central nervous system (CNS) embryonal tumors are malignant neoplasms of undifferentiated embryonic cells that typically occur in the pediatric population. They are further divided into many subgroups by distinct histologic and genetic profiles. We present the largest study to date to identify differential survival outcomes within each subgroup by treatment regimen. The SEER (Surveillance Epidemiology and End Results) database was queried from 1973 to 2015 for embryonal tumors of primary CNS origin (n= 3900). The effects of patient demographics, tumor characteristics, and treatment regimen were analyzed using a multivariate Cox proportional hazard model in CNS embryonal tumor subtypes divided into medulloblastoma, atypical teratoid/rhabdoid tumor, and primitive neuroectodermal tumor. No significant patient demographic factors were found to be associated with increased mortality. In all 3 CNS embryonal tumor subtypes, most monotherapy and combinatorial treatment paradigms showed a higher hazard ratio compared with gross total resection with adjuvant chemoradiotherapy (hazard ratio, 1.72-22.94; P < 0.05 for all). In a subgroup analysis of patients with medulloblastoma ≤3 years of age, patients who did not receive radiation showed lower survival probabilities at 1, 5, and 10 years (odds ratio [OR], 0.37, P < 0.0001; OR, 0.39, P < 0.0001; OR, 0.34, P < 0.0001, respectively). Kaplan-Meier analysis of medulloblastoma histologic subtypes showed that use of radiation imparted a higher survival probability in the desmoplastic/nodular medulloblastoma and medulloblastoma not otherwise specified groups (P < 0.001 for both). CNS embryonal tumors are highly malignant in all populations and the best survival is seen with aggressive combination therapies. Radiation therapy may have a role in prolonging survival in patients with medulloblastoma ≤3 years of age.

Pathology-confirmed versus non pathology-confirmed cancer diagnoses: incidence, participant characteristics, and survival

Cancer diagnoses which are not confirmed by pathology are often under-registered in cancer registries compared to pathology-confirmed diagnoses. It is unknown how many patients have a non pathology-confirmed cancer diagnosis, and whether their characteristics and survival differ from patients with a pathology-confirmed diagnosis. Participants from the prospective population-based Rotterdam Study were followed between 1989 and 2013 for the diagnosis of cancer. Cancer diagnoses were classified into pathology-confirmed versus non pathology-confirmed (i.e., based on imaging or tumour markers). We compared participant characteristics and the distribution of cancers at different sites. Furthermore, we investigated differences in overall survival using survival curves adjusted for age and sex. During a median (interquartile range) follow-up of 10.7 (6.3–15.9) years, 2698 out of 14,024 participants were diagnosed with cancer, of which 316 diagnoses (11.7%) were non pathology-confirmed. Participants with non pathology-confirmed diagnoses were older, more often women, and had a lower education. Most frequently non pathology-confirmed cancer sites included central nervous system (66.7%), hepato-pancreato-biliary (44.5%), and unknown primary origin (31.2%). Survival of participants with non pathology-confirmed diagnoses after 1 year was lower compared to survival of participants with pathology-confirmed diagnoses (32.6% vs. 63.4%; risk difference of 30.8% [95% CI 25.2%; 36.2%]). Pathological confirmation of cancer is related to participant characteristics and cancer site. Furthermore, participants with non pathology-confirmed diagnoses have worse survival than participants with pathology-confirmed diagnoses. Missing data on non pathology-confirmed diagnoses may result in underestimation of cancer incidence and in an overestimation of survival in cancer registries, and may introduce bias in aetiological research.

Blood extracellular vesicles (EVs) of central nervous system origin: a window into the brain.

Blood extracellular vesicles (EVs) of central nervous system origin: a window into the brain.

