Long-term allopurinol use decreases the risk of prostate cancer in patients with gout: a population-based study.

BACKGROUND: Clinical observations indicated an increased risk of developing prostate cancer in gout patients. Chronic inflammation is postulated to be one crucial mechanism for prostate carcinogenesis. Allopurinol, a widely used antigout agent, possesses potent anti-inflammation capacity. We elucidated whether allopurinol decreases the risk of prostate cancer in gout patients. METHODS: We analyzed data retrieved from Taiwan National Health Insurance Database between January 2000 and December 2012. Patients diagnosed with gout during the study period with no history of prostate cancer and who had never used allopurinol were selected. Four allopurinol use cohorts (that is, allopurinol use (>365 days), allopurinol use (181-365 days), allopurinol use (91-180 days) and allopurinol use (31-90 days)) and one cohort without using allopurinol (that is, allopurinol use (No)) were included. The study end point was the diagnosis of new-onset prostate cancer. Multivariable Cox proportional hazards regression and propensity score-adjusted Cox regression models were used to estimate the association between the risk of prostate cancer and allopurinol treatment in gout patients after adjusting for potential confounders. RESULTS: A total of 25 770 gout patients (aged between 40 and 100 years) were included. Multivariable Cox regression analyses revealed that the risk of developing prostate cancer in the allopurinol use (>365 days) cohort was significantly lower than the allopurinol use (No) cohort (adjusted hazard ratio (HR)=0.64, 95% confidence interval (CI)=0.45-0.9, P=0.011). After propensity score adjustment, the trend remained the same (adjusted HR=0.66, 95% CI=0.46-0.93, P=0.019). CONCLUSIONS: Long-term (more than 1 year) allopurinol use may associate with a decreased risk of prostate cancer in gout patients.

An abbreviated Faecal Incontinence Quality of Life Scale for Chinese-speaking population with colorectal cancer after surgery: cultural adaptation and item reduction.

No instrument is available to assess the impact of faecal incontinence (FI) of quality of life for Chinese-speaking population. The purpose of the study was to adapt the Faecal Incontinence Quality of Life Scale (FIQL) for patients with colorectal cancer, assess the factor structure and reduce the items for brevity. A sample of 120 participants were enrolled. Internal consistency, test-retest reliability, and convergent and contrasted-groups validity were assessed. Construct validity was analysed using an exploratory and confirmatory factor analyses (CFA). The internal consistency (Cronbach's α of the total scale and four subscales = 0.98 and 0.97, 0.96, 0.92, 0.82 respectively), test-retest reliability (intraclass correlation coefficients ≥.98 for all scales with p < .001) and significant correlations of all scales with selected subscales of the Medical Outcomes Study 36-Item Short-Form Health Survey and the Wexner scale suggested satisfactory reliability and validity. The severe FI group (with a Wexner score ≥9) scored significantly lower on the scale than the less severe FI group (with a Wexner score <9) did (p < .001). The CFA supported a two-factor structure and demonstrated an excellent model fit of the 15-item abbreviated version of the FIQL-Chinese. The FIQL-Chinese has satisfactory validity and reliability and the abbreviated version may be more practical and applicable.

Systematic review and meta-analysis of acupuncture to reduce cancer-related pain.

We conducted a systematic review and meta-analysis to evaluate the effects of acupuncture on malignancy-related, chemotherapy (CT)- or radiation therapy (RT)-induced, surgery-induced, and hormone therapy (HT)-induced pain. Randomised controlled trials (RCTs) examining the effects of acupuncture on cancer-related pain were reached from the EMBASE, PubMed, PsycINFO, Cochrane Central Register of Controlled Trials, CINAHL, Airiti library, Taiwan Electrical Periodical Service, Wanfang Data (a Chinese database) and China Knowledge Resource Integrated Database from inception through June 2014. Heterogeneity, moderator analysis, publication bias and risk of bias associated with the included studies were examined. A total of 29 RCTs yielding 36 effect sizes were included. The overall effect of acupuncture on cancer-related pain was -0.45 [95% confidence interval (CI) = -0.63 to -0.26]. The subanalysis indicated that acupuncture relieved malignancy-related and surgery-induced pain [effect size (g) = -0.71, and -0.40; 95% CI = -0.94 to -0.48, and -0.69 to -0.10] but not CT- or RT-induced and HT-induced pain (g = -0.05, and -0.64, 95% CI = -0.33 to 0.24, and -1.55 to 0.27). Acupuncture is effective in relieving cancer-related pain, particularly malignancy-related and surgery-induced pain. Our findings suggest that acupuncture can be adopted as part of a multimodal approach for reducing cancer-related pain.

