l-Amino Acid Based Phenol- and Catechol-Functionalized Poly(ester-urethane)s for Aromatic π-Interaction Driven Drug Stabilization and Their Enzyme-Responsive Delivery in Cancer Cells.

Exploiting aromatic π-interaction for the stabilization of polyaromatic anticancer drugs at the core of the polymer nanoassemblies is an elegant approach for drug delivery in cancer research. To demonstrate this concept, here we report one of the first attempts on enzyme-responsive polymers from aryl-unit containing amino acid bioresources such as l-tyrosine and 3,4-dihydroxy-l-phenylalanine (l-DOPA). A silyl ether protection strategy was adopted to make melt polymerizable monomers, which were subjected to solvent free melt polycondensation to produce silyl-protected poly(ester-urethane)s. Postpolymerization deprotection yielded phenol- and catechol-functionalized poly(ester-urethane)s with appropriate amphiphilicity and produced 100 ± 10 nm size nanoparticles in an aqueous solution. The aromatic π-core in the nanoparticle turns out to be the main driving force for the successful encapsulation of anticancer drugs such as doxorubicin (DOX) and topotecan (TPT). The electron-rich catechol aromatic unit in l-DOPA was found to be unique in stabilizing the DOX and TPT, whereas its l-tyrosine counterpart was found to exhibit limited success. Aromatic π-interactions between l-DOPA and anticancer drug molecules were established by probing the fluorescence characteristics of the drug-polymer chain interactions. Lysosomal enzymatic biodegradation of the poly(ester-urethane) backbone disassembled the nanoparticles and released the loaded drugs at the cellular level. The nascent polymer was nontoxic in breast cancer (MCF7) and WT-MEF cell lines, whereas its DOX and TPT loaded nanoparticles showed remarkable cell growth inhibition. A LysoTracker-assisted confocal microscopic imaging study directly evidenced the polymer nanoparticles' biodegradation at the intracellular level. The present investigation gives an opportunity to design aromatic π-interaction driven drug stabilization in l-amino acid based polymer nanocarriers for drug delivery applications.

Protocol for intranasal chemoprevention delivery in a urethane mouse lung cancer model.

Mouse iloprost lung cancer chemoprevention studies typically use oral delivery. Here, we present a protocol for intranasal iloprost delivery within a urethane lung adenocarcinoma mouse model. We detail steps for intraperitoneal urethane injection in mice, followed by nine-week monitoring, intranasal iloprost treatment, and lungs harvesting for analysis. This iloprost delivery approach parallels an ongoing phase II clinical trial of inhaled iloprost for lung cancer chemoprevention. This protocol diversifies options for chemoprevention studies and offers a relevant and translatable model. For complete details on the use and execution of this protocol, please refer to Sompel et al. (2022).

Long-term function of Hydrofit as hemostatic sealant: abridged republication.

The newly-designed hemostatic sealant, Hydrofit, was developed in Japan and consists of a urethane-based polymer without blood products. By applying Hydrofit gel to an anastomosis site on the aorta, water contact initiates a chemical change in the forming elastomer which adheres rapidly and tightly. We experienced an extirpation of Hydrofit gel that had been applied 4 years and 8 months previously in a 42-year-old female who underwent aortic valve replacement and graft replacement of the ascending aorta. The Hydrofit left around the aortic graft suture line was without infection and functioned very well as an elastic sealant for a long period.

Investigation of effects of urethane foam mattress hardness on skin and soft tissue deformation in the prone position using magnetic resonance imaging.