SAT-287 Hypogonadotropic Hypogonadism in RPL10 Mutation-Associated Syndromic Intellectual Disability

Background: A multitude of inactivating genetic mutations have been implicated in Idiopathic Hypogonadotropic Hypogonadism (IHH), either in Kallmann syndrome or in norm-osmic IHH. Over the last decade, a limited number of studies described variations in ribosomal protein L10 (RPL10) gene as a cause of X-linked syndromic intellectual disability; this was associated with a constellation of features, including: short stature, microcephaly, dysmorphic facies, intellectual disability, epilepsy. RPL10 gene is located on chromosome Xq28 in the region of G6PD and color vision genes. Literature review suggests that RPL10 is implicated in central nervous system (CNS) development and is identified as an X-linked autism-susceptibility gene. Clinical Case: Herein, we present an adolescent male who was found to be hemizygous for a novel missense variant, p.Asn73Ser (c.218A>G) in exon 5 of the RPL10 gene. He is also hemizygous for a novel missense variant p.Glu766Asp (c.2298G>T) in exon 19 of the CUL4B gene. Hemizygous mutations in CUL4B gene have been associated with X-linked intellectual disability with short stature, hypogonadotropic hypogonadism and abnormal gait. Patient has microcephaly, dysmorphic facial features, short stature and global developmental delays with profound intellectual disability. He is nonverbal, non-ambulatory and has bilateral sensorineural hearing loss, near blindness, seizure disorder, dystonia. At 16 years of age he developed neurologic complications: right side focal motor weakness, followed by left side weakness 4 months later. Subsequently, he developed central hypotonia with peripheral hypertonia. He developed primary acquired hypothyroidism with negative thyroid antibodies at age 15 years and also has hypogonadotropic hypogonadism. He became exclusively fed via G-tube due to aspiration pneumonia. Brain MRI showed subependymal heterotopia, thinning of the posterior corpus callosum, signal abnormality of the left hippocampus with mild volume loss of the right hippocampus; normal pituitary and pineal glands. This patient has 2 novel genetic mutations, both affecting central nervous system. Conclusion: This is the first description of IHH occurring in a patient with novel gene mutations of CUL4B and RPL10. While CUL4B gene mutations are known to be involved in CNS dysfunction, including IHH, it remains to be determined if mutations in RPL10 play a role in endocrinopathies of CNS origin.

Novel mechanism and biomarker of chronic progressive multiple sclerosis

AbstractRecent progress in understanding the pathogenicity of multiple sclerosis (MS) has enabled us to develop new drug entities available in the clinic. However, we still have not succeeded in preventing conversion from relapsing–remitting MS to secondary progressive MS (SP‐MS), and in curing this intractable form of MS. Furthermore, diagnosis is usually retrospective, relying on gradual worsening of neurological signs/symptoms. This is due to the lack of understanding of the pathogenicity driving disease progression in MS and of reliable biomarkers reflecting the disease status. Two relevant components are involved in the brain pathology of SP‐MS: neurodegeneration and inflammation. Neurodegeneration can occur spontaneously in a neuron‐intrinsic manner under chronic inflammation, such as glutamate excitotoxicity, mitochondrial/oxidative injury with iron deposit in the brain and loss of trophic support. Meanwhile, inflammatory and/or immune cells stimulated after repeated relapses, including T cells, B cells, and myeloid cells of peripheral and central nervous system origin, could mediate the processes of neurodegeneration. Among them, a higher frequency of leptomeningeal follicle‐like structures observed in SP‐MS patients suggests that immune cells sheltered behind a blood–brain barrier are still active under smoldering central nervous system inflammation. Accordingly, our recent comparative analysis between MS and its animal model, experimental autoimmune encephalomyelitis, raises a new possibility that ectopic expression of eomesodermin in helper T cells constitutes a previously unappreciated subset of helper T cells with cytotoxic potential against neuronal cells. In the present review article, the mechanisms proposed in the pathogenesis of SP‐MS are summarized, and a new pathogenic mechanism for neurodegeneration mediated by unique cytotoxic helper T cells is proposed.

The first brain: Species comparisons and evolutionary implications for the enteric and central nervous systems.

