[Research progress on robot-assisted subretinal and intravascular injection surgeries].

Various retinal diseases require subretinal and/or intravascular injections, which are precise and challenging ocular microsurgeries. Robot-assisted surgery is expected to promote surgery precision, visualization, and success rates. This review summarizes recent research progress on robot-assisted surgery for subretinal and intravascular injections, emphasizing effectiveness, safety, and intelligence, and aiming to provide valuable insights for research on the application of surgical robots in the treatment of retinal diseases.

[Feasibility analysis of immediate implant placement in the maxillary molar region].

Objective: To study the clinical outcomes and feasibility of immediate implantation after flap surgery and minimally invasive extraction in the maxillary molar area and to provide a reference for it. Methods: Forty-one patients (41 molars in total) with maxillary molars that could not be preserved, treated from June 2018 to June 2020 at the Department of Oral and Maxillofacial Surgery at the Affiliated Hospital of Qingdao University, were selected. There are 24 males and 17 females with the age of (49.7±1.8) years (range 18-66 years). Pre-operative cone-beam CT (CBCT) was taken for measurement and analysis. After flap surgery and minimally invasive tooth extraction, the inflammatory granulation tissues attached to the soft and hard tissues were completely scraped and clipped, followed by the preparation of the implants in the correct three-dimensional position. Torque value and implant stability quotient (ISQ) were recorded after implant placement and with non-submerged healing. CBCT examination was taken 6 months after surgery and ISQ value was checked before crown restoration. CBCT examination was also taken 1 year after the permanent restoration. The survival rate of 6 months after surgery, the success rate of 1 year after permanent restoration, and the size of jump gaps immediately after surgery, 6 months after surgery, 1 year after permanent restoration respectively, were performed. The ISQ values were compared immediately and 6 months after surgery. Results: A total of 41 implants were placed in 41 patients. Six months after surgery, the survival rate was 100% (41/41). Twelve months after permanent restoration, the success rate of the implant restoration was 100% (41/41). The torque value after implant implantation was (42.77±0.79) N·cm. The buccal and palatal jump gaps were (3.15±0.16) mm and (2.86±0.18) mm immediately after surgery, respectively. The mesial and distal jump gaps were (2.94±0.19) mm and (3.77±0.21) mm, respectively. CBCT showed that no jump gap around the implants at 6 months after surgery and 1 year after permanent restoration. The ISQ values at immediately and 6 months after surgery were (74.78±0.59) and (80.20±0.49) respectively, and the difference was statistically significant (t=-9.03, P<0.001). Conclusions: Immediate dental implantation in the correct three-dimensional position could achieve good osseointegration by means of flap surgery, minimally invasive extraction and thorough removal of inflammatory tissue on the surface of soft and hard tissues. The clinical outcomes were satisfactory.

[Analysis of unplanned reoperation following vitreoretinal surgery].

Objective: To determine the incidence of unplanned reoperation following vitreoretinal surgery and identify the reasons for unplanned reoperations. Methods: Case records of all patients undergoing vitreoretinal surgery at Peking Union Medical College Hospital between June 2014 and June 2017 were reviewed to determine the incidence of unplanned reoperations during the primary admission and within 90 days following vitreoretinal surgery. Results: A total of 3 356 case records were reviewed. During the primary admission, 97 times of unplanned reoperation occurred in 81 cases [45 males and 36 females, aged (47.3±16.8) years].The incidence of unplanned reoperation was 2.4% (81/3 356). The most common primary diseases were retinal detachment (25 cases, 30.9%), proliferative diabetic retinopathy (23 cases, 28.4%) and silicone oil filled eye (17 cases, 21.0%). The most common reasons for unplanned reoperation were new onset or recurrent retinal detachment (33 times, 34.0%), increased intraocular pressure (23 times, 23.7%), as well as hyphema and inflammation (16 times, 16.5%). The percentages of the primary diseases and reasons for unplanned reoperation within 90 days following vitreoretinal surgery were not significantly different when compared with those during the primary admission. Desired results could be achieved in all cases after unplanned reoperation. Conclusions: The primary diseases of unplanned reoperation for vitreoretinal surgery are complicated retinal detachment, diabetic retinopathy and silicone oil filled eyes. New onset or recurrent retinal detachment, increased intraocular pressure, hyphema and inflammation are common causes of reoperation.