Compound deficiencies in multiple fibroblast growth factor signalling components differentially impact the murine gonadotrophin-releasing hormone system.

Gonadotrophin-releasing hormone (GnRH) neurones control the onset and maintenance of fertility. Aberrant development of the GnRH system underlies infertility in Kallmann syndrome [KS; idiopathic hypogonadotropic hypogonadism (IHH) and anosmia]. Some KS patients harbour mutations in the fibroblast growth factor receptor 1 (Fgfr1) and Fgf8 genes. The biological significance of these two genes in GnRH neuronal development was corroborated by the observation that GnRH neurones were severely reduced in newborn transgenic mice deficient in either gene. In the present study, we hypothesised that the compound deficiency of Fgf8 and its cognate receptors, Fgfr1 and Fgfr3, may lead to more deleterious effects on the GnRH system, thereby resulting in a more severe reproductive phenotype in patients harbouring these mutations. This hypothesis was tested by counting the number of GnRH neurones in adult transgenic mice with digenic heterozygous mutations in Fgfr1/Fgf8, Fgfr3/Fgf8 or Fgfr1/Fgfr3. Monogenic heterozygous mutations in Fgfr1, Fgf8 or Fgfr3 caused a 30-50% decrease in the total number of GnRH neurones. Interestingly, mice with digenic mutations in Fgfr1/Fgf8 showed a greater decrease in GnRH neurones compared to mice with a heterozygous defect in the Fgfr1 or Fgf8 alone. This compounding effect was not detected in mice with digenic heterozygous mutations in Fgfr3/Fgf8 or Fgfr1/Fgfr3. These results support the hypothesis that IHH/KS patients with digenic mutations in Fgfr1/Fgf8 may have a further reduction in the GnRH neuronal population compared to patients harbouring monogenic haploid mutations in Fgfr1 or Fgf8. Because only Fgfr1/Fgf8 compound deficiency leads to greater GnRH system defect, this also suggests that these fibroblast growth factor signalling components interact in a highly specific fashion to support GnRH neuronal development.

Associations of breakfast skipping with obesity and health-related quality of life: evidence from a national survey in Taiwan.

OBJECTIVE: This study investigated the associations of breakfast skipping with obesity and health-related quality of life (QOL). We also tested the hypothesis that there is a dose-dependent relationship between frequency of breakfast consumption and prevalence of obesity. SUBJECTS AND DESIGN: This cross-section study used a national representative sample (n=15 340) from the 2005 Taiwan National Health Interview Survey. Breakfast skippers were defined as those who ate breakfast about once a week or less often and those who never ate breakfast. Individuals were classified as 'obese' if their body mass index was >or=27. Health-related QOL was assessed using the Medical Outcome Studies 36-Item Short-Form (SF-36) Health Survey. Logistic regression was used to examine the odds ratio of obesity and associated 95% confidence intervals (CIs) in breakfast skippers compared with breakfast eaters. Multivariable logistic regression modeling was used to adjust all risk estimates for covariates. RESULTS: The unadjusted odds ratio of obesity in breakfast skippers was 1.23 (95% CI: 1.06, 1.43). The odds of developing obesity for breakfast skippers was 1.34 (95% CI: 1.15, 1.56) controlling for age, sex, marital status, educational level, monthly income, smoking, alcohol, betel nut chewing and exercise habit. The Cochran-Armitage trend test revealed that the prevalence rate of obesity decreased as the frequency of breakfast consumption increased (P=0.005). Breakfast skippers had significantly worse health-related QOL than breakfast eaters (P<0.001). Moreover, breakfast skippers had significantly lower scores in 5 out of 8 domain scores of the SF-36, namely general health perceptions (P<0.001), vitality (P<0.001), social functioning (P=0.036), emotional role (P<0.001) and mental health (P<0.001). CONCLUSION: The findings from this study add support to the potential role of breakfast eating in obesity prevention.

L-type calcium channels are involved in mediating the anti-inflammatory effects of magnesium sulphate.