The enteric nervous system (ENS) and the central nervous system (CNS) of mammals both contain integrative neural circuitry and similarities between them have led to the ENS being described as the brain in the gut. To explore relationships between the ENS and CNS across the animal kingdom. We found that an ENS occurs in all animals investigated, including hydra, echinoderms and hemichordates that do not have a CNS. The general form of the ENS, which consists of plexuses of neurons intrinsic to the gut wall and an innervation that controls muscle movements, is similar in species as varied and as far apart as hydra, sea cucumbers, annelid worms, octopus and humans. Moreover, neurochemical similarities across phyla imply a common origin of the ENS. Investigation of extant species suggests that the ENS developed in animals that preceded the division that led to cnidaria (exemplified by hydra) and bilateria, which includes the vertebrates. The CNS is deduced to be a bilaterian development, later than the divergence from cnidaria. Consistent with the ENS having developed independent of the CNS, reciprocal connections between ENS and CNS occur in mammals, and separate neurons of ENS and CNS origin converge on visceral organs and prevertebral ganglia. We conclude that an ENS arose before and independently of the CNS. Thus the ENS can be regarded as the first brain.

Expression of cocaine- and amphetamine-regulated transcript (CART) in hen ovary

BackgroundCocaine- and amphetamine-regulated transcript (CART), discovered initially by via differential display RT-PCR analysis of brains of rats administered cocaine, is expressed mainly in central nervous system or neuronal origin cells, and is involved in a wide range of behaviors, such as regulation of food intake, energy homeostasis, and reproduction. The hens egg-laying rate mainly depends on the developmental status of follicles, expression of CART have not been identified from hen follicles, the regulatory mechanisms of CART biological activities are still unknown. The objective of this study was to characterize the mRNA expression of CART in hen follicular granulosa cells and determine CART peptide localization and regulatory role during follicular development.MethodsSmall white follicles (1–2 mm in diameter) were treated for RNA isolation; Small white follicles (1–2 mm in diameter) and large white follicles (4–6 mm in diameter) were treated for immunohistochemical localization and large white follicles (4–6 mm in diameter), small yellow follicles (6–8 mm in diameter), large yellow follicles (9–12 mm in diameter), mature follicles (F5, F4, F3, F2, F1, >12 mm in diameter) were treated for RNA isolation and Real time PCR.ResultsThe results showed that full length of the CDS of hen CART was 336 bp encoding a 111 amino acid polypeptide. In the hen ovary, CART peptide was primarily localized to the theca layer, but not all, the oocyte and granulosa layer, with diffused, weaker staining than relative to the theca cell layer. Further, amount of CART mRNA was more (P < 0.05) in granulosa cells of 6–8 mm follicles compared with that in granulosa cells of other follicles. However, CART mRNA amount was greater in theca cells of 4–6 mm follicles relative to follicles of other sizes (P < 0.05).ConclusionsResults suggest that CART could play a potential role in developmental regulation of chicken follicles.

Kod kojih tegoba se radi EKG dijagnostika u ambulanti GZZHMP Beograd

Introduction: Ambulatory unit of City Institute for Urgent Medical Care Belgrade (CIFUMCB) is a part of the primary healthcare system, and as such it is equipped with standardized diagnostic tools, electrocardiograph (ECG) being one of them. The diagnostic method of electrocardiography is performed on a daily basis in order to differentiate a variety of symptoms. Since the majority of patients coming to the ambulatory unit of CIFUMCB for help are first time visitors, unfamiliar to the physician who usually has no insight at all at their previous medical documentation, it is clear how this simple diagnostic tool becomes useful in revealing the underlying cause of a certain health issue. Aim: to present all kinds of patients’ complaints that required ECG diagnostic in the Ambulatory unit of CIFUMCB. Methodology: The electronic database of the Ambulatory Unit of CIFUMCB was utilized from January 1-22, 2015 on 206 examined patients. Health problems of the patients who had undergone ECG diagnosis were analyzed. A single patient could have had more than one health problem, in addition to the one of interest. Results: Among 206 examined patients nearly 50% had undergone ECG diagnostic. The reasons for performing ECG recording were: high blood pressure, chest pain and other difficulties such as shortness of breath, cough, rapid heartbeat, headache and dizziness, numbness in arms, nausea, and fever. Upon comparison of various health problems from different groups, usually from cardiovascular, respiratory and central nervous system origin, there was no statistically significant difference. Conclusion: The most common indications for ECG diagnostic among our patients were high blood pressure, followed by chest pain, irregular and rapid heartbeat, headaches and dizziness. Only 10% of these patients were referred to specialist for further assessment and treatment.

