Cytotoxicity considerations and electrically tunable release of dexamethasone from polypyrrole for the treatment of back-of-the-eye conditions.

Age-related macular degeneration (AMD) and diabetic macular edema (DME) are common causes of blindness in people aged over 55 years. Current treatment involves frequent intravitreal administration of corticosteroids such as dexamethasone. The aim of this research was to formulate an electrically controlled delivery system for dexamethasone. Polypyrrole (PPy) was polymerized with dexamethasone sodium phosphate (Dex-P) through two approaches. Firstly, conventional films (CFs) of PPy were electropolymerized by applying a constant current density of 2 mA/cm2 for 4 min. Secondly, for the first time, we report drug-loaded ethanol-washed films (EWFs). EWFs were prepared in the same manner as CFs, except ethanol washing steps were introduced in the middle and at the end of PPy electropolymerization. The ethanol washing removed unbound PPy oligomers resulting in the formation of smooth surfaces with two distinct layers when viewed in cross-section. The EWFs showed superior electrochemical activity compared to CFs. Sustained release was observed from both CFs and EWFs with bursts of release triggered by electrical stimulation. The EWFs were initially more responsive to the electrical trigger, offering future opportunities to fine tune release. The cytotoxicity of aqueous extracts collected from both films was evaluated on human adult retinal pigment epithelium (ARPE-19) cells using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay with negligible toxicity observed. The results suggest PPy-Dex-P films are highly suitable for the development of electro-responsive implants for the treatment of AMD and DME.

Electro-responsive macroporous polypyrrole scaffolds for triggered dexamethasone delivery.

Corticosteroids such as dexamethasone are first line ophthalmic treatment for non-infectious posterior uveitis. Corticosteroids are often administered via intravitreal injection to treat this condition with frequent injections associated with poor treatment adherence and complications such as endophthalmitis. Current ocular implants provide sustained corticosteroid release at predetermined rates and lack the ability for dose individualisation. This study describes the successful fabrication of electrically responsive macroporous polypyrrole (PPy) thin films, and their subsequent application to triggered dexamethasone release. Colloidal crystal films composed of 370nm polymethylmethacrylate colloids were first deposited on ITO coated glass substrates, and subsequently used as sacrificial templates for the fabrication of high surface area, 3-dimensionally ordered macroporous PPy inverse opal (PPy IO) thin films. SEM, UV-Vis reflectance and cyclic voltammetry measurements established that the redox state of the PPy IO films could be controlled via electrical stimulation, which in turn influences both porosity and optical properties of the films. Incorporation of the anti-inflammatory corticosteroid, dexamethasone phosphate (DexP), in the PPy IO films during their fabrication resulted in an effective delivery platform for triggered DexP release. A sustained release profile was observed for the PPy IO-DexP films, bursts of release could be triggered by electrical stimulation. The amount of DexP released from the PPy IO-DexP films was significantly higher than that released from the conventional non-porous PPy-DexP films of comparable mass. Results suggest that electrically responsive PPy IO structures are highly suitable for on-demand drug delivery applications. This technology may enable physicians to fine-tune the required dose according to disease state and patients' needs to enhance the safety and efficacy of corticosteroid treatment.

Hydrogen production by tuning the photonic band gap with the electronic band gap of TiO2.

Tuning the photonic band gap (PBG) to the electronic band gap (EBG) of Au/TiO2 catalysts resulted in considerable enhancement of the photocatalytic water splitting to hydrogen under direct sunlight. Au/TiO2 (PBG-357 nm) photocatalyst exhibited superior photocatalytic performance under both UV and sunlight compared to the Au/TiO2 (PBG-585 nm) photocatalyst and both are higher than Au/TiO2 without the 3 dimensionally ordered macro-porous structure materials. The very high photocatalytic activity is attributed to suppression of a fraction of electron-hole recombination route due to the co-incidence of the PBG with the EBG of TiO2 These materials that maintain their activity with very small amount of sacrificial agents (down to 0.5 vol.% of ethanol) are poised to find direct applications because of their high activity, low cost of the process, simplicity and stability.

