Intranasal human-recombinant nerve growth factor administration improves cognitive functions in a child with severe traumatic brain injury.

BACKGROUND: Behavioral and neuropsychological functions are frequent long-term sequelae of severe traumatic brain injury (TBI). Neuropeptides, such as nerve growth factor (NGF), can enhance neurogenesis and improve cognitive functions after TBI, playing a pivotal role in neuroplasticity. A limited number of studies documented the safety and efficacy of intranasal NGF administration in children with severe TBI. CASE REPORT: A fourteen-year-old boy with a diffuse axonal injury secondary to severe TBI was treated with human-recombinant NGF administration. This patient underwent treatment with intranasal hr-NGF administration at a total dose of 50 gamma/kg, three times a day for seven consecutive days. The treatment schedule was performed for 4 cycles, at one month distance each. NGF administration improved radiologic functional assessment evaluated with positron emission tomography scan (PET) and single photon emission computed tomography (SPECT), with an important improvement in clinical conditions. Significant improvements were also observed, mainly in cognitive processes, memory, the planning of a communication strategy, execution skills, attention, and verbal expression. No side effects were reported. CONCLUSIONS: Additional studies are required to gain a deeper insight into this neurotrophin's neuroprotective function, but our findings reveal a potential efficacy of intranasal hr-NGF administration in enhancing cognitive and clinical outcomes among children with diffuse axonal injury after severe TBI.

Overt hypothyroidism in pregnancy and language development in offspring: is there an association?

PURPOSE: Overt hypothyroidism during pregnancy is linked to various obstetric complications, such as premature birth and fetal death. While some studies have shown that maternal hypothyroidism can impact a child's Intelligence Quotient (IQ) and language development, findings are controversial. The aim of this study was to explore the connection between treated maternal hypothyroidism during pregnancy and offspring neurodevelopment, focusing on learning and language and examining related maternal obstetric complications. METHODS: Group 1 included 31 hypothyroid women with elevated thyroid stimulating hormone (TSH) (> 10 mU/L, > 10 µIU/mL) during pregnancy, and Group 2 had 21 euthyroid women with normal TSH levels (0.5-2.5 mU/L, 0.5-2.5 µIU/mL). Children underwent neuropsycological assessments using the Griffiths-II scale. RESULTS: Pregnancy outcome showed an average gestational age at delivery of 38.2 weeks for hypothyroid women, compared to 40 weeks for controls, and average birth weight of 2855.6 g versus 3285 g for controls, with hypothyroid women having children with higher intrauterine growth restriction (IUGR) prevalence and more caesarean sections. The 1-min APGAR score was lower for the hypothyroid group's children, at 8.85 versus 9.52. Neuropsychological outcomes showed children of hypothyroid mothers scored lower in neurocognitive development, particularly in the learning and language subscale (subscale C), with a notable correlation between higher maternal TSH levels and lower subscale scores. CONCLUSION: Fetuses born to hypothyroid mothers appeared to be at higher risk of IUGR and reduced APGAR score at birth. Neurocognitive development seemed to affect language performance more than the developmental quotient. This alteration appeared to correlate with the severity of hypothyroidism and its duration.

Recommendations on the use of computed tomography in the stroke code: Consensus document SENR, SERAU, GEECV-SEN, SERAM.

The Spanish Society of Emergency Radiology (SERAU), the Spanish Society of Neuroradiology (SENR), the Spanish Society of Neurology through its Cerebrovascular Diseases Study Group (GEECV-SEN) and the Spanish Society of Medical Radiology (SERAM) have met to draft this consensus document that will review the use of computed tomography in the stroke code patients, focusing on its indications, the technique for its correct acquisition and the possible interpretation mistakes.

Complications after abdominal surgery.

Complications after abdominal surgery are often seen in emergency departments. Many postoperative complications (e.g., infections, abscesses, hematomas, and active bleeding) are common to all types of surgery; others are specific to different types of surgery. Computed tomography (CT) is the technique normally used to diagnose postoperative complications. This article reviews the changes that occur after some of the most common abdominal interventions that can be mistaken for pathological processes, the findings that can be considered normal after surgical intervention, and the most common early complications. It also describes the optimal protocols for CT studies depending on the different types of complications that are suspected.

A critical appraisal of clinical practice guidelines for the diagnosis and management of benign paroxysmal positional vertigo.

