脱氢表雄酮(DHEA)在辅助生殖技术中的研究进展

卵巢功能差患者的生育问题一直是辅助生殖领域中的难题。临床中卵巢功能差患者添加脱氢表雄酮(DHEA)可能通过类固醇合成底物、雄激素配体、降低胚胎非整倍体率和改善卵巢微环境等机制改善其临床结局,为卵巢功能差患者治疗提供新思路。     

Dose–response relationship for the pharmacokinetic interaction of grapefruit juice with dextromethorphan investigated by human urinary metabolite profiles

Grapefruit juice (GFJ) has been shown to affect the pharmacokinetics of a large number of drugs, essentially by inhibition of efflux transporters and CYP3A4 monooxygenase in the small intestine. The GFJ dose usually used in human studies was one glass single-strength (1×). Information on a respective dose–response relationship is not available. We investigated the effect of GFJ of different concentration (0.25×, 0.5×, 1×, 2×) dosed in biweekly intervals in 19 volunteers. Components considered responsible for drug interactions, naringin, naringenin, bergamottin, and 6′,7′-dihydroxybergamottin were determined by LC–tandem mass spectrometry. Immediately after ingestion of GFJ, participants took an aqueous solution of dextromethorphan (DEX) as probe drug. Urine was collected in two sampling periods, 0–2 and 2–4 h, and excreted amounts of DEX and five metabolites associated with CYP3A4 and/or CYP2D6 enzyme activity were determined. Effects of GFJ were analyzed by the Wilcoxon matched-pairs signed-rank test against an average of four water control experiments. Two effects were highly significant: (i) a delay of total metabolite excretion in the first 2 h and (ii) an inhibition of the CYP3A4-dependent metabolic pathways. Effect magnitude and significance levels were dose-dependent and indicated 200 ml 1× GFJ as “lowest observed effect level” LOEL.     

Mechanism of recurrent spontaneous abortions in women with mosaicism of X-chromosome aneuploidies

OBJECTIVE: To investigate the mechanism of recurrent miscarriages in women with mosaicism of X-chromosome aneuploidies. DESIGN: Prospective case-control study. SETTING: University-based reproductive clinic housed in a medical center with genetic laboratories. PATIENT(S): Eighteen women who experienced recurrent miscarriages and had mosaicism of X-chromosome aneuploidies; two control groups, one with a balanced structural autosomal rearrangement and the other without chromosomal abnormalities. INTERVENTION(S): Criteria were established for the diagnosis of low-grade X-chromosome mosaicism by using peripheral blood lymphocytes. Patients were evaluated for the pathogenesis of recurrent miscarriages. Their abortion rate was assessed, and each abortus was karyotyped. MAIN OUTCOME MEASURE(S): Abortion rate and karyotype of the abortus. RESULT(S): In comparison with patients with X-chromosome mosaicism with a balanced structural autosomal rearrangement, patients with X-chromosome mosaicism without a balanced autosomal structural rearrangement had a significantly higher incidence of diminished ovarian reserve (DOR) and had a somewhat higher prevalence of uterine anomalies. In comparison with controls without chromosomal abnormalities, the patients with a balanced autosomal structural rearrangement also had higher incidence of both conditions, but the differences were not statistically significant. At least two factors are implicated in recurrent miscarriages in women with X-chromosome mosaicism. Among them, DOR is the most prevalent (occurring in 44.4% of cases), followed by uterine anomalies (16.7% of cases). Cases with DOR had a higher abortion rate than did those without (68.6% vs. 44.1%). Cases with DOR also had a slightly higher rate of abnormal karyotypes in the abortus than did those without (73.7% vs. 42.9%). CONCLUSION(S): The oocytes of women with X-chromosome mosaicism are in a suboptimal state of development and are prone to embryonic lethality.     

Gene expression of opioid and dopamine systems in mouse striatum: effects of CB1 receptors, age and sex

RATIONALE: Endocannabinoid, opioid, and dopamine systems interact to exhibit cannabinoid receptor neuromodulation of opioid peptides and D(4) dopamine receptor gene expression in CB(1)-cannabinoid-deficient mouse striatum. OBJECTIVE: Using CB(1)-transgenic mice, we examine primary age-sex influences and interactions on opioid and dopamine system members' gene expression in striatum. MATERIALS AND METHODS: Real-time quantitative polymerase chain reaction was used to analyze gene expression of opioid peptides [preproenkephalin (PPENK); preprodynorphin (PPDYN)], opioid receptors [delta-opioid receptor (delta-OR); mu-opioid receptor (micro-OR)] and dopamine receptor subtypes (D(1) through D(5)) in male/female CB(1)(+/+)/CB(1)(-/-) mice striata at two adult ages [young (60-90 days); old (140-300 days)]. RESULTS: (1) Increased PPENK and PPDYN, owing to genotype [CB(1)(+/+) vs. CB(1)(-/-)], depended on sex. When genotype-independent, they depended on sex (PPENK) or age (PPDYN). (2) delta-OR was age-dependent (higher in old). (3) micro-OR, owing to genotype, was age-dependent [higher in old CB(1)(-/-) males]. When genotype-independent, it depended on sex (higher in females). (4) Female D(1) was genotype-independent and age-dependent, while male D(1) was higher in old over young CB(1)(+/+) mice. (5) D(5), owing to genotype, was sex-dependent [higher in young female CB(1)(-/-) mice]. (6) D(2), genotype-independent, was higher in old over young male mice. (7) Young female D(3) was higher in CB(1)(-/-) over CB(1)(+/+) mice. Male D(3) was age-dependent (higher in old mice). (8) D(4), owing to genotype, was sex-dependent [higher in CB(1)(-/-) over CB(1)(+/+) females]. Genotype-independent D(4) was sex-dependent in young mice (higher in females) and age-dependent in males (higher in old). CONCLUSIONS: Greater striatal expression is genotype-dependent in females (opioid-peptides, D(3), D(4), D(5)) and genotype-independent in both females (PPENK, mu-OR, D(4)) and old males (PPDYN, delta-OR, D(2), D(3), D(4)).     