BACKGROUND: Magnesium sulphate (MgSO(4)) has potent anti-inflammatory capacity. It is a natural calcium antagonist and a potent L-type calcium channel inhibitor. We sought to elucidate the possible role of calcium, the L-type calcium channels, or both in mediating the anti-inflammatory effects of MgSO(4). METHODS: RAW264.7 cells, an immortalized murine macrophage-like cell line, were treated with phosphate buffered saline, MgSO(4), lipopolysaccharide (LPS), LPS plus MgSO(4), LPS plus MgSO(4) plus extra-cellular supplement with calcium chloride (CaCl(2)), or LPS plus MgSO(4) plus the L-type calcium channel activator BAY-K8644. After harvesting, the production of inflammatory molecules was evaluated. Because the production of endotoxin-induced inflammatory molecules is regulated by the crucial transcription factor nuclear factor (NF)-kappaB, we also evaluated the expression of NF-kappaB. RESULTS: LPS significantly induced the production of inflammatory molecules, including macrophage inflammatory protein-2, tumour necrosis factor-alpha, interleukin (IL)-1beta, IL-6, nitric oxide/inducible nitric oxide synthase, and prostaglandin E(2)/cyclo-oxygenase-2. LPS also induced NF-kappaB activation, as inhibitor-kappaB degradation, NF-kappaB nuclear translocation, and NF-kappaB-DNA binding activity were significantly increased in LPS-treated RAW264.7 cells. MgSO(4), in contrast, significantly inhibited the LPS-induced inflammatory molecules production and NF-kappaB activation. Moreover, the effects of MgSO(4) on inflammatory molecules and NF-kappaB were reversed by extra-cellular calcium supplement with CaCl(2) and L-type calcium channel activator BAY-K8644. CONCLUSIONS: MgSO(4) significantly inhibited endotoxin-induced up-regulation of inflammatory molecules and NF-kappaB activation in activated RAW264.7 cells. The effects of MgSO(4) on inflammatory molecules and NF-kappaB may involve antagonizing calcium, inhibiting the L-type calcium channels, or both.

Bupivacaine inhibits COX-2 expression, PGE2, and cytokine production in endotoxin-activated macrophages.

BACKGROUND: Upregulation of cyclooxygenase-2 (COX-2) and resultant prostaglandin E(2) (PGE(2)) overproduction has been shown to play a crucial role in initiating a systemic inflammatory response during sepsis. Sepsis also induces robust production of pro-inflammatory cytokines tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), and IL-6 as well as anti-inflammatory cytokine IL-10. We sought to elucidate the effects of bupivacaine on COX-2 expression and production of PGE(2) and cytokines using an endotoxin-activated murine macrophages model. METHODS: Confluent murine macrophages (RAW264.7 cells) were treated with lipopolysaccharide (LPS, 100 ng/ml) or LPS plus bupivacaine (1, 10, or 100 microM). Bupivacaine was added immediately after LPS. After reacting for 18 h, cell cultures were harvested for subsequent analysis. RESULTS: LPS significantly upregulated COX-2 transcription and PGE(2) production in macrophages. LPS also significantly increased the production of TNF-alpha, IL-1beta, IL-6 and IL-10 in macrophages. Bupivacaine significantly inhibited the effects of LPS on COX-2 transcription and PGE(2) production in a dose-dependent manner. In a dose-dependent manner, bupivacaine also significantly inhibited the effects of LPS on the production of TNF-alpha, IL-1beta, and IL-6. However, bupivacaine exerted no significant effects on LPS-induced IL-10 production. CONCLUSION: Bupivacaine significantly inhibited COX-2 expression, PGE(2) and cytokine production in endotoxin-activated macrophages.

Pre-operative measurement of heart rate variability predicts hypotension during general anesthesia.

BACKGROUND: Peri-operative hymodynamic instability is one of the major concerns for anesthesiologists when performing general anesthesia for individuals with autonomic dysfunction. The purpose of this study was to examine the potential usage of pre-operative measurement of heart rate variability (HRV) in identifying which individuals, with or without diabetes, may be at risk of blood pressure (BP) instability during general anesthesia. METHODS: We studied 46 patients with diabetes and 87 patients without diabetes ASA class II or III undergoing elective surgery. Participants' cardiovascular autonomic function and HRV were assessed pre-operatively, and hymodynamic parameters were monitored continuously intra-operatively by an independent observer. RESULTS: Only 6% of the participants were classified as having cardiovascular autonomic neuropathy (CAN) based on traditional autonomic function tests whereas 15% experienced hypotension. Total power (TP, P = 0.006), low frequency (LF, P = 0.012) and high frequency (HF, P = 0.028) were significantly lower in individuals who experienced hypotension compared with those who did not. Multivariate logistic regression analysis revealed that TP [odds ratio (OR) = 0.15, 95% confidence interval (CI) = 0.05-0.47, P = 0.001] independently predicted the incidence of hypotension, indicating that each log ms2 increase in total HRV lowers the incidence of hypotension during general anesthesia by 0.15 times. After stepwise multiple linear regression analysis (R2= 11.5%), HF (beta = -11.1, SE = 2.79, P < 0.001) was the only independent determinant of the magnitude of systolic blood pressure (SBP) reduction at the 15th min after tracheal intubation. CONCLUSIONS: Spectral analysis of HRV is a sensitive method for detecting individuals who may be at risk of BP instability during general anesthesia but may not have apparent CAN according to traditional tests of autonomic function.