BACKGROUND: Delays in the diagnosis and therapy of benign paroxysmal positional vertigo can greatly impact quality of life and increase healthcare costs for patients. This study aimed to appraise the quality of clinical practice guidelines for the diagnosis and management of benign paroxysmal positional vertigo. METHODS: A comprehensive database search of clinical practice guidelines was completed up to 30 October 2021. Four independent reviewers used the Appraisal of Guidelines for Research and Evaluation II instrument in the quality appraisal. RESULTS: The highest score was in 'clarity and presentation' (58.33 ± 22.7). The lowest score was in 'applicability' (13.96 ± 30.1). Overall, four clinical practice guidelines were 'low quality' and only one guideline was 'high quality'. CONCLUSION: This review identified a significant lack of quality in clinical practice guideline development for benign paroxysmal positional vertigo, highlighting the need for a more rigorous approach for future guideline development.

Preclinical and clinical evaluation of the LRRK2 inhibitor DNL201 for Parkinson's disease.

Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic risk factors for Parkinson's disease (PD). Increased LRRK2 kinase activity is thought to impair lysosomal function and may contribute to the pathogenesis of PD. Thus, inhibition of LRRK2 is a potential disease-modifying therapeutic strategy for PD. DNL201 is an investigational, first-in-class, CNS-penetrant, selective, ATP-competitive, small-molecule LRRK2 kinase inhibitor. In preclinical models, DNL201 inhibited LRRK2 kinase activity as evidenced by reduced phosphorylation of both LRRK2 at serine-935 (pS935) and Rab10 at threonine-73 (pT73), a direct substrate of LRRK2. Inhibition of LRRK2 by DNL201 demonstrated improved lysosomal function in cellular models of disease, including primary mouse astrocytes and fibroblasts from patients with Gaucher disease. Chronic administration of DNL201 to cynomolgus macaques at pharmacologically relevant doses was not associated with adverse findings. In phase 1 and phase 1b clinical trials in 122 healthy volunteers and in 28 patients with PD, respectively, DNL201 at single and multiple doses inhibited LRRK2 and was well tolerated at doses demonstrating LRRK2 pathway engagement and alteration of downstream lysosomal biomarkers. Robust cerebrospinal fluid penetration of DNL201 was observed in both healthy volunteers and patients with PD. These data support the hypothesis that LRRK2 inhibition has the potential to correct lysosomal dysfunction in patients with PD at doses that are generally safe and well tolerated, warranting further clinical development of LRRK2 inhibitors as a therapeutic modality for PD.

Neurological development and iron supplementation in healthy late-preterm neonates: a randomized double-blind controlled trial.

Late-preterm infants (LPT) are at increased risk for long-term neurodevelopmental sequelae and iron deficiency. The aim of the study is to assess the positive effect of iron supplementation on psychomotor development in healthy LPT. We designed a randomized placebo-controlled double-blind trial dividing the newborns into two groups. Every patient was assessed using the Griffiths Mental Development Scales (GMDS)-II edition at 12-month post-conceptional age. The study was performed at the Neonatology Unit of our Hospital, in Italy. Sixty-six healthy LPT infants born between 340/7 and 366/7 weeks of gestational age were enrolled in the study. One group received martial prophylaxis from the third week of life to 6 months of post-conceptional age (2 mg/kg/day of iron pidolate), the other received placebo. Fifty-two of the enrolled infants were assessed using the GMDS at 12-month of post-conceptional age. Statistical analysis of the mean scores of the Griffiths subscales was performed. There was a difference in the mean developmental quotient (DQ) (p < 0.01) between the two groups: iron group mean DQ 121.45 ± 10.53 vs placebo group mean DQ 113.25 ± 9.70. Moreover, mean scores of the Griffiths subscales A, B, and D showed significant differences between the two groups (scale A p < 0.05, scale B p < 0.02, scale D p < 0.01, respectively).Conclusions: We recommend that all LPT neonates receive iron supplementation during the first 6 months of life in order to improve their 1-year neurodevelopmental quotient. What is Known: • Late-preterm infants (LPT) are at increased risk for long-term neurodevelopmental sequelae and also for iron deficiency. • Iron deficiency is an independent risk factor for adverse neurological outcomes. What is New: • Healthy late-preterm who received iron supplementation during the first 6 months of life achieved better neurological outcomes at 12-month post-conceptional age than LPT who received placebo. • Our study strongly supports the need for the implementation of martial prophylaxis in LPT neonates.

