TST加外切缝合术治疗环状混合痔的临床观察

为探讨选择性痔上黏膜切除术（TST）加外切缝合术治疗环状混合痔的效果,将50例环状混合痔患者随机分为观察组和对照组各25例,观察组采用TST加外切缝合术治疗,对照组采用PPH治疗。跟踪随访、观察记录术后疗效及并发症。结果显示,两组疗效差异无统计学意义（P〉0．05）;在术后并发症等方面观察组优于对照组（P〈0．05）。结果表明,TS＇I’加外切缝合术治疗环状混合痔安全性高,治疗效果显著。     

Progression of clinical tuberculosis is associated with a Th2 immune response signature in combination with elevated levels of SOCS3

In this study, we explored the local cytokine/chemokine profiles in patients with active pulmonary or pleural tuberculosis (TB) using multiplex protein analysis of bronchoalveolar lavage and pleural fluid samples. Despite increased pro-inflammation compared to the uninfected controls; there was no up-regulation of IFN-γ or the T cell chemoattractant CCL5 in the lung of patients with pulmonary TB. Instead, elevated levels of IL-4 and CCL4 were associated with high mycobacteria-specific IgG titres as well as SOCS3 (suppressors of cytokine signaling) mRNA and progression of moderate-to-severe disease. Contrary, IL-4, CCL4 and SOCS3 remained low in patients with extrapulmonary pleural TB, while IFN-γ, CCL5 and SOCS1 were up-regulated. Both SOCS molecules were induced in human macrophages infected with Mycobacterium tuberculosis in vitro. The Th2 immune response signature found in patients with progressive pulmonary TB could result from inappropriate cytokine/chemokine responses and excessive SOCS3 expression that may represent potential targets for clinical TB management.     

Controlled sleep restriction for rhythmic movement disorder

Rhythmic movement disorder is a parasomnia that is difficult to treat. In our study, 3 weeks of controlled sleep restriction with hypnotic administration in the first week resulted in almost complete resolution of the movements in 6 children. This therapeutic success suggests that rhythmic movement disorder results from a voluntary self-soothing behavior.     

Antidepressant-like effect of the extract from leaves of Schinus molle L. in mice: evidence for the involvement of the monoaminergic system

Schinus molle L. (Anacardiaceae), among other uses, is popularly employed for the treatment of depression. In this study, the antidepressant-like effect of the hexanic extract from leaves of S. molle was investigated in the mouse tail suspension test (TST), a predictive model of depression. The immobility time in the TST was significantly reduced by the extract (dose range 30-600 mg/kg, p.o.), without accompanying changes in ambulation when assessed in an open-field test. The efficacy of extract was found to be comparable to that of fluoxetine (10 mg/kg, p.o.). The anti-immobility effect of the extract (100 mg/kg, p.o.) was prevented by pretreatment of mice with p-chlorophenylalanine methyl ester (PCPA, 100 mg/kg, i.p., an inhibitor of serotonin synthesis, for four consecutive days), NAN-190 (0.5 mg/kg, i.p., a 5-HT(1A) receptor antagonist), WAY100635 (0.1 mg/kg, s.c., a selective 5-HT(1A) receptor antagonist), ketanserin (5 mg/kg, i.p., a 5-HT(2A/2C) receptor antagonist), MDL72222 (0.1 mg/kg, i.p., a 5-HT(3) receptor antagonist), prazosin (1 mg/kg, i.p., an alpha(1)-adrenoceptor antagonist), yohimbine (1 mg/kg, i.p., an alpha(2)-adrenoceptor antagonist), SCH23390 (0.05 mg/kg, s.c., a D(1) receptor antagonist) or sulpiride (50 mg/kg, i.p., a D(2) receptor antagonist). It may be concluded that the hexanic extract of S. molle produces an antidepressant-like effect that seems to be dependent on its interaction with the serotonergic, noradrenergic and dopaminergic systems. These results provide evidence that the extract from S. molle shares with established antidepressants some pharmacological effects, at least at a preclinical level.     

Involvement of dopamine (DA)/serotonin (5-HT)/sigma (sigma) receptor modulation in mediating the antidepressant action of ropinirole hydrochloride, a D2/D3 dopamine receptor agonist