A systematic approach to the neurological examination of llamas and alpacas

The clinical presentation of neurologic disorders in camelids varies widely depending on the underlying cause and localisation of the disease. Metabolic, cardiovascular and musculoskeletal conditions may also present with neurological signs and must thus be differentiated from those of true peripheral or central nervous system origin, through careful evaluation of history, clinical examination and diagnostic testing. Mentation and behaviour of camelids is generally evaluated from a distance, with subsequent assessment of cranial nerve function, gait, posture and postural reactions, spinal reflexes and muscle tone. Gait assessment often focuses on the differentiation between lower motor neuron weakness (LMN paresis) and general proprioceptive ataxia (with associated upper motor neuron weakness), in order to better localise spinal cord disorders. In this context, tail pull examinations may further aid in discerning upper versus lower motor neuron weakness. A thorough systematic neurological examination is thus paramount to achieve the following goals: determine the presence or absence of neurologic signs; localisation of the lesion (neuro-anatomic diagnosis); determine the etiology of a neurological condition.

Effectiveness of transcutaneous electrical nerve stimulation to relieve the tensed masticatory muscle: A retrospective study

Introduction: Myositis, a painful inflammatory condition of masticatory muscles, characterized by protracted local muscle soreness or myofascial pain, is most commonly caused by a source of nociception found in the muscle tissues having origin in central nervous system. Various therapeutic modalities used are pharmacologic, physical, or psychological. Transcutaneous electrical nerve stimulation (TENS), a physical sensory stimulant therapy using high frequency and low-intensity electric current stimulates the nonnociceptive A-beta cutaneous afferents that activate the pain inhibitory mechanism. Its action is immediate with 50%-70% analgesic effect and induces few or no after effects. Purpose of Study: The objective of this retrospective analytical study was to assess the efficacy of TENS therapy in patients suffering from myositis. Materials and Methods: The clinical data of the patients of myositis treated with TENS during 2011-2012 in OPD of a dental school in India were retrieved from department archives and analyzed. In all these patients, severity of pain was assessed on visual analog scale at baseline and at every follow-up visit. The data were analyzed statistically using unpaired t-test. Results: Out of 22 patients treated, 18 showed significant improvement while three were unresponsive and in one patient the condition deteriorated. Conclusions: TENS may be an effective, economical, and easy to use therapy with minimal side effects in patients suffering from myositis.

Gender Differences in Hiccup Patients: Analysis of Published Case Reports and Case-Control Studies

ContextAlthough sporadic male predominance in hiccup patients has been reported, the association between gender differences and triggering factors has rarely been evaluated in patients with hiccups. ObjectivesThe aim of this study was to investigate whether gender differences exist in hiccup patients by analyzing all previously published hiccup literature containing gender and etiology information. MethodsPublished literature on this topic was identified using a standardized search strategy in the PubMed, SCOPUS, and CINAHL electronic databases. The literature search included studies published from January 1990 to December 2013. Searches were limited to English-language publications. Of 476 identified studies, 318 studies were eligible including eight case-control studies that contained nonhiccup control groups. Triggering factors for hiccups were categorized into two types: central nervous system (CNS) and non-CNS causes. Odds ratios (ORs) were calculated for the eight case-control studies and event rates for the other studies by meta-analysis. In addition, gender differences and mean ages were analyzed for the case studies. ResultsPooled OR was 2.42 (95% confidence interval [CI] 1.40–4.17) with inclination for male predominance. Subgroup analysis by cause showed clear male predominance in the non-CNS type with OR of 11.72 (95% CI 3.16–43.50), whereas indistinct in the CNS type with OR of 1.74 (95% CI 0.95–3.16). Of the remaining 310 studies with 864 patients, previous findings were consistent. Male predominance was consistent in non-CNS (85.1%, 95% CI 78.2–90.2) and unknown origin (82.2%, 95% CI 75.8–87.2) patients, whereas mitigating the sex discrepancy in those with CNS origin (65.8%, 95% CI 53.1–76.5). ConclusionWe demonstrated male predominance in hiccup patients. This gender difference for hiccups was more pronounced in patients with non-CNS causes, whereas indistinct in patients with CNS causes.