Obstetrical complications and outcome in patients with endometriosis.

Endometriosis is a disease that has a profound impact on the quality of life of women, due to the associated chronic pelvic pain, dysmenorrhea, dyspareunia and infertility. However, even getting long-awaited pregnancy (often after assisted reproductive technologies), patients with endometriosis have a high risk of obstetric complications, such as miscarriage, preterm birth, preeclampsia, placental abnormalities, hemorrhage in labor, birth of small for gestational age infants, stillbirth and higher cesarean section rate. In addition, during pregnancy acute complications of endometriosis may occur, such as spontaneous hemoperitoneum, which is rare but life-threatening conditions that in most cases require surgical intervention. The mechanisms of the observed complications in pregnant women with endometriosis are not fully understood. This review presents literature data and personal considerations on the effect of endometriosis on pregnancy outcome and the occurrence of complications, as well as their possible underlined mechanisms. Based on this, we proposed ways to reduce the risk of obstetric complications in pregnant women with a history of endometriosis.

Prenylated Flavonoids and C-15 Isoprenoid Analogues with Antibacterial Properties from the Whole Plant of Imperata cylindrica (L.) Raeusch (Gramineae).

The local botanical Imperata cylindrica in Cameroon was investigated for its antibacterial potency. The methanol extract afforded a total of seven compounds, including five hitherto unreported compounds comprising three flavonoids (1-3) and two C-15 isoprenoid analogues (4 and 5) together with known derivatives (6 and 7). The novelty of the flavonoids was related to the presence of both methyl and prenyl groups. The potential origin of the methyl in the flavonoids is discussed, as well as the chemophenetic significance of our findings. Isolation was performed over repeated silica gel and Sephadex LH-20 column chromatography and the structures were elucidated by (NMR and MS). The crude methanol extract and isolated compounds showed considerable antibacterial potency against a panel of multi-drug resistant (MDR) bacterial strains. The best MIC values were obtained with compound (2) against S. aureus ATCC 25923 (32 µg/mL) and MRSA1 (16 µg/mL).

Experimental analysis of the influence of cortical bone layers and bone quantity on implant primary stability.

The systematic analysis of parameters impacting implant primary stability is difficult to achieve with human cadavers or animal models, particularly for complex trans-sinus procedures to determine the effects of cortical layers and bone engagement on implant stability before and after a simulated load in vitro. Solid rigid polyurethane blocks, partially intersected by an 8-mm-thick space, were created to imitate tri-cortical situations, the presence of the sinus cavity, and the posterior maxilla with different degrees of bone atrophy. Implants were inserted through the cavity at an angle of 30˚ (scenarios 1 and 2) to imitate the clinical protocol. Controls simulating uni-cortical anchorage and no sinus cavity were also included (controls 1 and 2). Four parameters were measured: peak insertion torque, insertion work, resistance to lateral bending loads and extraction torque. Scenarios 1 and 2 displayed similar peak insertion torque to control 2, where all three groups anchored equal amounts of bone surrogate. The distribution of surrogate bone in contact with trans-cavity implants influenced both extraction torque and the degree of lateral bending. Sufficient peak insertion torque can be attained with a trans-sinus tricortical implant anchorage providing sufficient apical and coronal bone is engaged.

Multidetector computed tomography in planning the treatment of atrial fibrillation. / Tomografía computarizada multidetector en la planificación del tratamiento de la fibrilación auricular.