The effect of gold loading and particle size on photocatalytic hydrogen production from ethanol over Au/TiO2 nanoparticles.

Catalytic hydrogen production from renewables is a promising method for providing energy carriers in the near future. Photocatalysts capable of promoting this reaction are often composed of noble metal nanoparticles deposited on a semiconductor. The most promising semiconductor at present is TiO2. The successful design of these catalysts relies on a thorough understanding of the role of the noble metal particle size and the TiO2 polymorph. Here we demonstrate that Au particles in the size range 3-30 nm on TiO2 are very active in hydrogen production from ethanol. It was found that Au particles of similar size on anatase nanoparticles delivered a rate two orders of magnitude higher than that recorded for Au on rutile nanoparticles. Surprisingly, it was also found that Au particle size does not affect the photoreaction rate over the 3-12 nm range. The high hydrogen yield observed makes these catalysts promising materials for solar conversion.

Coupling of carbon monoxide molecules over oxygen-defected UO2(111) single crystal and thin film surfaces.

While coupling reactions of carbon-containing compounds are numerous in organometallic chemistry, they are very rare on well-defined solid surfaces. In this work we show that the reductive coupling of two molecules of carbon monoxide to C2 compounds (acetylene and ethylene) could be achieved on oxygen-defected UO2(111) single crystal and thin film surfaces. This result allows in situ electron spectroscopic investigation of a typical organometallic reaction such as carbon coupling and extends it to heterogeneous catalysis and solids. By using high-resolution photoelectron spectroscopy (HRXPS) it was possible to track the changes in surface states of the U and O atoms as well as identify the intermediate of the reaction. Upon CO adsorption U cations in low oxidation states are oxidized to U4+ ions; this was accompanied by an increase of the O-to-U surface ratios. The HRXPS C 1s lines show the presence of adsorbed species assigned to diolate species (-OCH=CHO-) that are most likely the reaction intermediate in the coupling of two CO molecules to acetylene and ethylene.

Perspectives of treatment efficacy with the substance dependent physician: a national survey.

A national survey was conducted to assess the judgments of two sets of respondents (administrators of state physician health programs and highly experienced clinicians) about the effectiveness of treatment programs for chemically dependent physicians. Administrators consistently estimated higher rates of patient success (and less relapse) than their practitioner counterparts. Clinicians also identified factors (patient, therapist, group composition, context) they believed to be the most robust predictors of outcome with chemically impaired doctors. Implications of the findings for the conceptualization and design of prospective treatment outcome studies are addressed.

Confidentiality dilemmas in group psychotherapy with substance-dependent physicians.

OBJECTIVE: The purposes of this article are 1) to review federal and state laws relevant to confidentiality in group therapy with impaired physicians and 2) to provide empirical data concerning the actual confidentiality practices and experiences of group therapists treating chemically impaired physicians. METHOD: In the clinical research phase, 25 state medical societies identified 45 rehabilitation centers as those to which the societies preferentially referred chemically impaired physicians. Fifty-one group leaders from 33 of these rehabilitation centers completed the survey questionnaire employed in this project. RESULTS: Because of the risk of potentially irreversible social and professional injury, physician patients were exceedingly concerned about breaches of confidentiality. Co-members' infractions most often involved the violator sharing with close friends and family members the name and abuse history of a fellow physician. In contrast, transgressors rarely leaked information about a co-member's drug-related illegal behaviour. CONCLUSIONS: Chemically impaired physicians would feel safer in sharing secrets in group therapy if more jurisdictions adopted legislation making co-members liable for violating confidentiality. Currently the pertinent body of law is confusing and inconsistent and provides little protection to impaired physicians who enter group therapy. The authors propose ideas for model legislation.