AIM: In operating rooms, the occurrence of pressure ulcers caused by being in the prone position is the highest among that of pressure ulcers caused by being in other surgical positions. Thus, we investigated effects of hardness and shape of urethane foam mattresses for preventing pressure ulcers during surgery performed with patients in the prone position. We aimed to elucidate how mattresses of variable hardness and shapes affect compression and displacement of the skin and soft tissues with external force in the prone position. MATERIAL AND METHODS: We assessed effects of two shapes [rectangular cube (RC) and trapezoid cube (TC)] and four degrees of hardness (50, 87.5, 175, and 262.5 N) in each shape. We performed magnetic resonance imaging (MRI) of the iliac crests with external force while participants reclined in the prone position on eight different mattresses. RESULTS: Compression of the skin and soft tissue was significantly higher with 87.5-, 175-, and 262.5-N mattresses than that with 50-N mattresses. Skin and soft tissue displacement was higher with TC mattress than that with RC mattress, and the extent of skin surface and internal soft tissue displacement was different. CONCLUSIONS: Compression of the skin and soft tissue depends on mattress hardness; however, a threshold value (175 N) for hardness exists, above which no further changes in the parameters were observed. Skin and soft tissue displacement does not depend on mattress hardness, but rather on its shape. Furthermore, mattress inclination increases skin surface displacement.

Repair of a Giant Omphalocele in an Infant With a Pericardial Implant Crosslinked With Oligourethane.

The giant omphalocele (GO) represents a challenge for the pediatric surgeon in its management and wall abdominoplasty. Here, we report the outcome of a case in which a GO in a newborn patient was repaired with an implant derived from decellularized bovine pericardium crosslinked with oligourethane. The implantation time was extended for 6 months. This was then followed up by the retrieval of the implant and the subsequent reconstruction in a second surgical time by the closure of the abdominal wall fascia. A short hospital stay, early integration into the patient's family environment, as well as early onset of the oral route without special care of the implant or reconstructed wall nor food restrictions were observed. The reduced presence of the complications described in the literature after application of surgical meshes suggests that this implant can be an effective and safe alternative method in the treatment of abdominal wall defects such as GO.

Electrical Stimulation of the Spinal Dorsal Root Inhibits Reflex Bladder Contraction and External Urethra Sphincter Activity: Is This How Sacral Neuromodulation Works?

INTRODUCTION: Using a rat model, we aimed to confirm the inhibitory effect of dorsal spinal root (afferent) stimulation and test if bilateral stimulation is more effective than unilateral stimulation. External urethral sphincter (EUS) electromyography (EMG) is also assessed in conjunction with cystometrogram. MATERIALS AND METHODS: Eighteen female Sprague-Dawley rats were tested following urethane anesthesia. Via urethral catheterization, the bladder was infused with normal saline to evoke rhythmic bladder reflex contractions (BRC). L6 spinal nerves were isolated and stimulated. RESULTS: L6 stimulation was effective in inhibiting BRC. L6 bilateral dorsal root (DR) stimulation of 50% intensity was required to cause inhibition as compared to unilateral stimulation. In EUS EMG recordings, there was a strong association between EUS EMG activities and bladder contraction. When the bladder contraction was inhibited effectively by L6 DR stimulation, a considerable reduction was also found in the EUS EMG activities. CONCLUSIONS: L6 DR stimulation abolished BRC in our rat model. Bilateral L6 DR stimulation produced a 50% reduction in stimulation intensity, providing a similar BRC block. Abolishing BRC also appeared to coincide with a reduction in EUS EMG, implicating that sacral neuromodulation might act centrally, at least rostrally at the T8-9 spinal level.

Retrieval analysis of a failed TriboFit polycarbonate urethane acetabular buffer.

The purpose of this research was to determine the failure mechanisms and damage features of a TriboFit acetabular buffer implanted directly against a native, prepared acetabulum which was revised after 11months. Retrieval analyses were carried out via light microscopy, gravimetric wear assessment, and observer scoring of visible damage features on the buffer. The volume of material abraded from the backside of the buffer was estimated via three-dimensional reconstruction using a laser scanner. Scanning electron microscopy was used to confirm damage features and mechanisms. Severe abrasion to the backside of the buffer was the primary damage feature, while stippling damage was seen on the articular surface of the buffer. Material loss due to backside abrasion was approximated to be between 0.13360.085 g (gravimetric analyses) and 0.19360.053 g (three-dimensional reconstruction). Implantation of the TriboFit buffer against the patient's native acetabulum without a metal backing allowed for significant movement of the buffer against the bone, resulting in the abrasion seen on this implant. The stippling damage on the articular surface indicates an adhesive wear mechanism which exacerbates movement of the buffer against the acetabulum, thereby increasing backside abrasion.

