DIURNAL EFFECTS OF FLUOXETINE AND NALOXONE ON THE HUMAN HYPOTHALAMIC-PITUITARY-ADRENAL AXIS

1. Central serotonergic pathways are hypothesized to be involved in the stimulation of hypothalamic adrenocorticotropic hormone (ACTH) secretagogue release by both circadian- and stress-induced mechanisms. We aimed to investigate this hypothesis by measuring the effect of the highly specific serotonin re-uptake inhibitor fluoxetine (FX) on ACTH and Cortisol release in the morning and in the afternoon in humans, both by itself and in combination with the opioid antagonist naloxone (Nal). Naloxone causes ACTH release in humans by removing an endogenous inhibitory opioid tone on central noradrenergic pathways stimulatory to hypothalamic corticotropin-releasing hormone (CRH) secretion. Serotonergic agents may act directly or indirectly through these central noradrenergic pathways and, if so, would be expected to be additive to or synergistic with Nal in causing ACTH and Cortisol release. 2. Oral FX (40 mg) was given at approximately 07.00 or 11.00 h, either alone or with intravenous Nal 3 h later, to normal human volunteers. Plasma ACTH and Cortisol levels were measured for 5 h after FX dosing. 3. Fluoxetine produced a small but non-significant increase in Nal-stiimilated ACTH and Cortisol release in both morning and afternoon studies. Naloxone alone did not cause different ACTH and Cortisol responses in the morning and afternoon. 4. These results suggest that serotonergic pathways are not major regulators of the hypothalamic-pituitary-adrenal axis in humans or that FX has counteracting acute inhibitory effects on the axis, such as inhibition of hypothalamic arginine vasopressin secretion, which has been demonstrated in chronic animal studies.     

Linkage of polymorphic congenital cataract to the gamma-crystallin gene locus on human chromosome 2q33-35

Cataract is one of the major causes of blindness in humans. We describe here an autosomal dominant polymorphic congenital cataract (PCC) which is characterised by wide variations in phenotype of non-nuclear lens opacities, even among affected members of the same family. PCC families included a large, unique pedigree (254 members, 103 affected individuals), and genetic linkage was conducted using a variety of polymorphic markers. Evidence for linkage was found for chromosome 2q33- 35 with PCC mapping near D2S72 and TNP1. A tri-nucleotide microsatellite marker for gamma-crystallin B gene (CRYG1) was found to co-segregate with PCC and yielded a maximum lod score of 10.62 at (theta = 0). A multipoint analysis demonstrated that the most probable location of the PCC gene was within an 8 cM genetic interval containing the gamma-crystallin gene cluster. These data provide strong evidence of the existence of an autosomal dominant mutation for PCC in or near the gamma-crystallin gene cluster. This defect is characterised by complete penetrance but variable expression of the cataract phenotype. Our study also suggests that non-nuclear human cataracts might be caused by some abnormality in gamma-crystallin genes.      

Aicardi–Goutières syndrome presenting with haematemesis in infancy

Aicardi–Goutières syndrome is a genetic childhood encephalopathy characterized by basal ganglia calcification, chronic cerebrospinal lymphocytosis and elevated cerebrospinal fluid interferon-alpha, mimicking acquired congenital viral infections. As more is discovered about the pathogenesis of Aicardi–Goutières, it is becoming evident that a dysfunction of the immune system is likely to be responsible for the disease phenotype. We describe a previously healthy 2-month-old female infant who presented with haematemesis and seizures and was subsequently diagnosed with Aicardi–Goutières syndrome. To our knowledge, this is the first documented case of Aicardi–Goutières syndrome presenting with haematemesis. The gastrointestinal tract is an area of high cell loss, revealing early signs of systemic inflammation and we postulate that a systemic proinflammatory milieu occurs in Aicardi–Goutières syndrome.
Conclusion: Aicardi–Goutières syndrome can present with haematemesis, adding to the growing evidence that the Aicardi–Goutières syndrome spectrum encompasses an immune-mediated multisystem involvement. Gastrointestinal inflammation should also be considered in these patients and treated appropriately.     