Heroin, morphine, and hydromorphone determination in postmortem material by high performance liquid chromatography.

A procedure has been developed for the simultaneous determination of heroin, morphine, and hydromorphone from postmortem tissues by reversed phase high performance liquid chromatography (HPLC) using electrochemical detection. This method permits the direct determination of unmetabolized heroin from antemortem or postmortem urine as evidence of illegal drug use. Presumptive confirmation of heroin was based on the ability to hydrolyze the HPLC heroin fraction to morphine. Heroin was also confirmed in urine by gas chromatographic/mass spectroscopic (GC/MS) analysis of the HPLC fraction. Analysis of postmortem blood, gastric contents, urine, and injection site tissues have revealed the presence of morphine and hydromorphone, while heroin has only been identified in urine.

Neuroendocrine-immune interactions: immunoregulatory signals mediated by neurohumoral agents.

While we generally think of the brain and nervous system as central to most basic life processes, the concept of immune regulation or modulation is a relatively new idea. The novelty of such an association may be rooted in classic concepts of neurologic function describing direct innervation of controlled tissues and stimulation across synapses. The involvement of the neuroendocrine system in the precise control of metabolic and a variety of cellular functions should preface its involvement in defense against and/or surveillance for aberrant cell replication. Moreover, a principal characteristic of any control mechanism is feedback from the affected system (be it an organ or single cell). In this framework, it is not unreasonable to expect bidirectional interactions between the nervous and immune systems. Direct innervation of lymphoid tissues was described a number of years ago. More recently, immunoregulatory function has been demonstrated in vitro with a variety of neuroendocrine molecules such as the biogenic amines, SP, CGRP, SOM, vasopressin, ACTH, the endorphins, enkephalins, neurotensin, NGF and VIP. Now it has been shown that many of these same or similar neuroregulatory molecules are produced by cells of the immune system. The possibility that neurotransmitters or peptides, or both, may play a role in vivo in the maintenance of immunocompetence is supported by the finding that specific receptors for the neurohumoral modulators are present on the surface of immunocompetent cells. Current hypotheses speculate that feedback control mechanisms are manifested through the production of lymphokines, PGs and leukotrienes. Though it has not been possible to clearly demonstrate the reciprocal interaction between the neuroendocrine and immune systems in vivo, the evidence to date points to its inevitability.

Carcinoma of the colon in patients 35 years of age and younger.

Of 705 patients who were treated at the Vanderbilt University and Metropolitan Nashville General Hospitals from 1973 to 1984 for carcinoma of the colon, 45 (6.3%) were 35 years of age or younger at the time of diagnosis. There were 25 men and 20 women; the average age was 29.3 years. Twenty-six patients (57.7%) presented with pain, 19 reported a change in bowel habits, and 18 had gastrointestinal bleeding which led to diagnostic investigation. At the time of diagnosis, only two patients had lesions which could be classified as Dukes' A, eight were Dukes' B, 28 were Dukes' C, and the remaining seven had Dukes' D lesions with distant metastasis. Nineteen patients had poorly differentiated tumors; survival in this group averaged 1 year. In the 19 patients who had well or moderately well-differentiated tumors, survival averaged 4.3 years. Fifteen patients had unresectable tumors at the time of initial treatment, and survival in this group has averaged 1.5 years. Thirty patients had tumors which were considered to be resectable by the operating surgeon, and nine of these 30 patients are alive without evidence of recurrence for an average of 5.6 years. The prognosis of carcinoma of the colon in the young has been poor, with the major factors being the unfavorable histologic features of these tumors and the advanced disease at the time of presentation in these patients. Those few patients who present early in the course of their disease respond well to radical resection.

Mycotic embolism and embolomycotic aneurysms. Neglected lessons of the past.