OBJECTIVE: To know the anatomy of the pulmonary veins (PVs) by multidetector computed tomography (MDCT) in patients with atrial fibrillation (AF) prior to ablation. MATERIALS AND METHODS: MDCT was performed in 89 patients with AF, analyzing the number of PVs, accessory variants and veins, diameter and ostial shape, distance to the first bifurcation and thrombus in the left atrial appendage. RESULTS: The most frequent venous pattern was 4 PVs (two right and two. left) in 49 patients (55.1%). The superior veins had a statistically significant greater mean ostial diameter than the inferior veins (Right Superior Pulmonary Vein (RSPV)> Right Inferior Pulmonary Vein (RIPV); p=0.001 and Left Superior Pulmonary Vein (LSPV)> Left Inferior Pulmonary Vein (LIPV); p<0.001). The right pulmonary veins ostial diameters were significantly larger than the left pulmonary veins ostial diameters (RSPV> LSPV; p<0.001 and RIPV> LIPV; p<0.001). The most circular ostium was presented by the VPID (ratio: 0.885) compared to the LIPV (p<00.1) and LSPV (p<0.001). The superior veins had a statistically significant greater mean distance to first bifurcation than the inferior veins (RSPV> RIPV; p=0.008 and LSPV> LIPV; p=0.038). Mean distance to first bifurcation has been greater in left PVs respect to the right PVs (LSPV> RSPV; p<0.001and LIPV> RIPV; p<0.001). Other findings found in AI: diverticula (30), accessory auricular appendages (5), septal aneurysms (8), septal bags (6) and 1 thrombus in the left atrial appendage. CONCLUSION: MDCT prior to ablation demonstrates the anatomy of the left atrium (LA) and pulmonary veins with significant differences between the diameters and morphology of the venous ostia.

Urgent Multidetector Computed Tomography in Colon Cancer: Postsurgical Changes and Early Complications. / Tomografía computarizada multidetector urgente de la cirugía del cáncer colorrectal: Cambios posquirúrgicos y complicaciones tempranas.

Complications after surgery for colorectal cancer are common in emergency departments. Multidetector computed tomography plays a fundamental role in the follow-up of patients after surgery, because it enables the detection of relapse and complications. Radiologists need to be familiar with different surgical techniques and the normal postsurgical changes so that we can differentiate them from potential complications and relapse. This article reviews the multidetector computed tomography findings that can be considered normal after surgical intervention for colorectal cancer as well as the most common early complications seen in postsurgical colorectal cancer patients presenting at emergency departments.

Gene expression analysis indicates reduced memory and cognitive functions in the hippocampus and increase in synaptic reorganization in the frontal cortex 3 weeks after MDMA administration in Dark Agouti rats.

BACKGROUND: 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") is a widely used entactogenic drug known to impair cognitive functions on the long-run. Both hippocampal and frontal cortical regions have well established roles in behavior, memory formation and other cognitive tasks and damage of these regions is associated with altered behavior and cognitive functions frequently described in otherwise healthy MDMA users. Meanwhile, in post-traumatic stress disorder (PTSD) patients seem to benefit from therapeutic application of the drug, where damage in hippocampal cue extinction may play a role. The aim of this study was to examine the hippocampus, frontal cortex and dorsal raphe of Dark Agouti rats with gene expression arrays (Illumina RatRef bead arrays) looking for possible mechanisms and new candidates contributing to the consequences of a single dose of MDMA (15 mg/kg) 3 weeks earlier. RESULTS: The number of differentially expressed genes in the hippocampus, frontal cortex and the dorsal raphe were 481, 155, and 15, respectively. Gene set enrichment analysis of the microarray data revealed reduced expression of 'memory' and 'cognition', 'dendrite development' and 'regulation of synaptic plasticity' gene sets in the hippocampus, parallel to the downregulation of CaMK II subunits, glutamate-, CB1 cannabinoid- and EphA4, EphA5, EphA6 receptors. Downregulated gene sets in the frontal cortex were related to protein synthesis, chromatin organization, transmembrane transport processes, while 'dendrite development', 'regulation of synaptic plasticity' and 'positive regulation of synapse assembly' gene sets were upregulated besides elevated levels of a CaMK II subunit and NMDA2B glutamate receptor. Changes in the dorsal raphe region were mild and in most cases not significant. CONCLUSION: The present data raise the possibility of new synapse formation / synaptic reorganization in the frontal cortex 3 weeks after a single neurotoxic dose of MDMA. In contrast, a prolonged depression of new neurite formation in the hippocampus is proposed by downregulations of members in long-term potentiation pathway and synaptic plasticity emphasizing the particular vulnerability of this brain region and proposing a mechanism responsible for cognitive problems in healthy individuals. At the same time, these results underpin benefits of MDMA in PTSD, where the drug may help memory extinction.

Multidetector computed tomography evaluation of candidates for transcatheter aortic valve implantation. / Evaluación de los pacientes candidatos a implante transcatéter de válvula aórtica mediante tomografía computarizada multidetector.