RETRACTED: Modulation of macrophage phenotype through controlled release of interleukin-4 from gelatine coatings on titanium surfaces.

Pro-inflammatory phenotype (M1) macrophages initiate angiogenesis, while their prolonged activation can induce chronic inflammation. Anti-inflammatory phenotype (M2) macrophages promote vessel maturation and tissue regeneration. Biomaterials which can promote M2 polarisation after appropriate inflammation should enhance angiogenesis and wound healing. Herein, Interleukin-4 (IL-4), an anti-inflammatory cytokine, was adsorbed onto a titanium surface. Then, a genipin cross-linked gelatine hydrogel was coated onto the surface to delay IL-4 release. The cross-linking degree of the hydrogel was modulated by the different amount of genipin to control release of IL-4. When 0.7 wt% (weight %) genipin was used as a cross-linker, the sample (GG07-I) released less IL-4 within the first several days, followed by a sustained release time to 14 d. Meanwhile, the release rate of IL-4 in GG07-I reached a peak between 3 d and 7 d. In culture with macrophages in vitro, GG07-I and GG07 exhibited good cytocompatibility. The phenotypical switch of macrophages stimulated by the samples was determined by FACS, ELISA and PCR. Macrophages cultured with GG07-I, GG07 and PT were firstly activated to the M1 phenotype by interferon-gamma (IFN-γ). Then, due to the release of IL-4 in 5 to 7 d, GG07-I enhanced CD206, increased the secretion and gene expression of M2 marker, such as interleukin-10 (IL-10), arginase-1 (ARG-1) and platelet derived growth factor-BB (PDGF- BB). GG07-I prompted the switch from M1 to M2 phenotype. Those appropriate secretion of cytokines would benefit both vascularisation and osseointegration. Thus, the biomaterial directing inflammatory reaction has good prospects for clinical treatments.

The change of plasma pituitary adenylate cyclase-activating polypeptide levels after aneurysmal subarachnoid hemorrhage.

OBJECTIVE: Elevated circulating pituitary adenylate cyclase-activating polypeptide (PACAP) levels have been demonstrated to be associated with clinical outcomes of severe traumatic brain injury. The current study aimed to confirm whether elevated plasma PACAP levels are predictive of clinical outcomes of aneurysmal subarachnoid hemorrhage (aSAH). MATERIALS AND METHODS: One hundred and eighteen aSAH patients and 118 controls were recruited. Plasma PACAP concentrations were determined using enzyme-linked immunosorbent assay. Patients were followed up until death or completion of 6 months after aSAH. An unfavorable outcome was defined as Glasgow Outcome Scale score of 1-3. RESULTS: The admission PACAP levels were significantly elevated in all patients (296.6 ± 119.7 pg/ml) compared with controls (77.1 ± 17.9 pg/ml, P < 0.001). Plasma PACAP levels were independently associated with clinical severity indicated by World Federation of Neurological Surgeons (WFNS) score (t = 4.745, P < 0.001) and Fisher score (t = 4.239, P < 0.001) using a multivariate linear regression. PACAP was identified as an independent predictor for 6-month mortality [odds ratio (OR), 1.014; 95% confidence interval (CI), 1.005-1.030; P < 0.001] and 6-month unfavorable outcome (OR, 1.012; 95% CI, 1.006-1.028; P < 0.001) and 6-month overall survival (hazard ratio, 1.016; 95% CI, 1.008-1.023; P < 0.001) using a binary logistic regression analysis and a Cox's proportional hazard analysis, respectively. PACAP had similar predictive values compared with WFNS score and Fisher score according to the receiver operating characteristic curve analysis. CONCLUSIONS: Higher plasma PACAP levels are associated with clinical severity and long-term prognosis of aSAH patients, and PACAP has potential to be a good prognostic biomarker of aSAH.

Relevance and clinical significance of serum resistin level in obese T2DM rhesus monkey models.