Metabolic gene expression changes in astrocytes in Multiple Sclerosis cerebral cortex are indicative of immune-mediated signaling.

Emerging as an important correlate of neurological dysfunction in Multiple Sclerosis (MS), extended focal and diffuse gray matter abnormalities have been found and linked to clinical manifestations such as seizures, fatigue and cognitive dysfunction. To investigate possible underlying mechanisms we analyzed the molecular alterations in histopathological normal appearing cortical gray matter (NAGM) in MS. By performing a differential gene expression analysis of NAGM of control and MS cases we identified reduced transcription of astrocyte specific genes involved in the astrocyte-neuron lactate shuttle (ANLS) and the glutamate-glutamine cycle (GGC). Additional quantitative immunohistochemical analysis demonstrating a CX43 loss in MS NAGM confirmed a crucial involvement of astrocytes and emphasizes their importance in MS pathogenesis. Concurrently, a Toll-like/IL-1β signaling expression signature was detected in MS NAGM, indicating that immune-related signaling might be responsible for the downregulation of ANLS and GGC gene expression in MS NAGM. Indeed, challenging astrocytes with immune stimuli such as IL-1β and LPS reduced their ANLS and GGC gene expression in vitro. The detected upregulation of IL1B in MS NAGM suggests inflammasome priming. For this reason, astrocyte cultures were treated with ATP and ATP/LPS as for inflammasome activation. This treatment led to a reduction of ANLS and GGC gene expression in a comparable manner. To investigate potential sources for ANLS and GGC downregulation in MS NAGM, we first performed an adjuvant-driven stimulation of the peripheral immune system in C57Bl/6 mice in vivo. This led to similar gene expression changes in spinal cord demonstrating that peripheral immune signals might be one source for astrocytic gene expression changes in the brain. IL1B upregulation in MS NAGM itself points to a possible endogenous signaling process leading to ANLS and GGC downregulation. This is supported by our findings that, among others, MS NAGM astrocytes express inflammasome components and that astrocytes are capable to release Il-1β in-vitro. Altogether, our data suggests that immune signaling of immune- and/or central nervous system origin drives alterations in astrocytic ANLS and GGC gene regulation in the MS NAGM. Such a mechanism might underlie cortical brain dysfunctions frequently encountered in MS patients.

Deep brain stimulation for the treatment of resistant hypertension.

Hypertension is a leading risk factor for the development of several cardiovascular diseases. As the global prevalence of hypertension increases, so too has the recognition of resistant hypertension. Whilst figures vary, the proportion of hypertensive patients that are resistant to multiple drug therapies have been reported to be as high as 16.4 %. Resistant hypertension is typically associated with elevated sympathetic activity and abnormal homeostatic reflex control and is termed neurogenic hypertension because of its presumed central autonomic nervous system origin. This resistance to conventional pharmacological treatment has stimulated a plethora of medical devices to be investigated for use in hypertension, with varying degrees of success. In this review, we discuss a new therapy for drug-resistant hypertension, deep brain stimulation. The utility of deep brain stimulation in resistant hypertension was first discovered in patients with concurrent neuropathic pain, where it lowered blood pressure and improved baroreflex sensitivity. The most promising central target for stimulation is the ventrolateral periaqueductal gray, which has been well characterised in animal studies as a control centre for autonomic outflow. In this review, we will discuss the promise and potential mechanisms of deep brain stimulation in the treatment of severe, resistant hypertension.

LOX-1 expression and oxidized LDL uptake and toxicity in the HN33 neuronal cell line

Cardiovascular risk factors appear to influence the risk and progression of neurodegenerative disease, but the mechanisms involved are poorly understood. We investigated the possible involvement of oxidized low-density lipoprotein receptor (LOX-1) and oxidized low-density lipoprotein (Ox-LDL) in neurodegeneration by studying the expression of LOX-1 and the effects of Ox-LDL in HN33 cells, a neuronal cell line of central nervous system origin. HN33 cells showed LOX-1 protein expression, hypoxic induction of LOX-1, Ox-LDL uptake and Ox-LDL toxicity. LOX-1/Ox-LDL signaling may contribute to the association between cardiovascular risk factors and neurodegenerative disease.