Platonin attenuates LPS-induced CAT-2 and CAT-2B induction in stimulated murine macrophages.

BACKGROUND: Platonin, a cyanine photosensitizing dye, is a potent immunomodulator that suppresses acute inflammation. Platonin not only inhibits interleukin (IL)-1beta, IL-6, and tumor necrosis factor (TNF)-alpha production but also improves circulatory failure in septic rats. In addition, platonin reduces plasma nitric oxide (NO) formation during sepsis. However, the effects of platonin on inducible NO synthase (iNOS) and cationic amino-acid transporter (including CAT-2, CAT-2 A, and CAT-2B) expressions during sepsis remain uninvestigated. METHODS: Five groups of confluent murine macrophages (RAW264.7 cells) were randomly allocated to receive a 1-h pretreatment of one of five doses of platonin (0.1 microM, 1 microM, 10 microM, 100 microM, or 1000 microM) followed by lipopolysaccharide (LPS; 100 ng ml(-1)). For negative, positive, and platonin control, three other groups of cell cultures were randomly allocated to receive phosphate-buffered saline, LPS, or platonin (1000 microM). The cultures were harvested after exposing them to LPS for 18 h or a comparable duration in those groups without LPS. NO production, L-arginine transport, and expression of the relevant enzymes were then evaluated. RESULTS: Platonin significantly attenuated LPS-induced up-regulation of iNOS expression and NO production in stimulated murine macrophages in a dose-dependent manner. Platonin also significantly inhibited up-regulation of CAT-2 and CAT-2B expression as well as L-arginine transport in LPS-stimulated murine macrophages in a dose-dependent manner. In contrast, CAT-2 A expression in murine macrophages was not affected by LPS and/or platonin. CONCLUSIONS: Platonin attenuates NO production and L-arginine transport in LPS-stimulated murine macrophages possibly through inhibiting iNOS, CAT-2, and CAT-2B expression.

Testosterone and estrogen act via different pathways to inhibit puberty in the male Siberian hamster (Phodopus sungorus).

The peripubertal transition in male mammals is accompanied by a gradual decrease in sensitivity to the inhibitory effects exerted by gonadal hormones, such as T and E2. Here, we investigated the effects of chronic T and its metabolites, 5alpha-dihydrotestosterone and E2 on the hypothalamo-pituitary-gonadal axis at puberty. We also examined if T effects are distinct or mediated through its conversion to 5alpha-dihydrotestosterone or E2. Twenty-day-old male Siberian hamsters were sc implanted with a SILASTIC brand capsule containing varying doses of T, 5alpha-dihydrotestosterone, or E2. Several functional parameters of the hypothalamo-pituitary-gonadal axis were evaluated including hypothalamic GnRH concentration, pituitary and plasma FSH levels, pituitary FSH and LH mRNA, and testicular status. Our results showed that gonadal steroids inhibited puberty in a dose-dependent manner as evaluated by testes mass (undiluted steroid: T, 27 +/- 3 mg; 5alpha-dihydrotestosterone, 18 +/- 1 mg; and E2, 62 +/- 4 mg relative to cholesterol-implanted controls, 510 +/- 42 mg). Also, T decreased plasma FSH below detectable levels, but pituitary FSH concentration was unaffected (1.37 +/- 0.16 ng/microg protein) while E2-treated hamsters had normal plasma FSH levels (3.5 +/- 0.98 ng/ml) yet significantly lower pituitary FSH concentration (0.09 +/- 0.04 ng/microg protein). These results showed that the pathways of T and E2 action on the hypothalamo-pituitary-gonadal axis are distinct.

Effects on the bispectral index during elective caesarean section: a comparison of propofol and isoflurane.