During the past decade, nine patients with bacterial endocarditis have required management of mycotic emboli and/or aneurysms in this center. In these patients, 25 separate mycotic emboli or aneurysms were identified. Among these were four visceral, 11 lower extremity, one aortic, one hypogastric, and eight cerebral lesions. Multiple sites were involved in seven of the nine patients (78%). Presenting symptoms were secondary to acute expansion of mycotic aneurysms in three patients and secondary to rupture of aneurysms in four patients. Mycotic emboli produced cerebral infarction in two patients and acute ischemia in six patients. Asymptomatic mycotic aneurysms of the middle cerebral, hepatic, hypogastric, and profunda femoris arteries and asymptomatic emboli to the profunda femoris and tibial arteries were found during angiographic study. Management included resection alone (7 aneurysms), resection and graft replacement (2 aneurysms and 2 emboli), embolectomy (2), or observation. There was no mortality or loss of limb in these patients. This experience underscores the frequent multiplicity of mycotic emboli and/or aneurysms and stresses the importance of empiric angiographic survey to exclude silent yet potentially lethal visceral and cerebral mycotic foci in patients with bacterial endocarditis and peripheral emboli or aneurysms.

Penetrating colon trauma.

Of 56 patients with penetrating colon injuries over 6 years, 15% underwent exteriorized repair, 21% received a colostomy, and 64% were treated with primary repair. Of the eight exteriorized repairs, four required conversion to colostomies. In the entire group of 12 colostomies, there were two deaths, four abscesses, and one empyema. Thirty-six patients (64%) underwent primary repair. In this group there was one superficial wound infection, one empyema, but no intra-abdominal abscesses. Eighty per cent had associated injuries. All laparotomy incisions in the primary repair group except two were closed primarily. Large amounts of saline irrigant were used in all cases. All patients received broad spectrum antibiotics pre- and postoperatively. Primary repair of colon injuries can be done safely in many cases. Proper attention must be given to the associated injuries, the patient's general condition, and the time interval between injury and repair. We now find few indications for exteriorization of injured colons. Colostomies are done if our criteria for safe primary repair are not fulfilled.

Penetrating injuries to the neck. Selective management.

The management of penetrating neck trauma remains a controversial subject. Two distinct approaches have been advocated: "mandatory" versus "selective" exploration of all neck wounds. Surgical intervention in our institution is based upon the latter, a selective principle of individualization of the patient and his injury. Obvious early exploration is indicated for patients with evidence of major vascular injury, visceral injury, or with progressive neurologic deficit. In the absence of such signs of injury, the authors used a diagnostic protocol which includes esophagram and arteriography. This retrospective reviews and assesses the results of this selectively conservative policy.

Combined skeletal and vascular injuries of the lower extremities.

In order to determine the long-term results of surgical treatment in patients with significant combined skeletal and arterial injuries, the authors reviewed the records of those patients treated for this injury between 1970 and 1981, at their institutions. These cases were confined to fractures and/or dislocations of the femur, knee, and tibia which were associated with vascular injuries. Thirty-one patients with 32 injured extremities fit these criteria for our review. The distribution of the orthopedic injuries were as follows: femoral fractures, 16; tibial fractures, 20; and knee dislocations, four. Fifty percent of the injuries had neurologic deficit; significant soft tissue injury was present in 22 extremities; and all but 4 had attempted arterial revascularization. Vascular procedures included saphenous vein by-pass, saphenous vein interposition, end-to-end anastomosis and lateral arteriorrhaphy. Orthopedic repairs were generally accomplished by external means with only five cases treated by immediate internal fixation. Long-term results were categorized as excellent, fair, or poor. Amputations were classified as primary and secondary. Excellent results were found in only five of the reconstructed extremities. Thirty-five percent of the extremities were classified as having a fair result. Two extremities had a poor result. Four extremities were primarily amputated, and secondary amputation was performed on seven extremities. Associated nerve deficits and/or significant soft tissue injuries were found to be the major factors determining the eventual success or failure of reconstructive efforts.

