A phase II study of gemcitabine and cisplatin plus sorafenib in patients with advanced biliary adenocarcinomas.

BACKGROUND: This study evaluated the addition of sorafenib to gemcitabine and cisplatin in biliary adenocarcinoma first-line therapy. METHODS: Patients with advanced biliary adenocarcinomas received gemcitabine 1000 mg m(-2) and cisplatin 25 mg m(-2) on a 2 weeks on/1 week off cycle and sorafenib 400 mg twice daily. After the initial 16 patients were enrolled, the chemotherapy doses were amended in view of grade 3 and 4 hand-foot skin reaction and haematologic toxicity. Subsequently, 21 patients received gemcitabine 800 mg m(-2), cisplatin 20 mg m(-2) and sorafenib 400 mg. The primary end point was an improvement in 6-month progression-free survival (PFS6) from historical 57-77% (90% power, type I error of 10%). Pretreatment pERK, evaluated by immunostaining, was correlated with clinical outcome. RESULTS: A total of 39 patients were accrued. The most common grade 3-4 toxicities noted in >10% of patients were fatigue, elevated liver function tests and haematologic toxicities including thromboemboli, hyponatraemia and hypophosphataemia. Six-month progression-free survival was 51% (95% confidence interval (CI) 34-66%). Median PFS and overall survival were 6.5 (95% CI: 3.5-8.3) and 14.4 months (95% CI: 11.6-19.2 months), respectively. No correlation was observed between pERK and outcomes. CONCLUSION: The addition of sorafenib to gemcitabine and cisplatin in biliary adenocarcinomas did not improve efficacy over historical data, and toxicity was increased.

Role of the Median Preoptic Nucleus in Arterial Pressure Regulation and Sodium and Water Homeostasis during High Dietary Salt Intake.

Changes in the osmolality and level of angiotensin II (ANG II) are important peripheral signals modulating appropriate central sympathetic output and maintaining a normal arterial pressure during high salt intake. The median preoptic nucleus (MnPO) receives reciprocal inputs from the subfornical organ (SFO) and organum vasculosum of the lamina terminalis (OVLT), the circumventricular organs that have been shown to be necessary in multiple central effects of changes in the osmolality and circulating ANG II directed toward the maintenance of sodium and water homeostasis. We, therefore, hypothesized that the MnPO is a crucial part of the central neuronal mechanisms mediating the blood pressure control by altered osmolality and/or ANG II signaling during chronic high dietary salt intake. Male Sprague-Dawley rats were randomly assigned to either sham (operation), or electrolytic lesion of the MnPO. After a 7-day recovery, rats were instrumented with radiotelemetric transducers and aortic flow probes for the measurement of the mean arterial pressure + heart rate (HR) and cardiac output (CO), respectively. Femoral venous catheters were also implanted to collect blood for the measurements of plasma osmolality and sodium concentration, as well as plasma renin activity. Rats were given another 10 days to recover and then were subjected to a 28-day-long study protocol that included a 7-day control period (1.0% NaCl diet), followed by 14 days of high salt (4.0% NaCl), and a 7-day recovery period (1.0% NaCl). The data showed, that despite a slight increase in the MAP observed in both MnPO- (n = 12) and sham-lesioned (n = 8) rats during the high-salt period, there were no significant differences between the MAP, HR, and CO in the two groups throughout the study protocol. These findings do not support the hypothesis that the MnPO is necessary to maintain normal blood pressure during high dietary salt intake. However, MnPO-lesioned rats showed less sodium balance than sham-lesioned rats during the first 4 days of high salt intake. Although, these results may be explained partly by the plasma hyperosmolarity and hypernatremia observed in MnPO-lesioned rats; they also shed light on the role of the MnPO in central neuronal control of renal sodium handling during chronic high dietary salt intake.

Deacylation of lipopolysaccharide in whole Escherichia coli during destruction by cellular and extracellular components of a rabbit peritoneal inflammatory exudate.

Deacylation of purified lipopolysaccharides (LPS) markedly reduces its toxicity toward mammals. However, the biological significance of LPS deacylation during infection of the mammalian host is uncertain, particularly because the ability of acyloxyacyl hydrolase, the leukocyte enzyme that deacylates purified LPS, to attack LPS residing in the bacterial cell envelope has not been established. We recently showed that the cellular and extracellular components of a rabbit sterile inflammatory exudate are capable of extensive and selective removal of secondary acyl chains from purified LPS. We now report that LPS as a constituent of the bacterial envelope is also subject to deacylation in the same inflammatory setting. Using Escherichia coli LCD25, a strain that exclusively incorporates radiolabeled acetate into fatty acids, we quantitated LPS deacylation as the loss of radiolabeled secondary (laurate and myristate) and primary fatty acids (3-hydroxymyristate) from the LPS backbone. Isolated mononuclear cells and neutrophils removed 50% and 20-30%, respectively, of the secondary acyl chains of the LPS of ingested whole bacteria. When bacteria were killed extracellularly during incubation with ascitic fluid, no LPS deacylation occurred. In this setting, the addition of neutrophils had no effect, but addition of mononuclear cells resulted in removal of >40% of the secondary acyl chains by 20 h. Deacylation of LPS was always restricted to the secondary acyl chains. Thus, in an inflammatory exudate, primarily in mononuclear phagocytes, the LPS in whole bacteria undergoes substantial and selective acyloxyacyl hydrolase-like deacylation, both after phagocytosis of intact bacteria and after uptake of LPS shed from extracellularly killed bacteria. This study demonstrates for the first time that the destruction of Gram-negative bacteria by a mammalian host is not restricted to degradation of phospholipids, protein, and RNA, but also includes extensive deacylation of the envelope LPS.