Resistin is a type of hormone-like adipocytokines, which is secreted specifically by adipocytes. It may be a key factor in the development of type 2 diabetes mellitus (T2DM) from obesity- associated insulin resistance due to results that show that it has a close relationship with insulin resistance in rodents. We utilized the rhesus monkeys as study objects to preliminarily test the association with glucose metabolism and to conduct a correlation analysis for clinical parameters and serum resistin levels in obese rhesus monkey models of T2DM. The results suggested that resistin was significantly increased in T2DM monkeys (P <0.01), and that resistin had a positive correlation respectively with total cholesterol (TC), low-density lipoprotein (LDL-C), fasting plasma glucose (FPG), fasting insulin (FPI) and glycated hemoglobin (HbA1c), Insulin resistance index (HOA-IR), but a negative correlation with islet ß-cell function (HOMA-ß). In the course of glucose metabolism, reverse release change of resistin and insulin in T2DM monkeys occurred, but the phenomenon that was not observed in the control group, these findings indicated that resistin negatively regulated and interfered with carbohydrate metabolism in T2DM monkey models. The character of the releasing change of resistin might be a unique process in T2DM. Therefore, all of the results could provide references for clinical diagnostic criteria for human cases of T2DM, and could have clinical significance for obese T2DM diagnosis and degree of insulin resistance.

Ultrasonic dissection versus conventional electrocautery during gastrectomy for gastric cancer: a meta-analysis of randomized controlled trials.

OBJECTIVE: Use of ultrasonic surgical instrument is gaining popularity for dissection and coagulation in open surgery. However, there is still no consensus on the efficacy and safety of its use compared with conventional surgical technique in open gastrectomy for gastric cancer. The aim of this meta-analysis was to evaluate the role and surgical outcomes of ultrasonic dissection (UD) compared with conventional electrocautery (EC). METHODS: A systematic literature search was performed to identify all studies comparing UD and EC in gastric cancer surgery. Intraoperative and postoperative outcomes were compared using weighted mean differences (WMDs) and odds ratios (ORs). RESULTS: Five studies were included in this meta-analysis, comprising 489 patients. Meta-analysis results showed that compared with EC, UD was associated with significantly shorter operation time (P = 0.03), less intraoperative blood loss (P = 0.002), lower morbidity (P = 0.02), and reduced postoperative hospital stay (P = 0.03). However, there was no significant difference between the two surgical techniques with regards to postoperative abdominal drainage (P = 0.17), and total cost in hospital (P = 0.59). CONCLUSIONS: Compared to EC, the use of UD during open gastrectomy can provide several improved outcomes for operation time, intraoperative blood loss, overall morbidity, and postoperative hospital stay. It appears that UD can be used instead of conventional EC in open gastric cancer surgery, although more larger trials with long follow-up should be performed.

Genetic variability of ERCC1 and ERCC2 influences treatment outcomes in gastric cancer.

We performed a study to investigate the role of ERCC1 (rs11615, rs2298881, and rs3212986) and ERCC2 (rs13181, rs238406, and rs1799793) polymorphisms in the prognosis of gastric cancer. A total of 346 patients with gastric cancer were recruited between May 2009 and May 2012. Single nucleotide polymorphism genotyping was performed using the Sequenom MassARRAY platform. The GA+AA genotype of ERCC2 rs1799793 showed significant and favorable response to chemotherapy than the wide-type GG genotype in multivariate analysis (OR = 1.78, 95%CI = 1.13-2.81). In a Cox proportional hazard model, carriers of ERCC2 rs1799793 GA+AA genotype exhibited longer duration of survival than did those with the GG genotype (hazards ratio = 0.57, 95%CI = 0.35-0.92). In conclusion, our study suggests that ERCC2 rs1799793 polymorphic variation could be used as a predictor for the prognosis of gastric cancer.

Human oral mucosa and gingiva: a unique reservoir for mesenchymal stem cells.

Mesenchymal stem cells (MSCs) represent a heterogeneous population of progenitor cells with self-renewal and multipotent differentiation potential. Aside from their regenerative role, extensive in vitro and in vivo studies have demonstrated that MSCs are capable of potent immunomodulatory effects on a variety of innate and adaptive immune cells. In this article, we will review recent experimental studies on the characterization of a unique population of MSCs derived from human oral mucosa and gingiva, especially their immunomodulatory and anti-inflammatory functions and their application in the treatment of several in vivo models of inflammatory diseases. The ease of isolation, accessible tissue source, and rapid ex vivo expansion, with maintenance of stable stem-cell-like phenotypes, render oral mucosa- and gingiva-derived MSCs a promising alternative cell source for MSC-based therapies.

Plasma resistin, associated with single nucleotide polymorphism -420, is correlated with C-reactive protein in Chinese Han patients with spontaneous basal ganglia hemorrhage.