Assessing the Effects of Concurrent versus Sequential Cisplatin/Radiotherapy on Immune Status in Lung Tumor-Bearing C57BL/6 Mice.

Concurrent and sequential cisplatin-based chemoradiotherapy regimens are standard therapeutic approaches in cancer treatment. Recent clinical data suggest that these different dosing schedules may adversely affect antigen-specific immunotherapy. The goal of the present preclinical study was to explore the effects of concurrent and sequential cisplatin/radiotherapy on immune status in a lung cancer mouse model. A total of 150 C57BL/6 mice were randomized into six treatment groups: control; 8 Gy thoracic radiotherapy (dose schedules 1 and 2); cisplatin 2.5 mg/kg i.p.; cisplatin + radiotherapy (concurrent); and cisplatin + radiotherapy (sequential; n = 25, all groups). At the end of the study (week 41), serum cytokines were assessed by multiplex immunoassay, surface markers of spleen-derived lymphocytes were assessed by immunostaining and flow cytometry, lung tumor expression of programmed death ligands 1 and 2 (PD-L1/2) was evaluated by immunohistochemistry, and miRNA profiling was performed in serum and lymphocytes by quantitative real-time PCR. Lung whole mounts were prepared to assess treatment effects on lung tumor foci formation. The results showed that sequential chemoradiotherapy (two cycles of cisplatin followed by 8 Gy radiotherapy) had equivalent antitumor activity as concurrent therapy. However, sequential cisplatin/radiotherapy resulted in significant differences in several immune response biomarkers, including regulatory T cells, miR-29c, expression of costimulatory molecule CD28, and serum IFNγ. PD-L1 and PD-L2 were strongly expressed in tumor foci, but no trend was seen between groups. These results suggest that monitoring immune status may be necessary when designing treatment regimens combining immunotherapy with chemoradiotherapy.

Remote pharmacological preconditioning on median nerve territory increases Hsp32 expression and attenuates ischemia-reperfusion injury in rat heart.

AIMS: The aim of this study was to test the hypothesis that remote pharmacological preconditioning (RPP) induced myocardial heat shock protein (Hsp) 32 expression and attenuated the ischemia-reperfusion (I/R) injury of the heart in rats. MAIN METHODS: Animals were injected at the left median nerve territory with chloralose and urethane mixture. At different time intervals, myocardial Hsp32 gene expression was analyzed. Primary heart cultures were used to investigate the direct effect of drug mixture on Hsp32 expression. KEY FINDINGS: The results showed that Hsp32 was time- and dose-dependently increased by in vivo drug mixture treatment, but not in primary cultures. RPP significantly decreased the duration of arrhythmia and incidence of stony heart in rats with subsequent I/R injury. SIGNIFICANCE: We conclude that RPP on the left median nerve territory induced Hsp32 gene expression in the heart and attenuates myocardial damage functionally after subsequent I/R injury.

Safety of the nonabsorbable dural substitute in decompressive craniectomy for severe traumatic brain injury.