基于国医大师夏桂成“心宁肾实”理论的卵巢储备功能低下的膏方防治

卵巢储备功能低下(DOR)是导致女性月经周期紊乱及生殖障碍的常见疾病之一,临床治疗较为棘手。根据本病心肾失济的特点及膏方治疗优势,文章从国医大师夏桂成教授提出的“心宁则肾自实”理论着手,“宁心”之时活用“调心五法”,兼顾肝脾,重视血肉有情之品的运用,根据个人体质情况以开路方提高膏方疗效,改善患者生殖与生命健康,是治未病的体现与要求。     

Characteristics of serology-based vaccine potency models for foot-and-mouth disease virus

Background

Foot-and-mouth disease (FMD) vaccine potency testing involves hundreds of animals each year. Despite considerable efforts during the past decades, a challenge-free alternative vaccine potency test to replace the European protective dose 50% test (PD₅₀) has not been implemented yet. The aim of the present study was to further characterize the properties of serological vaccine potency models.

Methods

Logistic regression models were built for 5 serological assays from 3 different laboratories. The serum samples originated from 5 repeated PD₅₀ vaccine potency trials with a highly potent A/IRN/11/96 vaccine. Receiver Operating Characteristic analysis was used to determine a serological pass mark for predicting in vivo protected animals. Subsequently, an estimated PD₅₀ was calculated and the serotype dependency of the logistic models was investigated.

Results

Although differences were observed between the laboratories and the serological assays used, the logistic models accurately predicted the in vivo protection status of the animals in 74–93% of the cases and the antibody pass levels corresponded to 84–97% of protection, depending on the serological assay used. For logistic models that combine different serotypes, the model fit can be increased by inclusion of a serotype factor in the logistic regression function.

Conclusions

The in vitro estimated PD₅₀ method may be at least as precise as the in vivo PD₅₀ test and may accurately predict the PD₅₀ content of a vaccine. However, the laboratory-effect and the serotype-dependency should be further investigated.     

Immunotherapy of cancer via mediation of cytotoxic T lymphocytes by methionine enkephalin (MENK)

The aim of this study was to investigate the immunological mechanisms by which synthetic methionine enkephalin (MENK) exerts therapeutic effects on tumor growth. Our findings in vivo or in vitro show that MENK treatment either in vivo or in vitro could up-regulate the percentages of CD8+T cells, induce markers of activated T cells, increased cytotoxic activity against mouse S180 tumor cells and increase secretion of IFNγ. In addition, the adoptively transferred CD8+T cells, after either in vitro or in vivo treatment with MENK, result in significantly increased survival of S180 tumor-bearing mice and significant shrinkage in tumor growth. Opioid receptors are detected on normal CD8+T cells and exposure to MENK leads to increased expression of opioid receptors. Interaction between MENK and the opioid receptors on CD8+T cells appears to be essential for the activation of CTL, since the addition of naltrexone (NTX), an opioid receptor antagonist, significantly inhibits all of the effects of MENK. The evidence obtained indicates that the MENK-induced T cell signaling is associated with a significant up-regulation of Ca2+ influx into the cytoplasm and the translocation of NFAT2 into nucleus, and these signaling effects are also inhibited by naltrexone.     

Diagnostic Accuracy of the Veteran Affairs' Traumatic Brain Injury Screen

Objective

To comprehensively estimate the diagnostic accuracy and reliability of the Department of Veterans Affairs (VA) Traumatic Brain Injury (TBI) Clinical Reminder Screen (TCRS).

Opioid agonists inhibit excitatory neurotransmission in ganglia and at the neuromuscular junction in Guinea pig gallbladder

BACKGROUND & AIMS: Opiates administered therapeutically could have an inhibitory effect on the neuromuscular axis of the gallbladder, and thus contribute to biliary stasis and acalculous cholecystitis. METHODS: Intracellular recordings were made from gallbladder neurons and smooth muscle, and tension measurements were made from muscle strips. Opioid receptor-specific agonists tested: delta, DPDPE; kappa, U-50488H; and mu, DAMGO. RESULTS: Opioid agonists had no effect on gallbladder neurons or smooth muscle. Each of the opioid agonists potently suppressed the fast excitatory synaptic input to gallbladder neurons, in a concentration-dependent manner with half-maximal effective concentration values of about 1 pmol/L. Also, each agonist caused a concentration-dependent reduction in the amplitude of the neurogenic contractile response (half-maximal effective concentration values: DPDPE, 189 pmol/L; U-50488H, 472 pmol/L; and DAMGO, 112 pmol/L). These ganglionic and neuromuscular effects were attenuated by the highly selective opioid-receptor antagonist, naloxone. Opioid-receptor activation also inhibited the presynaptic facilitory effect of cholecystokinin in gallbladder ganglia. Immunohistochemistry with opioid receptor-specific antisera revealed immunostaining for all 3 receptor subtypes in nerve bundles and neuronal cell bodies within the gallbladder, whereas opiate-immunoreactive nerve fibers are sparse in the gallbladder. CONCLUSIONS: These results show that opiates can cause presynaptic inhibition of excitatory neurotransmission at 2 sites within the wall of the gallbladder: vagal preganglionic terminals in ganglia and neuromuscular nerve terminals. These findings support the concept that opiates can contribute to gallbladder stasis by inhibiting ganglionic activity and neurogenic contractions.