Cumulus cells are required for the increased apoptotic potential in oocytes of aged mice

Recent studies with female ICR mice have suggested that oocyte DNA fragmentation is one reason for poor oocyte quality and lower fertility associated with ageing. Since it was not determined if this increased 'apoptotic' potential in aged oocytes is due to changes within the oocyte itself or within the microenvironment of cumulus cells (CC) surrounding the germ cell, we sought to clarify if CC were required to affect the rate of apoptosis in oocytes maintained in vitro. Intact cumulus-oocyte complexes (COC) were retrieved by superovulation of virgin female ICR mice at 7 weeks ('young') or 34-35 weeks ('aged') of age. One-half of the COC in each group were incubated at 37 degrees C in human tubal fluid medium under paraffin oil for 24 h. The other half of the COC in each group were denuded of CC and incubated under the same conditions (denuded oocytes; DO). Following incubation, COC were stripped of adherent CC by gentle pipetting. All DO were then fixed and checked by light microscopy for morphological changes characteristic of apoptosis. In young mice, the presence of CC had no significant effect on oocyte death rate (18 +/- 9% and 14 +/- 6% apoptotic oocytes in COC and DO, respectively; P > 0.05). However, in aged mice the percentage of CC-enclosed oocytes that underwent apoptosis was significantly greater as compared to the death rate in DO (48 +/- 3% versus 19 +/- 8% apoptotic oocytes, respectively; P < 0.05). This increased death potential was due to the presence of CC since the occurrence of apoptosis in DO of aged versus young mice was not significantly different (19 +/- 8% versus 14 +/- 6% apoptotic oocytes, respectively; P > 0.05). These results demonstrate that the age-dependent acceleration of apoptosis in oocytes maintained in vitro requires the CC.      

Intracytoplasmic sperm injection in obstructive and non-obstructive azoospermia

We compared the results of intracytoplasmic sperm injection (ICSI) in: (i) obstructive versus non-obstructive azoospermia, (ii) obstructive azoospermia using epididymal versus testicular spermatozoa and (iii) acquired versus congenital obstructive azoospermia due to congenital absence of the vas deferens (CAVD). A retrospective analysis was done of 241 consecutive ICSI cycles done in 103 patients with non- obstructive azoospermia and 119 patients with obstructive azoospermia. In the obstructive group, 135 ICSI cycles were performed. Epididymal spermatozoa were used in 44 cycles and testicular spermatozoa in 91 cycles. In the non-obstructive group, 106 cycles were performed. The fertilization and pregnancy per cycle rates were 59.5 and 27.3% respectively using epididymal spermatozoa, 54.4 and 31.9% respectively using testicular spermatozoa in obstructive cases, and 39 and 11.3% respectively in non-obstructive cases. The fertilization and pregnancy per cycle rates were 56.6 and 37% respectively in acquired obstructive cases, and 55.2 and 20.4% respectively in CAVD. In conclusion, ICSI using spermatozoa from patients with acquired obstructive azoospermia resulted in significantly higher fertilization and pregnancy rates as compared to CAVD and non-obstructive cases.      

KRAS and colorectal cancer: ethical and pragmatic issues in effecting real-time change in oncology clinical trials and practice

Systemic therapy has led to a median survival time for patients with advanced colorectal cancer (CRC) almost fourfold longer than that expected with best supportive care, an outcome achieved through combining chemotherapeutic and targeted biologic agents. Although the latter can include anti-epidermal growth factor receptor antibodies, such as cetuximab and panitumumab, we now have strong evidence that patients whose tumors harbor mutated KRAS will not benefit from this class of agent. Acceptance of the reliability and importance of the KRAS data took several years to evolve, however, for a variety of reasons. The timeline from the presentation and publication of small, retrospective phase II studies to widespread acceptance of the KRAS predictive value and changes in behavior-specifically, modifications of ongoing national trials in advanced/metastatic CRC, changes in national guidelines and practice patterns, and adjustments to the labeled indications for the monoclonal antibodies-was lengthy. In this commentary, we discuss whether or not the process of data disclosure regarding KRAS status and treatment of advanced CRC patients was effective in permitting timely decisions regarding ongoing publicly funded clinical trials and whether or not such decisions were rational and ethical. The overall goals are to highlight lessons learned regarding early disclosure of clinical trial results, as well as vetting and adoption of new scientific data, and to propose modifications for handling similar situations in the future.     

高氧液联合美沙酮治疗海洛因依赖者

目的:观察高氧液对海洛因依赖者戒断综合症的治疗作用及康复治疗作用.方法:采用高氧液联合美沙酮(MTD)替代递减治疗50例海洛因依赖者,并以50例单纯MTD脱毒者进行对照观察.结果:高氧液联合MTD脱毒效果较单纯MTD脱毒控制症状彻底,过程平稳.特别是纠正食欲差、乏力、焦虑症状效果明显(P＜0.01).结论:高氧液联合MTD脱毒效果优于MTD脱毒治疗.