We examined a possible relationship -420C>G SNP of the resistin gene with plasma resistin and C-reactive protein concentrations in intracerebral hemorrhage. Three hundred and forty-four Chinese Han patients with intracerebral hemorrhage and 344 age- and gender-matched healthy controls were included in our study. Plasma resistin and C-reactive concentrations were measured and SNP -420C>G was genotyped. The genotype frequencies in controls and patients were not significantly different (P = 0.672). Plasma resistin and C-reactive protein levels were significantly different between the SNP -420C>G genotypes, even after adjustment for age, gender and body mass index. The common homozygote (C-C) had the lowest resistin and C-reactive protein plasma concentrations; the plasma resistin and C-reactive protein concentrations in the heterozygote (C-G) and the rare allele homozygote (G-G) did not differ significantly. Plasma resistin levels were significantly associated with plasma C-reactive protein level. We conclude that SNP -420C>G of the resistin gene could be involved in the inflammatory component of intracerebral hemorrhage through enhanced production of resistin.

Smoking cessation among Hong Kong Chinese smokers attending hospital as outpatients: impact of doctors' advice, successful quitting and intention to quit.

To identify factors affecting current smokers' intention to quit smoking and factors associated with successful quitting among ex-smokers in Hong Kong. A cross-sectional survey of Chinese patients attending medical and surgical Specialist Outpatient Clinics (SOPCs) of public hospitals in Hong Kong, using a structured questionnaire. Results of the 642 respondents, 21% were current smokers, 9% were ex-smokers and 69% were non-smokers. 74% of the smokers reportedly received quitting advice from doctors. Among the current smokers, past quitting attempts, receiving information from sources other than doctors, believing that doctor's advice was useful, believing that all smokers should quit smoking and a positive attitude towards quitting were associated with intention to quit. Among those who had attempted to quit, being older (aged 50 or above), being retired/unemployed and consuming more than 10 cigarettes per day were associated with successful quitting. We found that advice from doctors on quitting smoking did not have any impact on Chinese smokers quitting or future intention to quit and reflect the inadequacy of advice given by Hong Kong doctors. The predictors of intention to quit and successful quitting identified in the study could be used to design future smoking cessation services.

Vitamin E stimulates luteinizing hormone-releasing hormone and ascorbic acid release from medial basal hypothalami of adult male rats.

Vitamin E, a dietary factor, is essential for reproduction in animals. It is an antioxidant present in all mammalian cells. Previously, we showed that ascorbic acid (AA) acted as an inhibitory neurotransmitter in the hypothalamus by scavenging nitric oxide (NO). Earlier studies have shown the antioxidant synergism between vitamin E and ascorbic acid (AA). Therefore, it was of interest to evaluate the effect of vitamin E on luteinizing hormone-releasing hormone (LHRH) and AA release. Medial basal hypothalami from adult male rats of the Sprague Dawley strain were incubated with Krebs-Ringer bicarbonate buffer or graded concentrations of a water soluble form of vitamin E, tocopheryl succinate polyethylene glycol 1000 (TPGS, 22-176 microM) for 1 hr. Subsequently, the tissues were incubated with vitamin E or combinations of vitamin. E + N-methyl-D-aspartic acid (NMDA), an excitatory amino acid for 30 min to study the effect of prior and continued exposure to vitamin E on NMDA-induced LHRH release. AA and LHRH released into the incubation media were determined by high-performance liquid chromatography and radioimmunoassay, respectively. Vitamin E stimulated both LHRH and AA release. The minimal effective concentrations were 22 and 88 microM, respectively. NMDA stimulated LHRH release as previously shown and this effect was not altered in the combined presence of vitamin E plus NMDA. However, AA release was significantly reduced in the combined presence of vitamin E plus NMDA. To evaluate the role of NO in vitamin E-induced LHRH and AA release, the tissues were incubated with vitamin E or combinations of vitamin E + NG-monomethyl-L-arginine (NMMA), a competitive inhibitor of NO synthase. NMMA significantly suppressed vitamin E-induced LHRH and AA release indicating a role of NO in the release of both LHRH and AA. The data suggest that vitamin E plays a role in the hypothalamic control of LHRH and AA release and that the release is mediated by NO.

Lamprey GnRH-III acts on its putative receptor via nitric oxide to release follicle-stimulating hormone specifically.

