Effects of hyperoxic ventilation on hemodilution-induced changes in anesthetized dogs

BACKGROUND: In subjects who have undergone acute preoperative normovolemic hemodilution (ANH), intraoperative hemorrhage is generally treated by immediate return of autologous blood collected during ANH. Simply increasing blood oxygen content by hyperoxic ventilation (HV, inspiratory fraction [FIO2] 1.0) might compensate for the acute anemia, allow further ANH, and delay onset of autologous blood return. STUDY DESIGN AND METHODS: This study 1) evaluated the effects of HV (FIO2 1.0) upon ANH to a hemoglobin (Hb) concentration of 7 g per dL in anesthetized dogs ventilated with room air and 2) compared the effects of subsequent profound ANH (Hb, 3 g/dL) with and without an intravenous perfluorocarbon emulsion (perflubron 60% wt/vol) versus those of autologous red cell transfusion. The results of the entire study are presented in two parts. Organ tissue oxygenation was assessed in skeletal muscle and liver, and systemic oxygenation status was evaluated. Myocardial contractility was deduced from left ventricular pressure-volume relationship. Seven of 22 dogs underwent further hemodilution while breathing 100-percent O2, for a determination of the Hb concentration at which HV-induced effects were abolished. RESULTS: HV completely reversed the ANH-induced increase in cardiac index (4.6 +/− 0.7 vs. 3.8 +/− 0.9 L/min/m2 before and during HV; p < 0.05) and partially reversed the decrease in systemic vascular resistance (1784 +/− 329 vs. 2087 +/− 524 dyn × cm-5 × sec × m-2; p < 0.05). Despite unchanged global O2 delivery, organ tissue oxygenation improved during HV (mixed venous partial pressure of O2: 40 +/− 3 vs. 59 +/− 7 torr; coronary venous pressure of O2: 30 +/− 4 vs. 43 +/− 6 torr; p < 0.05; liver surface: 31 +/− 11 vs. 39 +/− 13 torr; skeletal muscle surface: 30 +/− 14 vs. 41 +/− 22 torr; p < 0.05). This improvement was due to an increased contribution of physically dissolved O2 in plasma to O2 delivery (3.2 +/− 0.2% before HV vs. 14.6 +/− 1% during HV; p < 0.05) and O2 consumption (whole body: 6 +/− 1% vs. 47 +/− 8%, p < 0.05; myocardium: 4.3 +/− 0.9% vs. 31 +/− 6%, p < 0.05). The beneficial effects of HV were lost after an additional volume-compensated exchange of 19 percent of blood volume (Hb, 5.6 g/dL). CONCLUSION: In anesthetized dogs ventilated with room air and hemodiluted to a Hb of 7 g per dL, simple oxygen therapy by HV (FIO2 1.0) rapidly improves tissue oxygenation and permits extended hemodilution to Hb of 5.8 g per dL until the HV-induced effects are lost.     

Utility of percutaneous epididymal sperm aspiration in situations of unexpected obstructive azoospermia

Surgical sperm retrieval through percutaneous epididymal aspiration was used to manage effectively unexpected obstructive azoospermia on the day of oocyte retrieval.      

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.     

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.     

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.