BACKGROUND: Awareness during general anesthesia has been a particular problem during caesarean section. About 7 percent of patients undergoing elective caesarean section have reported dreaming or recall of voices during the procedure. The bispectral index (BIS), a value derived from the electroencephalogram (EEG), has been shown to be useful in monitoring the depth of anesthesia. Supplementation of propofol or isoflurane for maintenance of anesthesia has been shown to effectively reduce the incidence of awareness. However, the effects of propofol or isoflurane on the BIS index have not been fully investigated. We therefore designed this study to compare the effects of isoflurane or propofol supplementation on the BIS index in 24 healthy parturients undergoing elective caesarean section. METHODS: All patients had induction of anesthesia and orotracheal intubation in rapid sequence made possible by 1 MAC isoflurane with 50% N2O-50% O2 as conveyer and atracurium. After delivery, patients were randomly assigned to either of two groups (isoflurane or propofol). Patients in the Isoflurane group (n = 12) received 0.5 MAC isoflurane in 67% N2O-33% O2 and fentanyl + droperidol. Patients in the propofol group (n = 12) received propofol (8 mg/kg/h) infusion combined with 67% N2O-33% O2 and fentanyl + droperidol. RESULTS: There was no difference between the two groups in total operation time, maternal blood loss, fetal Apgar scores. No differences between the two groups in heart rate, blood pressure or BIS index values were found throughout the surgery. No patient from either group reported recall of the operative procedure. However, 25% of patients (3 of 12) in the isoflurane group had poor uterine contraction, suggestive of doubtful appropriateness of the use of isoflurane for maintenance of anesthesia in delivery. CONCLUSIONS: We therefore concluded that supplementation of isoflurane or propofol for maintenance of anesthesia can satisfactorily decrease the BIS index and minimize the incidence of awareness in patients undergoing caesarean section under general anesthesia. The BIS index is a reliable monitor of the hypnotic component of anesthesia.

Premedication with low-dose oral midazolam reduces the incidence and severity of emergence agitation in pediatric patients following sevoflurane anesthesia.

BACKGROUND: Sevoflurane is a volatile anesthetic agent with low pungency, non-irritating odor, and low blood/gas partition coefficient that makes it an attractive alternative to halothane. However, a high incidence of emergence agitation (EA) has been reported in pediatric patients after sevoflurane anesthesia. The underlying mechanism of sevoflurane-induced EA remains unclear. Rapid recovery of consciousness (emergence) from sevoflurane anesthesia has been proposed as one possible mechanism. We, therefore, hypothesized that sedatives such as midazolam may counteract sevoflurane's rapid emergence and thus reduce the incidence and the severity of sevoflurane-induced EA. METHODS: A prospective, controlled, single-blinded study was carried out in 88 ASA class I or II pediatric patients scheduled for elective outpatient surgery. Patients were assigned to receive either midazolam (oral midazolam, 0.2 mg/kg as anesthetic premedication) or saline (oral normal saline as premedication) before the conduct of anesthesia. When separation from parents was due its process was watched and evaluated. Induction of anesthesia and maintenance of anesthesia were uniform in both groups. Induction of anesthesia was made possible with 8% sevoflurane and N2O in 50% O2. Intubation was performed straight without the aid of muscle relaxant and the ventilator was set to maintain normocapnia. Anesthesia was maintained with 3% sevoflurane and N2O in 50% O2 until the surgery was over. All matters of relevant time periods were recorded (induction, surgical procedure, extubation and transportation). In the post-anesthesia care unit (PACU), adverse events, the incidence and the severity of EA, analgesic requirement, duration of PACU stay, and parental as well as PACU nurses' satisfaction were evaluated. RESULTS: A significant lower incidence and less severity of EA were noted in patients premedicated with midazolam. Less postoperaive analgesia was required in patients who had received midazolam. Although midazolam-premedicated patients remained sedated after sevoflurane anesthesia, the duration of the PACU stay was not significantly different from that of saline-treated patients. Both parents and PACU nurses were more satisfied with midazolam as premedication. No solid evidence showed that there was close correlation between the process of separation from parents and the occurrence of EA. CONCLUSIONS: Premedication with oral midazolam is safe, convenient and effective in decreasing the occurrence of sevoflurane-induced EA. It does not delay discharge from PACU and is suitable for outpatient surgery.

Biological and immunological characterization of multiple GnRH in an opisthobranch mollusk, Aplysia californica.

