In vitro and in vivo targeting of hollow gold nanoshells directed at epidermal growth factor receptor for photothermal ablation therapy

Laser-induced phototherapy is a new therapeutic use of electromagnetic radiation for cancer treatment. The use of targeted plasmonic gold nanoparticles can reduce the laser energy necessary for selective tumor cell destruction. However, the ability for targeted delivery of the currently used gold nanoparticles to tumor cells is limited. Here, we describe a new class of molecular specific photothermal coupling agents based on hollow gold nanoshells (HAuNS; average diameter, approximately 30 nm) covalently attached to monoclonal antibody directed at epidermal growth factor receptor (EGFR). The resulting anti-EGFR-HAuNS exhibited excellent colloidal stability and efficient photothermal effect in the near-infrared region. EGFR-mediated selective uptake of anti-EGFR-HAuNS in EGFR-positive A431 tumor cells but not IgG-HAuNS control was shown in vitro by imaging scattered light from the nanoshells. Irradiation of A431 cells treated with anti-EGFR-HAuNS with near-infrared laser resulted in selective destruction of these cells. In contrast, cells treated with anti-EGFR-HAuNS alone, laser alone, or IgG-HAuNS plus laser did not show observable effect on cell viability. Using 111In-labeled HAuNS, we showed that anti-EGFR-HAuNS could be delivered to EGFR-positive tumors at 6.8% ID/g, and the microscopic image of excised tumor with scattering signal from nanoshells confirmed preferential delivery to A431 tumor of anti-EGFR-HAuNS compared with IgG-HAuNS. The absence of silica core, the relatively small particle size and high tumor uptake, and the absence of cytotoxic surfactant required to stabilize other gold nanoparticles suggest that immuno-HAuNS have the potential to extend to in vivo molecular therapy.     

Distal Revascularisation with Interval Ligation (DRIL): An Experience

INTRODUCTION

The global increase of chronic renal failure has resulted in a growing number of patients on haemodialysis using arteriovenous fistulas (AVFs). By virtue of their very function, AVFs at times shunt blood away from regions distally, resulting in an ischaemic steal syndrome. Distal revascularisation with interval ligation (DRIL) has been described as a procedure to treat symptomatic ischaemic steal. We present our experience in the management of this complication.

PATIENTS AND METHODS

Six patients with severe ischaemic steal were treated using a DRIL procedure between May 2004 and June 2007. There were three males and three females, all with elbow brachiocephalic AVFs. Symptoms ranged from severe rest pain to digital gangrene. Published results from international studies of 135 DRIL procedures were also reviewed.

RESULTS

Vascular access was maintained along with the elimination of ischaemic symptoms in the six patients using an ipsilateral reversed basilic vein graft. Interval ligation of the distal brachial artery was performed at the same time. All patients showed immediate and sustained clinical improvement of symptoms with a demonstrable increase in digital pulse oximetry.

CONCLUSIONS

DRIL is a beneficial treatment option that has proven successful at alleviating ischemic steal symptoms and preserving vascular access. This avoids placement of central lines, its associated risks, and the need to create an alternative sited fistula.     

NS11021, a novel opener of large-conductance Ca2+-activated K+ channels,enhances erectile responses in rats

Background and purpose:

Large-conductance Ca²⁺-activated K⁺ channels (BK_Ca), located on the arterial and corporal smooth muscle, are potential targets for treatment of erectile dysfunction (ED). This study investigated whether NS11021 (1-(3,5-Bis-trifluoromethyl-phenyl)-3-[4-bromo-2-(1H-tetrazol-5-yl)-phenyl]-thiourea), a novel opener of BK_Ca channels, relaxes erectile tissue in vitro and enhances erectile responses in intact rats. The effects were compared with sildenafil, an inhibitor of phosphodiesterase type 5.

Experimental approach:

Patch clamp was used to record whole cell current in rat isolated corpus cavernosum smooth muscle cells (SMCs) and human umbilical vein endothelial cells (HUVECs). Isometric tension was measured in intracavernous arterial rings and corpus cavernosum strips isolated from rats and men, and simultaneous measurements of intracellular Ca²⁺ concentration ([Ca²⁺]_i) and tension were performed in intracavernous arteries. Erectile response was measured in anaesthetized rats.