Pancreatitis induced by intravenous infusion of a fat emulsion in an alcoholic patient.

We report an alcoholic patient with acute relapsing pancreatitis in whom the intravenous infusion of a fat emulsion precipitated a bout of acute pancreatitis. The various relationships between pancreatitis, alcoholism, and hyperlipemia are not clear, and guidelines for the use of intravenous fat emulsions in patients with pancreatitis should take into account their complex interrelationship.

Carcinoma of the gallbladder and bile ducts. A retrospective review.

In retrospective review, 31 patients with carcinoma of the gallbladder and 39 patients with carcinoma of the extrahepatic bile ducts (excluding ampullary tumors) were identified. Case records and operative reports of patients seen between 1955 and 1980 were reviewed for the purpose of evaluating clinical features, preoperative studies, and operative treatment of these two disease processes. Similarities and differences between the two malignancies are highlighted. Demographic features of these patients supported findings of previous studies. Preoperative symptoms were typical of calculus disease often with the stigmata of malignancy superimposed. Laboratory findings provided a rather nonspecific confirmation of cholestasis. Roentgenogram examinations proved to be of little value in differentiating either disease process. A variety of surgical procedures was used by several surgeons to attempt cure or palliation in these tumors. Cholecystectomy was the most frequent procedure performed for patients with gallbladder carcinoma (18 cases). Curative cholecystectomy yielded an average 17.8 month survival. More radical procedures produced higher survival rates although the study size is of questionable statistical significance. Biliary-enteric bypass (choledochojejunostomy) was performed most often for patients with bile duct carcinoma (12 cases). The magnitude of the operation failed to affect the duration of patient survival except in patients with carcinomas of the distal common bile duct. Three Whipple procedures were performed for distal bile duct lesions yielding the one five-year survivor of this study but with an associated 30 per cent operative mortality. Operative strategy and options are discussed. The current literature dealing with these two malignancies is reviewed.

Histoplasma infection of abdominal aortic aneurysms.

Fungal endarteritis resulting from progressive disseminated histoplasmosis may cause arterial aneurysms, or lead to infection of pre-existing aneurysms. Three patients with Histoplasma capsulatum infections of abdominal aortic aneurysms are reported. All had previous disseminated histoplasmosis and atherosclerotic peripheral vascular disease. All were considered cured of systemic infection when their aneurysms were discovered. Atherosclerotic vascular lesions may become infected during the course of systemic fungal disease and may serve as a haven for viable organisms in patients whose dissemination recurs despite seemingly adequate antifungal therapy. In treating these patients, resection of all infected arterial tissue, revascularization through uninfected tissues, and long-term antimicrobial therapy are recommended.

Surgical experience with retrogastric and retropancreatic pheochromocytomas.

From 1972 to 1981 at Vanderbilt University Hospital there were seven patients with midline retrogastric or retropancreatic pheochromocytomas. Each of these tumors arose between the aorta and the inferior vena cava. This report details the difficulties in localization before and at operation in the smaller tumors in these sites. Our experience suggests that small midline pheochromocytomas in these sites may be readily missed by computerized tomographic scan, aortography, or surgical search at laparotomy unless subtraction arteriograms are used and the Kocher maneuver is employed at operation routinely.

A clinical review of small bowel neoplasms.

Small bowel neoplasms represent 3% to 6% of all gastrointestinal tumors and less than 1% of all malignancies. Of 92 cases of small bowel tumor seen between 1950 and 1978, 26% were benign and 74%, malignant. The symptoms and signs are related to the specific disease. Of the malignant neoplasms, 38% were carcinoid; 33%, adenocarcinoma; 14%, leiomyosarcoma; 11%, lymphosarcoma; and 4%, others. The average time of survival for the malignant group was 16 months. The advanced stage of disease at the time of diagnosis is thought to be the reason for the generally poor prognosis. Attention to vague symptoms and an aggressive diagnostic evaluation are important if survival is to be improved.