Lamprey gonadotropin-releasing hormone-III (l-GnRH-III), the putative follicle-stimulating hormone (FSH)-releasing factor (FSHRF), exerts a preferential FSH-releasing activity in rats both in vitro and in vivo. To test the hypothesis that l-GnRH-III acts on its own receptors to stimulate gonadotropin release, the functional activity of this peptide at mammalian (m) leutinizing hormone (LH)RH receptors transfected to COS cells was tested. l-GnRH-III activated m-LHRH receptors only at a minimal effective concentration (MEC) of 10(-6) M, whereas m-LHRH was active at a MEC of 10(-9) M, at least 1,000 times less than that required for l-GnRH-III. In 4-day monolayer cultured cells, l-GnRH-III was similarly extremely weak in releasing either LH or FSH, and, in fact, it released LH at a lower concentration (10(-7) M) than that required for FSH release (10(-6) M). In this assay, m-LHRH released both FSH and LH significantly at the lowest concentration tested (10(-10) M). On the other hand, l-GnRH-III had a high potency to selectively release FSH and not LH from hemipituitaries of male rats. The results suggest that the cultured cells were devoid of FSHRF receptors, thereby resulting in a pattern of FSH and LH release caused by the LHRH receptor. On the other hand, the putative FSH-releasing factor receptor accounts for the selective FSH release by l-GnRH-III when tested on hemipituitaries. Removal of calcium from the medium plus the addition of EGTA, a calcium chelator, suppressed the release of gonadotropins induced by either l-GnRH-III or LHRH, indicating that calcium is required for the action of either peptide. Previous results showed that sodium nitroprusside, a releaser of nitric oxide (NO), causes the release of both FSH and LH from hemipituitaries incubated in vitro. In the present experiments, a competitive inhibitor of NO synthase, L-NG-monomethyl-L-arginine (300 micro M) blocked the action of l-GnRH-III or partially purified FSHRF. The results indicate that l-GnRH-III and FSHRF act on putative FSHRF receptors by a calcium-dependent NO pathway.

Resting and circadian release of nitric oxide is controlled by leptin in male rats.

Because leptin stimulates nitric oxide (NO) release from the hypothalamus and anterior pituitary gland, we hypothesized that it also might release NO from adipocytes, the principal source of leptin. Consequently, plasma concentrations of leptin and NO, estimated from its metabolites NO(3) and NO(2) (NO(3)-NO(2)), were measured in adult male rats. There was a linear increase of both leptin and NO(3)-NO(2) with body weight that was associated with a parallel rise in fat mass. These findings indicate that release of leptin and NO is directly related to adipocyte mass. Furthermore, there was a parallelism in circadian rhythm of both substances, with peaks at 0130 h and nadirs at 0730 h. Measurement of both leptin and NO(3)-NO(2) in plasma from individual rats revealed that NO(3)-NO(2) increased linearly with leptin. Incubation of epididymal fat pads with leptin or its i.v. injection in conscious rats increased NO(3)-NO(2) release. The release of NO(3)-NO(2) in vivo and in vitro exceeded that of leptin by many fold, indicating that leptin activates NO synthase. Leptin increased tumor necrosis factor (TNF)-alpha release at a 100-fold lower dose than required for NO release in vitro and in vivo, suggesting that it also may participate in leptin-induced NO release. However, because many molecules of leptin were required to release a molecule of TNF-alpha in vivo and in vitro, we believe that leptin-induced TNF-alpha release is an associated phenomenon not involved in NO production. The results support the hypothesis that adipocytes play a major role in NO release by activating NO synthase in the adipocytes and the adjacent capillary endothelium.

Gonadotropin-releasing hormone neurons in the preoptic-hypothalamic region of the rat contain lamprey gonadotropin-releasing hormone III, mammalian luteinizing hormone-releasing hormone, or both peptides.