In transcatheter aortic valve implantation (TAVI), a biologic valve mounted in a stent is implanted without removing the native valve. This procedure was first done in humans by Alain Cribier in 2002 and was included in clinical guidelines after the multicenter PARTNER (Placement of AoRtic TraNscathetER) randomized clinical trial, which showed that TAVI obtained better outcomes than conservative medical treatment and is an alternative to surgery in patients with high surgical risk. Candidates for TAVI must be assessed to determine whether the procedure is feasible, because TAVI is not ideal for all patients who are considered inoperable. Multidetector computed tomography plays an important role in the anatomic evaluation of candidates and in guiding the procedure in those who are finally selected.

Immediate full-arch rehabilitation of the severely atrophic maxilla supported by zygomatic implants: a prospective clinical study with minimum follow-up of 6 years.

The aim of this study was to evaluate the outcomes of immediate full-arch prostheses supported by zygomatic implants alone or in combination with standard fixtures after a minimum of 6 years of loading. From October 2008 to April 2010, 15 patients with severely atrophic maxillae were treated using four zygomatic implants or two zygomatic implants in conjunction with two conventional fixtures. All subjects received a fixed screw-retained prosthesis within 3hours of surgery, while the final restoration was delivered after 6 months. Follow-up examinations were scheduled to evaluate zygomatic implant survival, conventional dental implant success, prosthetic success, plaque and bleeding scores, marginal bone loss for conventional dental implants, and patient satisfaction. Forty-two zygomatic fixtures and 18 standard implants were placed. Patients were followed up for a minimum of 79 months (range 79-97 months, average 90.61 months). No implant was lost, leading to implant and prosthetic survival rates of 100%. Bone loss for conventional implants averaged 1.39±0.10mm after 6 years of function, leading to a 100% implant success rate. High levels of patient satisfaction were recorded. These medium-term results indicate that immediate full-arch rehabilitation supported by zygomatic implants could be considered a viable treatment modality for the severely atrophic maxilla.

Gynecological pelvic pain as emergency pathology. / Dolor pélvico de origen ginecológico como patología urgente.

Acute pelvic pain is a common condition in emergency. The sources of acute pelvic pain are multifactorial, so it is important to be familiar with this type of pathologies. The purpose of this article is review the main causes of gynecological acute pelvic pain and their radiologic appearances to be able to make an accurate diagnosis and provide objective criteria for patient management.

Transcriptional evidence for the role of chronic venlafaxine treatment in neurotrophic signaling and neuroplasticity including also Glutamatergic [corrected] - and insulin-mediated neuronal processes.

OBJECTIVES: Venlafaxine (VLX), a serotonine-noradrenaline reuptake inhibitor, is one of the most commonly used antidepressant drugs in clinical practice for the treatment of major depressive disorder (MDD). Despite being more potent than its predecessors, similarly to them, the therapeutical effect of VLX is visible only 3-4 weeks after the beginning of treatment. Furthermore, recent papers show that antidepressants, including also VLX, enhance the motor recovery after stroke even in non depressed persons. In the present, transcriptomic-based study we looked for changes in gene expressions after a long-term VLX administration. METHODS: Osmotic minipumps were implanted subcutaneously into Dark Agouti rats providing a continuous (40 mg/kg/day) VLX delivery for three weeks. Frontal regions of the cerebral cortex were isolated and analyzed using Illumina bead arrays to detect genes showing significant chances in expression. Gene set enrichment analysis was performed to identify specific regulatory networks significantly affected by long term VLX treatment. RESULTS: Chronic VLX administration may have an effect on neurotransmitter release via the regulation of genes involved in vesicular exocytosis and receptor endocytosis (such as Kif proteins, Myo5a, Sv2b, Syn2 or Synj2). Simultaneously, VLX activated the expression of genes involved in neurotrophic signaling (Ntrk2, Ntrk3), glutamatergic transmission (Gria3, Grin2b and Grin2a), neuroplasticity (Camk2g/b, Cd47), synaptogenesis (Epha5a, Gad2) and cognitive processes (Clstn2). Interestingly, VLX increased the expression of genes involved in mitochondrial antioxidant activity (Bcl2 and Prdx1). Additionally, VLX administration also modulated genes related to insulin signaling pathway (Negr1, Ppp3r1, Slc2a4 and Enpp1), a mechanism that has recently been linked to neuroprotection, learning and memory. CONCLUSIONS: Our results strongly suggest that chronic VLX treatment improves functional reorganization and brain plasticity by influencing gene expression in regulatory networks of motor cortical areas. These results are consonant with the synaptic (network) hypothesis of depression and antidepressant-induced motor recovery after stroke.