BACKGROUND: Artificial dural substitutes are increasingly being used in decompressive craniectomy to prevent peridural fibrosis and facilitate cranioplasty for patients with head injury. The safety of the dural substitute should be systemically evaluated. We focus on Neuro-Patch (B. Braun, Boulogne, France), a nonabsorbable substitute and commonly used by neurosurgeons. METHODS: In this retrospective study, 132 patients undergoing 135 craniectomies and cranioplasties for traumatic brain injury were enrolled. We subdivided the operations into two groups on the basis of whether Neuro-Patch was used (N = 50) or not (N = 85). Risk factors of neurosurgical site infection were assessed first. Then, we compared the occurrence of infective, hemorrhagic, and hydrodynamic morbidities after craniectomy and cranioplasty between the two groups. RESULTS: The incidence of neurosurgical site infection after craniectomy or cranioplasty showed no intergroup difference (p = 1.000). Postoperatively, extra-axial hematoma, which consists of subdural or epidural hematoma, occurred in 9 of 50 craniectomies (18.00%) with Neuro-Patch and 3 of 85 craniectomies (3.53%) without Neuro-patch, which was significantly different (p = 0.009). The rates of hydrodynamic morbidities (subdural hygroma or cerebrospinal fluid leakage) after the procedures were similar between the two groups. CONCLUSIONS: The use of Neuro-Patch does not increase the incidence of neurosurgical site infection and hydrodynamic complications, including subdural hygroma and cerebrospinal fluid leakage, after decompressive craniectomy or cranioplasty for severe traumatic brain injury. However, extra-axial hematoma at the site of craniectomy is more often encountered in patients with Neuro-Patch and forms a compressive lesion on the adjacent brain.

History of multiple myeloma.

Multiple Myeloma has been recognized since Ancient Times. The first well-documented case was reported in 1844 by Samuel Solly. The most commonly recognized case is that of Thomas Alexander McBean, a highly respectable tradesman from London in 1850. Mr. McBean excreted a large amount of protein that was described by Henry Bence Jones in the middle of the 19th century. Jones was a well-known physician and made many contributions to medicine. One of the best known cases of multiple myeloma was that of Dr. Loos that was reported by Otto Kahler. The recognition of plasma cells and subsequently their product, a monoclonal protein has been described in detail. The authors have reviewed the treatment of multiple myeloma including the novel agents, thalidomide, bortezomib and lenalidomide.

Spinal cord injury immediately decreases anesthetic requirements in rats.

STUDY DESIGN: Pharmacologically blocking the spinal cord produces sedative effects and reduces anesthesia requirements in patients and animals. Whether spinal cord injury also reduces anesthesia requirements remains unclear. METHODS: We retrospectively analyzed data from urethane-anesthetized rats (15) to assess anesthesia requirements immediately after complete thoracic transection of the spinal cord. The depth of anesthesia was monitored up to 12 h after spinal transection by the reflexes to noxious stimuli and by electrophysiological recordings from the infragranular layers of the primary somatosensory cortex. Whenever animals displayed electrophysiological and/or behavioral signs of activation, we delivered an additional dose of anesthesia. Anesthetic requirements in animals receiving spinal transection (n=11) were compared with control animals receiving 'sham' lesion (n=9). RESULTS: The cumulative dose necessary to maintain a stable level of anesthesia was significantly lower in transected animals compared with control animals. By about 7 h after spinal cord injury, on average the cumulative dose of urethane was only 1.13±0.14 of the original dose, compared with 1.64±0.19 of the original dose in control animals. CONCLUSIONS: Spinal transection immediately decreased anesthetic requirements in rats. To establish whether these results are relevant for patients with spinal cord injury will require further investigation.

Cyclic and sleep-like spontaneous alternations of brain state under urethane anaesthesia.

BACKGROUND: Although the induction of behavioural unconsciousness during sleep and general anaesthesia has been shown to involve overlapping brain mechanisms, sleep involves cyclic fluctuations between different brain states known as active (paradoxical or rapid eye movement: REM) and quiet (slow-wave or non-REM: nREM) stages whereas commonly used general anaesthetics induce a unitary slow-wave brain state. METHODOLOGY/PRINCIPAL FINDINGS: Long-duration, multi-site forebrain field recordings were performed in urethane-anaesthetized rats. A spontaneous and rhythmic alternation of brain state between activated and deactivated electroencephalographic (EEG) patterns was observed. Individual states and their transitions resembled the REM/nREM cycle of natural sleep in their EEG components, evolution, and time frame ( approximately 11 minute period). Other physiological variables such as muscular tone, respiration rate, and cardiac frequency also covaried with forebrain state in a manner identical to sleep. The brain mechanisms of state alternations under urethane also closely overlapped those of natural sleep in their sensitivity to cholinergic pharmacological agents and dependence upon activity in the basal forebrain nuclei that are the major source of forebrain acetylcholine. Lastly, stimulation of brainstem regions thought to pace state alternations in sleep transiently disrupted state alternations under urethane. CONCLUSIONS/SIGNIFICANCE: Our results suggest that urethane promotes a condition of behavioural unconsciousness that closely mimics the full spectrum of natural sleep. The use of urethane anaesthesia as a model system will facilitate mechanistic studies into sleep-like brain states and their alternations. In addition, it could also be exploited as a tool for the discovery of new molecular targets that are designed to promote sleep without compromising state alternations.