Multiple lines of investigation have explored the role of dopaminergic systems in mental depression. Chronic treatment with antidepressant drugs has been reported to alter dopaminergic neurotransmission, most notably a sensitization of behavioural responses to agonists acting at D2/D3 dopamine receptors within the nucleus accumbens. Recent clinical evidences have shown that ropinirole, a D2/D3 dopamine receptor agonist, augments the action of various standard antidepressant drugs in treatment-resistant depression. The present study was undertaken to elucidate the possible mechanism of antidepressant action of ropinirole employing various behavioral paradigms of despair supported by the measurements of neurochemical changes in the tissue contents of dopamine (DA) and serotonin (5-HT) in the whole brain using high-performance-liquid chromatography (HPLC) with electrochemical detectors (ECD). In the mouse forced swim test (FST) or tail-suspension test (TST), ropinirole (1-10 mg/kg, i.p.) produced S-shaped dose-response curve in the percentage decrease in immobility period. Compared with vehicle, ropinirole (10 mg/kg., i.p.) had a significant anti-immobility effect without affecting locomotor activity. The reduction in the immobility period elicited by ropinirole (10 mg/kg, i.p.) in the FST was reversed by dopaminergic and sigma receptor antagonist, haloperidol (0.5 mg/kg, i.p.), and specific D2 dopamine receptor antagonist sulpiride (5 mg/kg i.p.), but not by SCH 23390 (0.5 mg/kg i.p), a D1 dopamine receptor antagonist. Rimcazole (5 mg/kg i.p.) (a sigma receptor antagonist), progesterone (10 mg/kg i.p.) (a sigma receptor antagonistic neurosteroid), BD 1047 (1 mg/kg i.p.) (a novel sigma receptor antagonist with preferential affinity for sigma-1 sites) also reversed the anti-immobility effect of ropinirole (10 mg/kg i.p.). The neurochemical studies of whole brain revealed that ropinirole at 10 mg/kg i.p. did not affect the tissue levels of dopamine but significantly increased serotonin levels. The study indicated that ropinirole possessed anti-immobility activity in FST by altering dopaminergic, serotonergic or sigma receptor function.     

Cost-effectiveness of interferon-gamma release assay screening for latent tuberculosis infection treatment in Germany

OBJECTIVES: To assess the cost-effectiveness of the new QuantiFERON-TB Gold In-Tube (QFT-G) [Cellestis; Carnegie, VIC, Australia] assay for screening and treating of persons who have had close contact with tuberculosis (TB) patients and are suspected of having latent tuberculosis infection (LTBI) [hereafter called close-contacts] in Germany. METHODS: The health and economic outcomes of isoniazid treatment of 20-year-old close-contacts were compared in a Markov model over a period of 20 years, using two different cutoff values for the tuberculin skin test (TST), the QFT-G assay alone, or the QFT-G assay as a confirmatory test for the TST results. RESULTS: QFT-G assay-based treatment led to cost savings of $542.9 and 3.8 life-days gained per LTBI case. TST-based treatment at a 10-mm induration size cutoff gained $177.4 and 2.0 life-days gained per test-positive contact. When the cutoff induration size for the TST was reduced to 5 mm, the incremental cost-effectiveness ratio fell below the willingness-to-pay threshold ($30,170 per life-years gained) but resulted in unnecessary treatment of 77% of contacts owing to false-positive TST results. Combination with the 5-mm induration size TST cutoff value compared to the results of the QFT-G assay alone reduced the total costs per 1,000 contacts by 1.8% to $222,869. The number treated to prevent 1 TB case was 22 for the two QFT-G assay-based procedures, 40 for the TST at a cutoff induration size of 10 mm, and 96 for the TST at a cutoff induration size of 5 mm. When the sensitivity rates of the TST and the QFT-G assay were compounded, the QFT-G assay strategy alone was slightly less costly (0.6%) than the two-step approach. CONCLUSIONS: Using the QFT-G assay, but especially combining the QFT-G assay following the TST screening of close-contacts at a cutoff induration size of 5 mm before LTBI treatment is highly cost-effective in reducing the disease burden of TB.     

Biotransformation and in vitro assessment of metabolism-associated drug–drug interaction for CRx-102, a novel combination drug candidate

CRx-102 is an oral synergistic combination drug which contains the cardiovascular agent, dipyridamole (DP) and a very low dose of the glucocorticoid, prednisolone (PRED). CRx-102 works through a novel mechanism of action in which DP selectively amplifies the anti-inflammatory activity of PRED without replicating its side effects. CRx-102 is in clinical trials for the treatment of osteoarthritis. Here we delineate the in vitro metabolism and explore the potential for a drug–drug interaction between the active agents in CRx-102. Our study using human hepatocyte suspensions showed that both DP and PRED were metabolized by CYP3A4 isozymes, resulting in the formation of diverse arrays of both oxidative and oxidative-reduced metabolites. Within phase 1 biotransformation, CYP3A4 was one of the pathways responsible for the metabolism of PRED, while phase 2 biotransformation played a significant role in the metabolism of DP. Glucuronidation of DP was substantial and was catalyzed by many UGT members, specifically those in the UGT1A subfamily. Based on the tandem mass (MS/MS) product ion spectra (PIS) acquired, the major metabolites of both agents, namely, monooxygenated, mono-N-deethanolaminated, dehydrogenated and O-glucuronidated metabolites of DP and the monooxygenated (e.g., 6-hydroxyl), dehydrogenated (prednisone) and reduced (20-hydroxyl) metabolites of PRED, were identified and elucidated. The affinities for DP biotransformation, including CYP3A4-mediated oxidative pathways and UGT-mediated O-glucuronidation, appeared high (K_m < 10 μM), as compared with the modest affinities of PRED biotransformation catalyzed by CYP3A4 (K_m ∼ 40–170 μM). DP, but not PRED, exerted a minimal inhibitory effect on the drug-metabolizing CYP isoforms, including CYP3A4, which was determined using a panel of CYP isoform-preferred substrate activities in pooled human liver microsomal (HLM) preparations and microsomal preparations containing the recombinant enzymes (K_i ∼ 2–12 μM). Using the DP maximal plasma concentration (C_max) observed in the clinic and a predictive mathematical model for metabolism-associated drug–drug interaction (DDI), we have demonstrated that there is little likelihood of a pharmacokinetic interaction between the two active agents in CRx-102.     