Gonadotropin-releasing hormone (GnRH) is a neurohormone central to the regulation of reproductive functions in vertebrates. Recently, several studies have reported the presence of GnRH immunoreactivity (IR) in a number of mollusks, suggesting that the distribution of GnRH may not be restricted to Phylum Chordata. In the present study, we extend our investigations to an opisthobranch mollusk, Aplysia californica, to characterize the source, chemical nature, and biological activity of molluscan GnRH-related molecules. Specific radioimmunoassays (RIAs) of various tissue extracts of Aplysia revealed that only ovotestis, hemocytes, and hemolymph contained significant amounts of GnRH that crossreacts with antisera raised against tunicate-I (tI) and mammalian (m) GnRH. Further RIAs and extractions revealed that the GnRH-IR in the hemolymph is biochemically and immunologically distinct from the GnRH-IR in the hemocytes and ovotestis. Using reverse-phase high-performance liquid chromatography coupled with RIAs, the GnRH-IR in the hemolymph was resolved into two major peaks. The first peak eluted earlier than most known forms of vertebrate GnRH, and the later peak coeluted with m, lamprey I, chicken II, and tI-GnRH. However, both peaks were broad and may contain a heterogeneous mixture of GnRH-IR. Immunocytochemical study showed that tI-GnRH-IR was present in the connective sheath surrounding the central nervous system, with a strong presence in what appeared to be vascular space, again suggesting the close association between Aplysia GnRH-IR and circulation. Finally, treatment of the neuroendocrine bag cells with chicken II GnRH significantly decreased the duration of the afterdischarge (AD, a characteristic pattern of electrical firing in bag cell neurons) and the number of action potentials fired during an AD, indicating the presence of a corresponding GnRH receptor in the Aplysia central nervous system. Overall, the results demonstrated the presence of multiple forms of GnRH-IR that crossreact with tI- and mGnRH antisera in A. californica and the ability of a vertebrate GnRH to alter Aplysia neural activity. Together, these data suggest that GnRH may be a factor released by the ovotestis and hemocytes into the circulation to alter neural functions. GnRH-IR produced by the latter may serve as a novel mediator of the neural and immune functions in Aplysia.

Role of the cAMP signaling pathway in the regulation of gonadotropin-releasing hormone secretion in GT1 cells.

We studied the signaling pathways coupling gonadotropin-releasing hormone (GnRH) secretion to elevations in cAMP levels in the GT1 GnRH-secreting neuronal cell line. We hypothesized that increased cAMP could be acting directly by means of cyclic nucleotide-gated (CNG) cation channels or indirectly by means of activation of cAMP-dependent protein kinase (PKA). We showed that GT1 cells express the three CNG subunits present in olfactory neurons (CNG2, -4.3, and -5) and exhibit functional cAMP-gated cation channels. Activation of PKA does not appear to be necessary for the stimulation of GnRH release by increased levels of cAMP. In fact, pharmacological inhibition of PKA activity caused an increase in the basal secretion of GnRH. Consistent with this observation activation PKA inhibited adenylyl cyclase activity, presumably by inhibiting adenylyl cyclase V expressed in the cells. Therefore, the stimulation of GnRH release by elevations in cAMP appears to be the result of depolarization of the neurons initiated by increased cation conductance by cAMP-gated cation channels. Activation of PKA may constitute a negative-feedback mechanisms for lowering cAMP levels. We hypothesize that these mechanisms could result in oscillations in cAMP levels, providing a biochemical basis for timing the pulsatile release of GnRH.

Retinal hamartoma in oral-facial-digital syndrome.

Only recently have intraocular findings been described in oral-facial-digital syndrome (OFDS), including 5 cases of chorioretinal colobomas and 1 case of optic nerve coloboma. We report a case of a new ocular anomaly associated with this syndrome: a retinal hamartoma in a male infant with OFDS. The patient had bilateral retinal masses that were suspicious for retinoblastoma because of a family history of retinoblastoma. Physical examination and imaging studies of the retinal masses could not differentiate between retinoblastoma, hamartoma, or persistent hyperplastic primary vitreous. Subsequent pathologic study of an enucleated globe was diagnostic of a retinal hamartoma. This case further illustrates the heterogeneity of ocular anomalies in OFDS and underscores the importance of a complete ophthalmologic evaluation in patients with this syndrome.

Lidocaine concentrations in plasma and cerebrospinal fluid after systemic bolus administration in humans.