Peptidomimetic inhibitors of HIV protease.

There are currently (July, 2002) six protease inhibitors approved for the treatment of HIV infection, each of which can be classified as peptidomimetic in structure. These agents, when used in combination with other antiretroviral agents, produce a sustained decrease in viral load, often to levels below the limits of quantifiable detection, and a significant reconstitution of the immune system. Therapeutic regimens containing one or more HIV protease inhibitors thus provide a highly effective method for disease management. The important role of protease inhibitors in HIV therapy, combined with numerous challenges remaining in HIV treatment, have resulted in a continued effort both to optimize regimens using the existing agents and to identify new protease inhibitors that may provide unique properties. This review will provide an overview of the discovery and clinical trials of the currently approved HIV protease inhibitors, followed by an examination of important aspects of therapy, such as pharmacokinetic enhancement, resistance and side effects. A description of new peptidomimetic compounds currently being investigated in the clinic and in preclinical discovery will follow.

Acute effects of pentobarbital, thiopental and urethane on lung oedema induced by alpha-naphthythiourea (ANTU).

This study was designed to investigate the possible participation of urethane, pentobarbital sodium and thiopental sodium anaesthesia in the lung oedema induced by alpha-naphthylthiourea (ANTU), which is a well known noxious chemical agent in the lung. ANTU when injected intraperitoneally (i.p.) into rats (10 mg x kg (-1) i.p.) produced lung oedema as indicated by an increase in lung weight/body weight (LW/BW) ratio and pleural effusion (PE) reaching a maximum within 4 h. Administration of urethane prior to ANTU, at doses of 100 and 200mg(100g)(-1), elicited a significant and dose-dependent inhibition in LW/BW ratio and PE. Thiopental sodium at doses of 25, 50 mg x kg (-1), also produced a significant and dose-dependent inhibition of both parameters. Prior i.p. injection of pentobarbital sodium at a dose of 40 mg x kg (-1) elicited a significant inhibition in both parameters. These results suggest that i.p. urethane, thiopental sodium and pentobarbital sodium pretreatment have a prophylactic effect on ANTU-induced lung injury in rats. The possible role of the anaesthetics in lung oedema induced by ANTU and the possible underlying mechanisms are discussed.

Videographic assessment of the embolic characteristics of three polymeric compounds: ethylene vinyl alcohol, cellulose acetate, and liquid urethane.

BACKGROUND AND PURPOSE: Aneurysms have been clinically and experimentally treated with various surgical and endovascular methods, including endovascular polymer instillation. Additional tools may help to identify advantages and disadvantages of polymeric aneurysm treatment. We assessed the value of high-resolution videography to compare in vitro embolization characteristics of ethylene vinyl alcohol copolymer (VIN), cellulose acetate polymer (ACE), and urethane copolymer (UCO). METHODS: In a "neck-up" glass aneurysm model, solutions of 8% and 12% VIN, 8% and 12% ACE, and 8% UCO were introduced through a microcatheter into a xanthan gum solution at three flow rates: full physiological (62 cm/s), half physiological, and flow arrest. Each formulation was then introduced into a "neck-down" aneurysm model at flow arrest, for a total of 20 experiments. Results were tabulated for six different categories: outflow tail formation, inflow-zone polymer-mass deformation, inflow-zone migration, detachment tail formation, adherent mass pullout, and conjectural net effect. RESULTS: Of the 20 experiments, nine had unacceptable results because of potential clinical complications. The results were unacceptable in four of eight VIN experiments, four of eight ACE experiments, and one of four UCO experiments. VIN performance was more dependent on flow arrest than the more viscous ACE. The growth of the ACE solutions was most circumferential, with balloonlike growth characteristics, little inflow-zone effects, and fewer outflow tails than seen with VIN. All compounds had the potential for partial catheter adhesion and catheter-adhesing tails. UCO had the highest percentage of favorable results and the lowest percentage of unfavorable results. CONCLUSION: Videographic analysis allows detailed assessment of the dynamic embolization characteristics of polymers, revealing potential advantages of compounds such as UCO.