Antidepressant-like effects of the mixture of honokiol and magnolol from the barks of Magnolia officinalis in stressed rodents

Honokiol and magnolol are the main constituents simultaneously identified in the barks of Magnolia officinalis, which have been used in traditional Chinese medicine to treat a variety of mental disorders including depression. In the present study, we reported on the antidepressant-like effects of oral administration of the mixture of honokiol and magnolol in well-validated models of depression in rodents: forced swimming test (FST), tail suspension test (TST) and chronic mild stress (CMS) model. The mixture of honokiol and magnolol significantly decreased immobility time in the mouse FST and TST, and reversed CMS-induced reduction in sucrose consumption to prevent anhedonia in rats. However, this mixture was unable to affect ambulatory or rearing behavior in the mouse open-field test. CMS induced alterations in 5-hydroxytryptamine (5-HT) and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) levels in various brain regions of rats. An increase in serum corticosterone concentrations and a reduction in platelet adenylyl cyclase (AC) activity were simultaneously found in the CMS rats. The mixture of honokiol and magnolol at 20 and 40 mg/kg significantly attenuated CMS-induced decreases of 5-HT levels in frontal cortex, hippocampus, striatum, hypothalamus and nucleus accumbens. And it markedly increased 5-HIAA levels in frontal cortex, striatum and nucleus accumbens at 40 mg/kg and in frontal cortex at 20 mg/kg in the CMS rats. A subsequent reduction in 5-HIAA/5-HT ratio was found in hippocampus and nucleus accumbens in the CMS rats receiving this mixture. Furthermore, the mixture of honokiol and magnolol reduced elevated corticosterone concentrations in serum to normalize the hypothalamic-pituitary-adrenal (HPA) hyperactivity in the CMS rats. It also reversed CMS-induced reduction in platelet AC activity, via upregulating the cyclic adenosine monophosphate (cAMP) pathway. These results suggested that the mixture of honokiol and magnolol possessed potent antidepressant-like properties in behaviors involved in normalization of biochemical abnormalities in brain 5-HT and 5-HIAA, serum corticosterone levels and platelet AC activity in the CMS rats. Our findings could provide a basis for examining directly the interaction of the serotonergic system, the HPA axis and AC-cAMP pathway underlying the link between depression and treatment with the mixture of honokiol and magnolol.     

Automatic titration and calculation by predictive equations for the determination of therapeutic continuous positive airway pressure for obstructive sleep apnea

BACKGROUND: It is unknown to what extent therapeutic continuous positive airway pressure (CPAP) levels obtained by various methods for the treatment of obstructive sleep apnea syndrome (OSAS) differ. This study aimed to explore the relationships among pressures titrated by an automatic CPAP (APAP) device and those calculated using different predictive equations, and to compare different ranges of calculated pressures with pressure values titrated by APAP. METHODS: In 140 OSAS patients, the 95th percentile pressure delivered by an APAP device (AutoSet T; ResMed; Sydney, NSW, Australia) during polysomnography, and pressures calculated by three equations (equation 1, Hoffstein and Miljetig [1994]; equation 2, Sériès et al [2000]; and equation 3, Stradling et al [2004]) were compared. RESULTS: Titrated and calculated pressures were weakly correlated. Significant differences were found between the mean (+/- SD) pressures (11.1 +/- 1.6, 8.3 +/- 1.8, 10.5 +/- 1.6, and 10.3 +/- 1.3 cm H(2)O, respectively) for 95th percentile APAP, and pressures calculated by equations 1, 2, and 3, except between values calculated by equations 2and 3. Differences between the calculated and APAP-derived pressures were negative for the low calculated values, and were progressively attenuated, or became positive, for the high values. The differences were smallest for calculated pressures from 11 to > 13 cm H(2)O, which were represented to a greater extent among the values calculated by equations 2 and 3 than by those calculated by equation 1. CONCLUSIONS: Considerably different therapeutic CPAP levels may be determined using various methods. The differences between the calculated and APAP-derived pressures are largest for calculated values of < 9 or > 15 cm H(2)O. The clinical consequences of these findings deserve further evaluation. Caution is still required before treating OSAS patients with calculated pressures.