UNLABELLED: Preclinical studies suggest that systemic lidocaine acts at the level of the spinal dorsal horn to inhibit hyperalgesia resulting from nerve injury, yet no clinical data are available to support this view. Therefore, we sought to characterize the time course of lidocaine in the plasma and cerebrospinal fluid (CSF) after an IV bolus injection of lidocaine 2 mg/kg in patients scheduled for surgery involving spinal anesthesia. Sixty-five patients were randomly allocated to one of five study groups (n = 13 per group) receiving IV lidocaine before CSF/ plasma sampling at 5, 10, 15, 30, or 60 min. Gas chromatographic analysis of these samples revealed a fast but transient peak (5-15 min) in lidocaine plasma levels (1.7+/-0.16 microg/mL), which declined rapidly thereafter. Only small concentrations of IV lidocaine were found in the CSF (6%- 8% of plasma concentration), but this fraction remained stable from 15 min until termination of the experiment. No statistical correlation was observed between plasma and CSF lidocaine levels. These data suggest that because of the prolonged availability of lidocaine at the spinal dorsal horn level, systemic administration of lidocaine suppresses central sensitization within the spinal cord after nerve injury in humans. IMPLICATIONS: Cerebrospinal fluid concentrations of lidocaine after its systemic bolus delivery in humans indicate that the spinal cord may be the major site of antinociceptive action by this route of drug administration.

The comparative potency of intravenous nicardipine and verapamil on the cardiovascular response to tracheal intubation.

BACKGROUND: Two different types of calcium channel blockers (namely nicardipine and verapamil) have been used widely in clinical practice. However, no clinical studies have previously been performed to ascertain the relative potency of intravenous verapamil and nicardipine in the attenuation of cardiovascular response to tracheal intubation. METHODS: We assessed the optimal dose and relative potency of verapamil and nicardipine in the attenuation of hemodynamic response to tracheal intubation in 135 healthy patients. Control group (Group D received normal saline i.v. Patients in Groups II-V received nicardipine 0.005, 0.01, 0.03 and 0.06 mg/kg i.v., respectively. Patients in Groups VI-IX received verapamil 0.03, 0.05, 0.1 and 0.15 mg/kg i.v., respectively. Anaesthesia was induced with propofol (2.5 mg/kg) and muscle relaxation was facilitated by vecuronium (0.2 mg/kg, i.v.). One min after induction, tracheal intubation was performed. Mean arterial pressure (MAP) was measured at 1 min interval from 10 min before induction to 15 min after induction. RESULTS: The ED50 with 95% confidence interval of nicardipine and verapamil for the attenuation of 50% mean arterial pressure (MAP) increase after tracheal intubation were 14.55 micrograms/kg (8.25-25.67) and 75.4 micrograms/kg (58.7-96.95), respectively. The ED50 with 95% confidence interval of verapamil for the reduction of the 50% heart rate (HR) increase post tracheal intubation was 57.4 micrograms/kg (18-182.2). No differences were found in the frequency of perioperative arrhythmia, post-operative hypotension, postoperative emesis, dizziness, muscle weakness and muscle soreness within two hours following surgery, when compared control with experimental groups (p > 0.05). CONCLUSIONS: These results suggest that verapamil and nicardipine attenuate the hypertensive response to tracheal intubation without significant adverse effects in healthy patients. The dose ratio (ED50 nicardipine and ED50 verapamil for MAP) with 95% confidence interval was revealed to be 2.3 (1.82-7.41).

Effect of Vitreoscilla hemoglobin dosage on microaerobic Escherichia coli carbon and energy metabolism.