Key results:

In patch clamp recordings, NS11021 increased currents sensitive to the selective BK_Ca channel blocker, iberiotoxin (IbTX) in SMCs, but did not modulate K⁺ current in HUVECs. NS11021 reduced [Ca²⁺]_i and tension in penile arteries. IbTX inhibited the vasorelaxation induced by NS11021 and sildenafil in human erectile tissue. NS11021 and sildenafil but not vehicle increased erectile responses in anaesthetized rats, an effect which was abolished after pretreatment with tetraethylammonium.

Conclusions and implications:

NS11021 leads to relaxation of both intracavernous arteries and corpus cavernosum strips primarily through opening of BK_Ca channels. It is also effective in facilitating erectile responses in anaesthetized rats. These results suggest a potential for use of BK_Ca openers in the treatment of ED.     

Prostanoid receptor antagonists: development strategies and therapeutic applications

Background and purpose:

Histamine H₃ receptor antagonists are currently being evaluated in clinical trials for a number of central nervous system disorders including narcolepsy. These agents can increase wakefulness (W) in cats and rodents following acute administration, but their effects after repeat dosing have not been reported previously.

Experimental approach:

EEG and EMG recordings were used to investigate the effects of acute and repeat administration of the novel H₃ antagonist GSK189254 on the sleep–wake cycle in wild-type (Ox+/+) and orexin knockout (Ox−/−) mice, the latter being genetically susceptible to narcoleptic episodes. In addition, we investigated H₃ and H₁ receptor expression in this model using radioligand binding and autoradiography.

Key results:

In Ox+/+ and Ox−/− mice, acute administration of GSK189254 (3 and 10 mg·kg⁻¹ p.o.) increased W and decreased slow wave and paradoxical sleep to a similar degree to modafinil (64 mg·kg⁻¹), while it reduced narcoleptic episodes in Ox−/− mice. After twice daily dosing for 8 days, the effect of GSK189254 (10 mg·kg⁻¹) on W in both Ox+/+ and Ox−/− mice was significantly reduced, while the effect on narcoleptic episodes in Ox−/− mice was significantly increased. Binding studies revealed no significant differences in H₃ or H₁ receptor expression between Ox+/+ and Ox−/− mice.

Conclusions and implications:

These studies provide further evidence to support the potential use of H₃ antagonists in the treatment of narcolepsy and excessive daytime sleepiness. Moreover, the differential effects observed on W and narcoleptic episodes following repeat dosing could have important implications in clinical studies.     

Rapid brain penetration of interleukin-1 receptor antagonist in rat cerebral ischaemia: pharmacokinetics,distribution, protection

Background and purpose:

Limited data on the brain penetration of potential stroke treatments have been cited as a major weakness contributing to numerous failed clinical trials. Thus, we tested whether interleukin-1 receptor antagonist (IL-1RA), established as a potent inhibitor of brain injury in animals and currently in clinical development, reaches the brain via a clinically relevant administration route, in experimental stroke.

Experimental approach:

Male, Sprague-Dawley rats [either naïve or exposed to middle cerebral artery occlusion (MCAo)] were given a single s.c. dose of IL-1RA (100 mg·kg⁻¹). The pharmacokinetic profile of IL-1RA was assessed in plasma and CSF up to 24 h post-administration. Brain tissue distribution of administered IL-1RA was assessed using immunohistochemistry. In a separate experiment, the neuroprotective effect of the single s.c. dose of IL-1RA in MCAo was assessed versus a placebo control group.

Key results:

A single s.c. dose of IL-1RA reduced damage caused by MCAo by 33%. This dose resulted in sustained, high concentrations in plasma and CSF, penetrated brain tissue exclusively in areas of blood–brain barrier breakdown and co-localized with morphologically viable neurones. CSF concentrations did not reflect massive parenchymal infiltration of IL-1RA in MCAo animals compared to naïve.

Conclusions and implications:

These data are the first to show that a potential treatment for stroke, IL-1RA, rapidly reaches salvageable brain tissue via an administration route that is clinically relevant. This allows confidence that IL-1RA, as a candidate for further clinical development, is able to confer its protective actions both peripherally and centrally.     