This study utilized a newly developed antiserum, specific for lamprey gonadotropin-releasing hormone III (l-GnRH-III), to determine the following: in which regions of the rat hypothalamus the neuronal perikarya producing l-GnRH-III are localized; and whether this peptide, known to selectively induce follicle-stimulating hormone release, is coexpressed in neurons containing mammalian luteinizing hormone-releasing hormone (m-LHRH). Double-label immunocytochemistry was performed by using an l-GnRH-III polyclonal antiserum and an LHRH monoclonal antiserum. Immunopositive neurons for l-GnRH-III, m-LHRH, or neurons coexpressing both peptides were detected within the organum vasculosum lamina terminalis (OVLT) region of the preoptic area (POA). Caudal to the OVLT, l-GnRH-III-positive neurons were also observed dorso-medially, above the third ventricle in the medial POA. The m-LHRH neurons were not observed in this area. The lateral POA region contained neurons positive for both peptides along with single-labeled neurons for each peptide. Importantly, neurons that expressed l-GnRH-III, m-LHRH, or both peptides were also detected in the ventral regions of the rostral hypothalamus, dorsolateral to the borders of the supraoptic nuclei. In both of these latter areas, neurons containing l-GnRH-III were slightly dorsal to neurons containing only m-LHRH. The l-GnRH-III perikarya and fibers were eliminated by absorption of the primary antiserum with l-GnRH-III, but not by l-GnRH-I, chicken-GnRH-II, or m-LHRH. These results indicate that, unlike other isoforms of GnRH found in the mammalian brain, l-GnRH-III neurons not only are observed in regions that control follicle-stimulating hormone release but also are colocalized with m-LHRH neurons in areas primarily controlling LH release. These findings suggest an interrelationship between these two peptides in the control of gonadotropin secretion.

Control of gonadotropin secretion by follicle-stimulating hormone-releasing factor, luteinizing hormone-releasing hormone, and leptin.

Fractionation of hypothalamic extracts on a Sephadex G-25 column separates follicle-stimulating hormone-releasing factor (FSHRF) from luteinizing hormone-releasing hormone (LHRH). The FSH-releasing peak contained immunoreactive lamprey gonadotropin-releasing hormone (lGnRH) by radioimmunoassay, and its activity was inactivated by an antiserum specific to lGnRH. The identity of lGnRH-III with FSHRF is supported by studies with over 40 GnRH analogs that revealed that this is the sole analog with preferential FSH-releasing activity. Selective activity appears to require amino acids 5-8 of lGnRH-III. Chicken GnRH-II has slight selective FSH-releasing activity. Using a specific lGnRH-III antiserum, a population of lGnRH-III neurons was visualized in the dorsal and ventral preoptic area with axons projecting to the median eminence in areas shown previously to control FSH secretion based on lesion and stimulation studies. Some lGnRH-III neurons contained only this peptide, others also contained LHRH, and still others contained only LHRH. The differential pulsatile release of FSH and LH and their differential secretion at different times of the estrous cycle may be caused by differential secretion of FSHRF and LHRH. Both FSH and LHRH act by nitric oxide (NO) that generates cyclic guanosine monophosphate. lGnRH-III has very low affinity to the LHRH receptor. Biotinylated lGnRH-III (10(-9) M) labels 80% of FSH gonadotropes and is not displaced by LHRH, providing evidence for the existence of an FSHRF receptor. Leptin has equal potency as LHRH to release gonadotropins by NO. lGnRH-III specifically releases FSH, not only in rats but also in cows.

Lipopolysaccharide-induced tumor necrosis factor-alpha release is controlled by the central nervous system.

OBJECTIVE: Lipopolysaccharide (LPS) injection in mammals orchestrates the release of many proinflammatory and anti-inflammatory cytokines. Intravenous administration of 0.2 mg/kg of LPS into unanesthetized rats with indwelling jugular catheters provoked a rapid, 50-fold increase in plasma tumor necrosis factor (TNF)-alpha within 30 min, which declined by 60% by 120 min. To test our hypothesis that such a rapid increase of TNF-alpha would be either neurally or hormonally controlled, the effect on TNF-alpha release of anesthesia (ketamine/acepromazine/xylazine) and catecholaminergic agonists and antagonists, either alone or in the presence of LPS, was determined. METHODS: Rats bearing indwelling external jugular catheters were injected with the test drug or saline after removal of 0.6 ml of blood (-10 min). At time zero, LPS or saline was administered. Thereafter, blood samples were drawn at 15, 30, 120, 240 and 360 min. TNF-alpha was measured by immunoassay. RESULTS: Among all the drugs tested, only propranolol increased plasma TNF-alpha. Anesthesia significantly blunted the LPS-induced TNF-alpha peak by 50%. Isoproterenol, a beta-adrenergic agonist, also blocked LPS-induced TNF-alpha release by 70% at 30 min and 90% at 120 min. On the contrary, propranolol, a beta-receptor blocker, induced a highly significant 3-fold increase in plasma TNF-alpha concentrations at 30 min and augmented the response to LPS 2-fold after endotoxin injection. Phentolamine, an alpha-receptor blocker, decreased the LPS-induced TNF-alpha release by 57% at 30 min. Similarly, alpha-bromoergocryptine, a dopamine D2 receptor agonist, decreased the LPS-induced TNF-alpha peak by 70% at 30 min and 50% at 120 min. CONCLUSIONS: We conclude that TNF-alpha is at least in part neurally controlled since the anesthetic blocked its response to LPS. The fact that isoproterenol decreased the LPS-induced TNF-alpha release, whereas propranolol augmented basal and LPS-induced release suggests that the sympathetic nervous system inhibits basal and LPS-stimulated TNF-alpha release via beta-adrenergic receptors. Since phentolamine blocked LPS-induced release, this release may be induced, in part at least, by LPS-stimulated adrenergic drive acting on alpha-adrenergic receptors. The suppressive action of bromoergocryptine, a dopamine D2 receptor agonist, on LPS-induced TNF-alpha release may be mediated in part by suppression of prolactin release, which triggers TNF-alpha release.