Deacylation of purified lipopolysaccharides by cellular and extracellular components of a sterile rabbit peritoneal inflammatory exudate.

The extent to which the mammalian host is capable of enzymatic degradation and detoxification of bacterial lipopolysaccharides (LPS) is still unknown. Partial deacylation of LPS by the enzyme acyloxyacyl hydrolase (AOAH) provides such a mechanism, but its participation in the disposal of LPS under physiological conditions has not been established. In this study, deacylation of isolated radiolabeled LPS by both cellular and extracellular components of a sterile inflammatory peritoneal exudate elicited in rabbits was examined ex vivo. AOAH-like activity, tested under artificial conditions (pH 5.4, 0.1% Triton X-100), was evident in all components of the exudate (mononuclear cells [MNC] > polymorphonuclear leukocytes [PMN] > inflammatory [ascitic] fluid [AF]). Under more physiological conditions, in a defined medium containing purified LPS-binding protein, the LPS-deacylating activity of MNC greatly exceeded that of PMN. In AF, MNC (but not PMN) also produced rapid and extensive CD14-dependent LPS deacylation. Under these conditions, almost all MNC-associated LPS underwent deacylation within 1 h, a rate greatly exceeding that previously found in any cell type. The remaining extracellular LPS was more slowly subject to CD14-independent deacylation in AF. Quantitative analysis showed a comparable release of laurate and myristate but no release of 3-hydroxymyristate, consistent with an AOAH-like activity. These findings suggest a major role for CD14(+) MNC and a secondary role for AF in the deacylation of cell-free LPS at extravascular inflammatory sites.

Potent CD14-mediated signalling of human leukocytes by Escherichia coli can be mediated by interaction of whole bacteria and host cells without extensive prior release of endotoxin.

How invading microorganisms are detected by the host has not been well defined. We have compared the abilities of Escherichia coli and lipopolysaccharides (LPS) purified from these bacteria to prime isolated neutrophils for phorbol myristate acetate-stimulated arachidonate release, to trigger respiratory burst in 1% blood, and to increase steady-state levels of tumor necrosis factor alpha mRNA in whole blood. In all three assays, bacteria were > or = 10-fold more potent than equivalent amounts of LPS and could trigger maximal cellular responses at ratios as low as one bacterium per 20 to 200 leukocytes. Both E. coli and LPS-triggered responses were enhanced by LPS-binding protein and inhibited by an anti-CD14 monoclonal antibody and the bactericidal/permeability-increasing protein (BPI). However, whereas O polysaccharide did not affect the potency of isolated LPS, intact E. coli carrying long-chain LPS (O111:B4) was less potent than rough E. coli (J5). Furthermore, material collected by filtration or centrifugation of bacteria incubated under conditions used to trigger arachidonate release or chemiluminescence was 5- or 30-fold less active, respectively, than whole bacterial suspensions. Extracellular BPI (not bound to bacteria) inhibited bacterial signalling, but BPI bound to bacteria was much more potent. Taken together, these findings indicate that E. coli cells can strongly signal their presence to human leukocytes not only by shedding LPS into surrounding fluids but also by exposing endotoxin at or near their surface during direct interaction with host cells.

Ruptured intracranial aneurysms as a cause of subdural haematoma. Potential diagnostic pitfalls and the surgical management of the acute patient.

Seven cases of aneurysms that ruptured into the subdural space and were treated surgically are reviewed. Six out of the seven presented with signs of uncal herniation, three of them for at least for four hours or more. They all died in spite of urgent decompression and drainage. Three others suffered from uncal herniation for less than four hours and they all did well. The seventh patient had a small subdural haematoma with no signs of compression of the underlying neural structures. This last patient also had a good outcome. The authors point out that the aneurysm causing the haematoma might be overlooked should one utilize CT (computerized tomography) scan alone without contrast. However, in most instances the history gives the aneurysm diagnosis despite the CT scan of haematoma only. Intravenous contrast CT scan may occasionally demonstrate the aneurysm, provided modern CT equipment is adequately utilised. Severe neurological deficit and uncal herniation might still be reversible provided decompression can be carried out in less than four hours. If accessible the aneurysm should also be clipped at the same time.

Prevention of primary wound infection in neurosurgical patients: a 10-year study.

Two neurosurgeons in private practice at three community hospitals followed a regimen of antimicrobial prophylaxis for 10 years. No primary wound infection occurred in a series of 2000 consecutive major operations. The study gives rise to certain recommendations for the prevention of postoperative sepsis in neurosurgical patients.

Carpet beetle larval parts in cervical cytology specimens.

Hairs from carpet beetle larvae were demonstrated in 77 vaginal or cervical smears over a 36-month period. A morphologic description of these structures is presented, and studies of possible sources of contamination are presented and discussed. In some cases, contamination apparently occurred during the taking of the smears through the use of contaminated cotton swabs or wooden spatulas. Other possible sources of contamination include tampons.

Ventriculosubgaleal shunting for acute head trauma.

In 12 cases of closed head injury without fracture or hematoma, but with clinical signs of increased intracranial pressure (ICP) and brain stem compression and with computed tomographic (CT) scan evidence of cerebral edema and contusion, subgaleal shunts were inserted for immediate decompression of the ventricular system and continuous drainage of hemorrhagic cerebrospinal fluid (CSF). Three patients with fixed dilated pupils and no reflexes or spontaneous respiration on admission did not improve and expired within 72 h. Nine patients who manifested Cushing's triad (bradycardia, bradypnea, and hypertension) shortly after admission made significant recovery and underwent catheter removal 1 wk later; 8 were able to be discharged home after extended periods of physiotherapy. No complications, postoperative hemorrhage or infection, were recorded.