Heat shock proteins following rat cerebral ischemic/reperfusion episode: effect of ketamine.

This paper reports the influence of ketamine on HSP70 expression, during an ischemic/reperfusion episode, in rat cerebral cortex and hippocampus. The results indicate that ketamine, injected 1h before the surgical treatment, increases HSP70 cellular concentration in both ischemic and sham-operated animals. The HSP70 levels, after the transient ischemic episode, are higher in ketamine treated than in urethane-treated animals respect to the control levels. After reperfusion an increase of HSP70 levels is observed; this induction is maintained for at least 22h, irrespective of the anaesthetic drug treatment. Comparing the cerebral areas examined, the hippocampus exhibits higher protein levels than those of the cerebral cortex.

Cariostatic effect and fluoride release from a visible light-curing adhesive for bonding of orthodontic brackets.

This study was designed to investigate the cariostatic potential in vivo of a visible light-curing adhesive for the bonding of orthodontic brackets. The fluoride release of the adhesive in water and saliva was also measured. Ten orthodontic patients with premolars to be extracted participated. One bracket with Heliosit-Orthodontic (no fluoride) was positioned on the buccal surface of one premolar (control), and another bracket with Orthodontic cement VP 862 (containing fluoride) was positioned on the experimental contralateral premolar. The adhesives were cured with a Heliolux II lamp, and the teeth were extracted after 4 weeks. The patients used a fluoride toothpaste during the experiment. The mineral content of the enamel adjacent to the brackets was determined by quantitative microradiography. The fluoride release from disk-shaped plates of the fluoride adhesive was measured in water for a 6-month period and in human saliva for 24 hours. The fluoride adhesive reduced lesion depths by about 48% than the nonfluoride adhesive (P less than 0.05, t test). The largest release of fluoride from the plates in water was observable within the first week. However, a significant amount of fluoride was still released after 6 months. The fluoride release in saliva was significantly lower in human saliva at pH 7 than in water (P less than 0.01, t test). When salivary pH was lowered to 4, to mimic a cariogenic challenge, the amount of fluoride released increased up to the value measured in water. It was concluded that the regular use of fluoride toothpastes is insufficient to inhibit lesion development around orthodontic brackets.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute respiratory distress syndrome (ARDS): the prophylactic effect of neurodepressant agents.

It has been suggested that acute respiratory distress syndrome (ARDS) is induced by a cybernetic imbalance of the central nervous system secondary to alarm reaction-provoked intravascular coagulation into cerebral microvessels. The brain metabolic and electrical resting state through the use of neurodepressant drugs might theoretically reduce the intensity and duration of the alarm reaction, thus diminishing the possibility of self-induced secondary brain lesions. In this work, Wistar rats were submitted to central (anterior hypothalamic electrolytic lesion) and peripheral (scald burn) trauma as effective models of reproducing an ARDS-like syndrome. Pretreatment of these animals with the following neurodepressant drugs: morphine, pentobarbital sodium, haloperidol, diazepam, chlorpromazine, and urethane, resulted in significant attenuation of the evolution of the ARDS-like syndrome, reinforcing the suggestion of a centrally-based origin of such pathologic manifestations.