自身免疫性肝炎的现代处理观点

自身免疫性肝炎（AIH）常见于女性,表现为肝酶异常（转氨酶升高）、血清自身抗体如抗核抗体（ANA）、抗平滑肌抗体（SMA）、抗可溶性肝抗原抗体／肝胰抗原（SLA／LP）、抗肝肾做粒体抗体（LKM）1阳性和γ-免疫球蛋白升高,但并非所有AIH患者均出现上述特征。AIH的组织学特点为界面性肝炎,以浆细胞和淋巴细胞浸润为主,但无特征性组织学表现。AIH的确诊较为困难,目前的流行病学资料中报道的AIH实际发病率和患病率可能偏低。     

Alveolar recruitment strategy and PEEP improve oxygenation,dynamic compliance of respiratory system and end‐expiratory lung volume in pediatric patients undergoing cardiac surgery for congenital heart disease

Objective: Optimizing alveolar recruitment by alveolar recruitment strategy (ARS) and maintaining lung volume with adequate positive end‐expiratory pressure (PEEP) allow preventing ventilator‐induced lung injury (VILI). Knowing that PEEP has its most beneficial effects when dynamic compliance of respiratory system (Crs) is maximized, we hypothesize that the use of 8 cm H₂O PEEP with ARS results in an increase in Crs and end‐expiratory lung volume (EELV) compared to 8 cm H₂O PEEP without ARS and to zero PEEP in pediatric patients undergoing cardiac surgery for congenital heart disease. Methods: Twenty consecutive children were studied. Three different ventilation strategies were applied to each patient in the following order: 0 cm H₂O PEEP, 8 cm H₂O PEEP without an ARS, and 8 cm H₂O PEEP with a standardized ARS. At the end of each ventilation strategy, Crs, EELV, and arterial blood gases were measured. Results: EELV, Crs, and P_aO₂/FiO₂ ratio changed significantly (P < 0.001) with the application of 8 cm H2O + ARS. Mean P_aCO₂– PETCO₂ difference between 0 PEEP and 8 cm H2O PEEP + ARS was also significant (P < 0.05). Conclusion: An alveolar recruitment strategy with relative high PEEP significantly improves Crs, oxygenation, P_aCO₂– PETCO₂ difference, and EELV in pediatric patients undergoing cardiac surgery for congenital heart disease.     

Solving the Organ Shortage Crisis: The 7th Annual American Society of Transplant Surgeons' State-of-the-Art Winter Symposium

The 2007 American Society of Transplant Surgeons' (ASTS) State-of-the-Art Winter Symposium entitled, 'Solving the Organ Shortage Crisis' explored ways to increase the supply of donor organs to meet the challenge of increasing waiting lists and deaths while awaiting transplantation. While the increasing use of organs previously considered marginal, such as those from expanded criteria donors (ECD) or donors after cardiac death (DCD) has increased the number of transplants from deceased donors, these transplants are often associated with inferior outcomes and higher costs. The need remains for innovative ways to increase both deceased and living donor transplants. In addition to increasing ECD and DCD utilization, increasing use of deceased donors with certain types of infections such as Hepatitis B and C, and increasing use of living donor liver, lung and intestinal transplants may also augment the organ supply. The extent by which donors may be offered incentives for donation, and the practical, ethical and legal implications of compensating organ donors were also debated. The expanded use of nonstandard organs raises potential ethical considerations about appropriate recipient selection, informed consent and concerns that the current regulatory environment discourages and penalizes these efforts.     

Effects of gender and age on paediatric headache

The aim of this study was to evaluate the impact of gender and age on headache characteristics and disability. Headache characteristics were assessed at an initial visit to a paediatric specialty care centre and five follow-up visits. A total number of 4121 patients were evaluated. Fifty-eight per cent of the sample was female. Boys were younger at their first headache and initial visit. They more frequently described headache pain as squeezing and location as top of the head. Girls reported more frequent and longer headaches. Girls more often described headache pain as sharp and location as back of the head. Age accounted for more variance than gender in headache severity, duration, frequency and disability. Gender differences exist in headache characteristics. Age is also an important factor in the variability in characteristics and disability. Longitudinal studies are needed to describe further the natural history of headaches in childhood and compare outcome between genders.