Differential effects of basolateral and apical iron supply on iron transport in Caco-2 cells.

Iron homeostasis in the human body is maintained primarily through regulation of iron absorption in the duodenum. The liver peptide hepcidin plays a central role in this regulation. Additionally, expression and functional control of certain components of the cellular iron transport machinery can be influenced directly by the iron status of enterocytes. The significance of this modulation, relative to the effects of hepcidin, and the comparative effects of iron obtained directly from the diet and/or via the bloodstream are not clear. The studies described here were performed using Caco-2 cell monolayers as a model of intestinal epithelium, to compare the effects of iron supplied in physiologically relevant forms to either the apical or basolateral surfaces of the cells. Both sources of iron provoked increased cellular ferritin content, indicating iron uptake from both sides of the cells. Supply of basolateral transferrin-bound iron did not affect subsequent iron transport across the apical surface, but reduced iron transport across the basolateral membrane. In contrast, the apical iron supply led to subsequent reduction in iron transport across the apical cell membrane without altering iron export across the basolateral membrane. The apical and basolateral iron supplies also elicited distinct effects on the expression and subcellular distribution of iron transporters. These data suggest that, in addition to the effects of cellular iron status on the expression of iron transporter genes, different modes and direction of iron supply to enterocytes can elicit distinct functional effects on iron transport.

The MEK1/2 inhibitor, selumetinib (AZD6244; ARRY-142886), enhances anti-tumour efficacy when combined with conventional chemotherapeutic agents in human tumour xenograft models.

BACKGROUND: The Ras/RAF/MEK/ERK pathway is frequently deregulated in cancer and a number of inhibitors that target this pathway are currently in clinical development. It is likely that clinical testing of these agents will be in combination with standard therapies to harness the apoptotic potential of both the agents. To support this strategy, it has been widely observed that a number of chemotherapeutics stimulate the activation of several intracellular signalling cascades including Ras/RAF/MEK/ERK. The MEK1/2 inhibitor selumetinib has been shown to have anti-tumour activity and induce apoptotic cell death as a monotherapy. METHODS: The aim of this study was to identify agents, which would be likely to offer clinical benefit when combined with selumetinib. Here, we used human tumour xenograft models and assessed the effects combining standard chemotherapeutic agents with selumetinib on tumour growth. In addition, we analysed tumour tissue to determine the mechanistic effects of these combinations. RESULTS: Combining selumetinib with the DNA-alkylating agent, temozolomide (TMZ), resulted in enhanced tumour growth inhibition compared with monotherapies. Biomarker studies highlighted an increase in γH2A.X suggesting that selumetinib is able to enhance the DNA damage induced by TMZ alone. In several models we observed that continuous exposure to selumetinib in combination with docetaxel results in tumour regression. Scheduling of docetaxel before selumetinib was more beneficial than when selumetinib was dosed before docetaxel and demonstrated a pro-apoptotic phenotype. Similar results were seen when selumetinib was combined with the Aurora B inhibitor barasertib. CONCLUSION: The data presented suggests that MEK inhibition in combination with several standard chemotherapeutics or an Aurora B kinase inhibitor is a promising clinical strategy.

Ultrasound guidance allows accurate needle placement and aspiration from small joints in patients with early inflammatory arthritis.

OBJECTIVES: To compare the accuracy of palpation-guided and high frequency ultrasound-guided needle placement in small joints and to develop a technique to obtain synovial fluid from these joints for diagnosis and research. METHODS: The accuracy of needle placement during palpation-guided proximal interphalangeal (PIP) or metacarpophalangeal (MCP) joint injection was assessed. This was compared with the accuracy of ultrasound-guided needle placement. A joint lavage technique was developed to obtain synovial fluid from these joints. RESULTS: Needle positioning was intra-articular in 59% of palpation-guided injections (6/12 PIP and 4/5 MCP joints). No fluid could be aspirated prior to injection. With ultrasound guidance, initial needle placement was intra-articular in 96% of cases (24/26 PIP and 27/27 MCP joints). Synovial fluid cells were lavaged from 63% of joints (19/25 PIP and 14/27 MCP joints). In only one case was a large effusion seen and this was aspirated directly. CONCLUSIONS: The use of high frequency ultrasound to guide needle placement within a small joint allows for significantly greater accuracy than a palpation-guided approach. When followed by lavage, synovial fluid cells and diluted synovial fluid can be obtained from the majority of small joints. This has important clinical and research implications.

Chromophore-enhanced laser-tumor tissue photothermal interaction using an 808-nm diode laser.

A diode laser was used to irradiate tumor tissue, with indocyanine green as the chromophore. The 808-nm wavelength radiation falls within the absorption peak of the chromophore (about 780 nm). The preliminary results in this report revealed clear and significant coupling of this laser and indocyanine green in laser-tissue photothermal interaction. The chromophore targeted tissue showed laser damage while peripheral tissues remained intact. Without the chromophore, this laser inflicted no apparent tissue damage in the non-contact mode with irradiance up to 1755 J/cm2.

The effects of acute sleep deprivation during residency training.

Verbal and symbol concentration, learning, problem solving, clear thinking, manual skills, and memory were tested in 42 surgical residents to assess the effects of acute sleep deprivation on specific neuropsychological parameters. A series of eight neuropsychological tests--digit symbols, digit vigilance, story memory, trail making, PASAT, Raven matrices, delayed story, and pegboard--and a questionnaire on mood states were completed by the residents both when fatigued (less than 4 hours of sleep: mean, 2.0 +/- 1.5 hours) and when rested (more than 4 hours of sleep: mean, 6.5 +/- 1.0 hours), with at least 7 days between tests. In order to eliminate the effects of learning from the first test series, randomization of residents was performed so that one half were first evaluated when rested and one half when fatigued. ANOVA, multiple regression analysis, and the Student t test were used to assess differences. In the acute sleep-deprived state, residents were less vigorous and more fatigued, depressed, tense, confused, and angry (p less than 0.05) than they were in rested state. Despite these changes in mood, however, the responses on all of the functional tests were no different statistically in those who were rested and those who were fatigued (even in those with less than 2 hours' sleep). We conclude that acute sleep deprivation of less than 4 hours alters mood state but does not change performance in test situations in which concentration, clear thinking, and problem solving are important.

Lymphogranuloma venereum in a pregnant woman.

Lymphogranuloma venereum was diagnosed postpartum in a young black woman, who was a drug abuser. Chlamydia trachomatis was isolated from aspirate of a left inguinal mass, and the patient was also seropositive for human immunodeficiency virus. During hospitalization she was treated with ampicillin, gentamicin, and doxycycline. Her twin infant girls had no evidence of C. trachomatis infection. The mother was discharged from the hospital after partial resolution of the left inguinal mass and was lost to follow-up.

Monophasic extraskeletal mandibular fixation in head and neck surgery.

Stabilization, reconstruction, and rehabilitation of certain mandibular fractures or continuity defects may be facilitated by external skeletal fixation. The utilization of a convenient and inexpensive monophasic extraskeletal fixation appliance in select instances of mandibular trauma or head and neck surgery is described herein and illustrated with case reports.

Clostridia isolated from faeces.

Clostridia were isolated from human faecal samples from England, Scotland, Wales, USA, Hong Kong, Uganda and Japan. Strains were identified on the basis of various biochemical reactions and on the type of fatty acid produced from glucose. Analysis of these acids was by gas-liquid chromatography. Clostridium paraputrificum was common in stool samples from England, Scotland, Wales, and USA, but rare in samples from Hong Kong, Uganda and Japan.