The amount of Vitreoscilla hemoglobin (VHb) expression was modulated over a broad range with an isopropyl-beta-D-thiogalactopyranoside- (IPTG-) inducible plasmid, and the consequences on microaerobic Escherichia coli physiology were examined in glucose fed-batch cultivations. The effect of IPTG induction on growth under oxygen-limited conditions was most visible during late fed-batch phase where the final cell density increased initially linearly with increasing VHb concentrations, ultimately saturating at a 2.7-fold increase over the VHb-negative (Vhb(-)) control. During the same growth phase, the specific excretions of fermentation by-products, acetate, ethanol, formate, lactate, and succinate from the culture expressing the highest amount of VHb were reduced by 25%, 49%, 68%, 72%, and 50%, respectively, relative to the VHb(-) control. During the exponential growth phase, VHb exerted a positive but smaller control on growth rate, growth yield, and respiration. Varying the amount of VHb from 0 to 3.8 mumol/g dry cell weight (DCW) increased the specific growth rate, the growth yield, and the oxygen consumption rate by 33%, 35%, and 60%, respectively. Increasing VHb concentration to 3.8 mumol/g DCW suppressed the rate of carbon dioxide evolution in the exponential phase by 30%. A metabolic flux distribution analysis incorporating data from these cultivations discloses that VHb(+) cells direct a larger fraction of glucose toward the pentose phosphate pathway and a smaller fraction of carbon through the tricarboxylic acid cycle from acetyl coenzyme A. The overall nicotinamide adenine dinucleotide [NAD(P)H] flux balance indicates that VHb-expressing cells generate a net NADH flux by the NADH/NADPH transhydrogenase while the VHb(-) cells yield a net NADPH flux under the same growth conditions. Flux distribution analysis also reveals that VHb(+) cells have a smaller adenosine triphosphate (ATP) synthesis rate from substrate-level phosphorylation but a larger overall ATP production rate under microaerobic conditions. The thermodynamic efficiency of growth, based on reducing equivalents generated per unit of biomass produced, is greater for VHb(+) cells. (c) 1996 John Wiley & Sons, Inc.

Basic fibroblast growth factor is a neurotropic factor in GT1 gonadotropin-releasing hormone neuronal cell lines.

Basic fibroblast growth factor (bFGF) plays an important role in development of the central nervous system and is neurotropic for a variety of neurons. In this study, we investigated whether bFGF is neurotropic for GT1 GnRH neuronal cell lines and if these cells express functional FGF receptors (FGFRs). The GT1 cell lines generated by genetically targeted tumorigenesis display highly differentiated properties of GnRH neurons. Addition of 2 and 10 ng/ml bFGF increased neurite outgrowth of GT1-7 cells and resulted in a significant increase of GT1 cell survival in serum-free medium. However, bFGF had no effect on [3H]thymidine incorporation at 24 or 48 h. RNase protection assays using riboprobes specific for murine FGFRs 1-3 showed that GT1 cells express FGFRs 1 and 3 but not 2. Occupancy of FGFRs with 10 ng/ml bFGF stimulated the sustained tyrosine phosphorylation of both the 42- and 44-kilodalton mitogen-activated protein kinases (MAPKs) for up to 6 h as shown by Western blot analysis. In addition, phosphorylation of the MAPKs was associated with enzyme activation as shown by an in-gel MAPK assay. GT1-1 and GT1-7 cells also express messenger RNA for bFGF, although the level of bioactive bFGF synthesized by GT1 cells appears suboptimal because GT1 cells can further respond to exogenously added bFGF. Thus, we have demonstrated that bFGF is a neurotropic factor in GT1 GnRh neuronal cell lines, raising the possibility that bFGF may play a role in the neurobiology of GnRH neurons.

The nature and distribution of gonadotropin-releasing hormones in brains and plasma of ranid frogs.

Highly specific antisera and reversed-phase HPLC were used to examine the nature and distribution of gonadotropin-releasing hormone (GnRH) in the brains and plasma of three species of Rana frog previously reported to vary in the types and brain distributions of GnRH. The three species examined, Rana pipiens, Rana esculenta, and Rana ridibunda, exhibit differences in total concentration and relative concentrations of GnRH in brain areas, but all three contain the mammalian and chicken-II forms of GnRH (mGnRH and cGnRH-II). Both forms were found in the telencephalon and diencephalon, but mGnRH is consistently the most abundant form in the preoptic-hypothalamic area (e.g., ratios of mGnRH:cGnRH-II > 3:1 in hypothalamus-median eminence), whereas, cGnRH-II is the most abundant in the telencephalon and the only form measured in the cerebellum and medulla. The total content of cGnRH-II in the whole brain is about 1.5-2 times higher than that of mGnRH, due to the larger size of the areas outside the preoptic-hypothalamic area. These general patterns were the same for adults and juveniles. We found no evidence of a third form of GnRH corresponding to salmon GnRH in hypothalamus or other brain areas of R. esculenta as previously reported. These analyses also revealed the presence of both forms of GnRH in plasma draining the hypothalamic area, but the concentration of cGnRH-II is relatively higher than that in the corresponding hypothalamic tissue, suggesting differentially greater release or slower degradation of this form. These results do not support the conclusion that the ranid frogs are highly variable in the nature and distribution of GnRH in the brain, although they suggest that both forms of GnRH are potentially involved in the direct regulation of pituitary gonadotropes.