Lipopolysaccharide-induced leptin release is neurally controlled.

Our hypothesis is that leptin release is controlled neurohormonally. Conscious, male rats bearing indwelling, external, jugular catheters were injected with the test drug or 0.9% NaCl (saline), and blood samples were drawn thereafter to measure plasma leptin. Anesthesia decreased plasma leptin concentrations within 10 min to a minimum at 120 min, followed by a rebound at 360 min. Administration (i.v.) of lipopolysaccharide (LPS) increased plasma leptin to almost twice baseline by 120 min, and it remained on a plateau for 360 min, accompanied by increased adipocyte leptin mRNA. Anesthesia largely blunted the LPS-induced leptin release at 120 min. Isoproterenol (beta-adrenergic agonist) failed to alter plasma leptin but reduced LPS-induced leptin release significantly. Propranolol (beta-receptor antagonist) produced a significant increase in plasma leptin but had no effect on the response to LPS. Phentolamine (alpha-adrenergic receptor blocker) not only increased plasma leptin (P < 0.001), but also augmented the LPS-induced increase (P < 0.001). alpha-Bromoergocryptine (dopaminergic-2 receptor agonist) decreased plasma leptin (P < 0.01) and blunted the LPS-induced rise in plasma leptin release (P < 0.001). We conclude that leptin is at least in part controlled neurally because anesthesia decreased plasma leptin and blocked its response to LPS. The findings that phentolamine and propranolol increased plasma leptin concentrations suggest that leptin release is inhibited by the sympathetic nervous system mediated principally by alpha-adrenergic receptors because phentolamine, but not propranolol, augmented the response to LPS. Because alpha-bromoergocryptine decreased basal and LPS-induced leptin release, dopaminergic neurons may inhibit basal and LPS-induced leptin release by suppression of release of prolactin from the adenohypophysis.

Ascorbic acid stimulates gonadotropin release by autocrine action by means of NO.

Because high concentrations of ascorbic acid (AA) are found in the adenohypophysis, we hypothesized that it might have an acute effect on the secretion of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the gland, particularly because we have reported that AA rapidly inhibits stimulated LH-releasing hormone (LHRH) release from medial basal hypothalamic explants. Incubation of anterior pituitary halves from adult male rats with graded concentrations of AA for 1 h induced highly significant release of both FSH and LH with a minimal effective concentration of 10(-5) M. Release remained on a plateau from 10(-5) to 10(-2) M. When both AA and an effective concentration of LHRH were incubated together, there was no additive response to LHRH and the response was the same as to either compound alone. The FSH and LH release in response to AA was blocked by incubation with N(G)-monomethyl-l-arginine (NMMA) (300 microM), a competitive inhibitor of NO synthase. NMMA also inhibited LHRH-induced LH and FSH release and gonadotropin release in the presence of both LHRH and AA, whereas sodium nitroprusside, a releaser of NO, stimulated LH and FSH release. Membrane depolarization caused by incubation in high potassium (K(+) = 28 or 56 mM) medium stimulated release of FSH, LH, and AA that was blocked by NMMA. We hypothesize that AA is released with FSH and LH from secretory granules. AA is transported back into gonadotropes by the AA transporter and increases intracellular [Ca(2+)]-activating NO synthase that evokes exocytosis of gonadotropins and AA by cGMP.