Astrocyte-neuron interaction in the substantia gelatinosa of the spinal cord dorsal horn via P2X7 receptor-mediated release of glutamate and reactive oxygen species.

The substantia gelatinosa (SG) of the spinal cord processes incoming painful information to ascending projection neurons. Whole-cell patch clamp recordings from SG spinal cord slices documented that in a low Ca(2+) /no Mg(2+) (low X(2+) ) external medium adenosine triphosphate (ATP)/dibenzoyl-ATP, Bz-ATP) caused inward current responses, much larger in amplitude than those recorded in a normal X(2+) -containing bath medium. The effect of Bz-ATP was antagonized by the selective P2X7 receptor antagonist A-438079. Neuronal, but not astrocytic Bz-ATP currents were strongly inhibited by a combination of the ionotropic glutamate receptor antagonists AP-5 and CNQX. In fact, all neurons and some astrocytes responded to NMDA, AMPA, and muscimol with inward current, demonstrating the presence of the respective receptors. The reactive oxygen species H2 O2 potentiated the effect of Bz-ATP at neurons but not at astrocytes. Hippocampal CA1 neurons exhibited a behavior similar to, but not identical with SG neurons. Although a combination of AP-5 and CNQX almost abolished the effect of Bz-ATP, H2 O2 was inactive. A Bz-ATP-dependent and A-438079-antagonizable reactive oxygen species production in SG slices was proven by a microelectrode biosensor. Immunohistochemical investigations showed the colocalization of P2X7-immunoreactivity with microglial (Iba1), but not astrocytic (GFAP, S100ß) or neuronal (MAP2) markers in the SG. It is concluded that SG astrocytes possess P2X7 receptors; their activation leads to the release of glutamate, which via NMDA- and AMPA receptor stimulation induces cationic current in the neighboring neurons. P2X7 receptors have a very low density under resting conditions but become functionally upregulated under pathological conditions.

Central P2Y12 receptor blockade alleviates inflammatory and neuropathic pain and cytokine production in rodents.

In this study the role of P2Y12 receptors (P2Y12R) was explored in rodent models of inflammatory and neuropathic pain and in acute thermal nociception. In correlation with their activity to block the recombinant human P2Y12R, the majority of P2Y12R antagonists alleviated mechanical hyperalgesia dose-dependently, following intraplantar CFA injection, and after partial ligation of the sciatic nerve in rats. They also caused an increase in thermal nociceptive threshold in the hot plate test. Among the six P2Y12R antagonists evaluated in the pain studies, the selective P2Y12 receptor antagonist PSB-0739 was most potent upon intrathecal application. P2Y12R mRNA and IL-1ß protein were time-dependently overexpressed in the rat hind paw and lumbar spinal cord following intraplantar CFA injection. This was accompanied by the upregulation of TNF-α, IL-6 and IL-10 in the hind paw. PSB-0739 (0.3mg/kg i.t.) attenuated CFA-induced expression of cytokines in the hind paw and of IL-1ß in the spinal cord. Subdiaphragmatic vagotomy and the α7 nicotinic acetylcholine receptor antagonist MLA occluded the effect of PSB-0739 (i.t.) on pain behavior and peripheral cytokine induction. Denervation of sympathetic nerves by 6-OHDA pretreatment did not affect the action of PSB-0739. PSB-0739, in an analgesic dose, did not influence motor coordination and platelet aggregation. Genetic deletion of the P2Y12R in mice reproduced the effect of P2Y12R antagonists on mechanical hyperalgesia in inflammatory and neuropathic pain models, on acute thermal nociception and on the induction of spinal IL-1ß. Here we report the robust involvement of the P2Y12R in inflammatory pain. The anti-hyperalgesic effect of P2Y12R antagonism could be mediated by the inhibition of both central and peripheral cytokine production and involves α7-receptor mediated efferent pathways.