The use of polymer-based electrospun nanofibers containing amorphous drug dispersions for the delivery of poorly water-soluble pharmaceuticals

Electrostatic spinning was applied to the preparation of drug-laden nanofiber for potential use in oral and topical drug delivery. While this technique is in its infancy with regard to pharmaceutical applications, a number of recent publications suggest that it may be of high value in the formulation of poorly water-soluble drugs by combining nanotechnology and solid solution/dispersion methodologies. The purpose of this article is to describe some of these recently published applications. For immediate release oral application, a water-soluble cellulose polymer was selected (i.e., hydroxypropylmethylcellulose, HPMC) while for topical application, a nonbiodegradable, water-insoluble polymer was investigated (i.e., a segmented polyurethane, SPU). Solutions of the polymer and the drugs in appropriate solvents could be spun across various potentials (16-24 kV) generating nanofibers with diameters ranging from 300 to 2000 nm. Dissolution studies found that the non-woven fabrics derived from HPMC and containing itraconazole dissolved over a time course of minutes to hours depending on the formulation used as well as the drug/polymer ratios. Drug release from the SPU samples was dependent on the incorporated drug as well as nanostructure obtained.     

Predictors of developmental disabilities after open heart surgery in young children with congenital heart defects

OBJECTIVES: To determine the prevalence of persistent developmental impairments in children with congenital heart defects and to identify factors that enhance risk for an adverse outcome. STUDY DESIGN: Eligible infants (n = 131) <2 years of age requiring open heart surgery were recruited prospectively. Subjects were assessed during surgery and again 12 to 18 months later with standardized developmental assessments and formal neurologic examinations. RESULTS: Mean age at follow-up testing was 19.1 +/- 6.6 months. Assessments indicated that 41% had abnormal neurologic examinations. Gross and/or fine motor delays were documented in 42%, and 23% demonstrated global developmental delay. Univariate and multiple regression models identified the following factors increasing the risk for persistent developmental deficits: preoperative and acute postoperative neurodevelopmental status and microcephaly, type of heart lesion, length of deep hypothermic circulatory arrest, age at surgery, and days in the intensive care unit (P <.05). CONCLUSIONS: Children with congenital heart defects commonly have ongoing neurologic, motor, and developmental deficits well after surgical correction. The cause is multifactorial and includes brain injury before, during, and after heart surgery.     

Endovenous laser treatment to promote venous occlusion

BACKGROUND AND OBJECTIVES: Current treatment methods of superficial venous insufficiency (SVI) can be painful or result in incomplete occlusion. The objective of this study was to evaluate a technique for laser endovenous ablation with a newly developed diffuser fiber. STUDY DESIGN/MATERIALS AND METHODS: Six lateral saphenous veins in three goats were used. A specifically designed diffuser laser fiber tip was employed in all trials to deliver a wavelength of 1,064 nm. Each segment was treated with a different energy fluence by changing the power setting of the laser or the withdrawal rate of the fiber. Energy fluence was calculated by dividing the Joules employed for each segment over the internal surface area of the vessel. Segments were evaluated with ultrasound and histologically. RESULTS: Seventy-five percent of the segments were occluded when an energy fluence of greater than 85 J/cm2 was employed. No perforations were observed, but perivascular changes were more common at higher energy fluence. CONCLUSIONS: Endovenous laser occlusion of veins with minimal perivascular effects can be achieved with laser wavelengths of 1,064 nm if an energy fluence of 84.9-224 J/cm2 is employed and circumferential effect is achieved.     

Asymptomatic optic neuropathy associated with Churg-Strauss syndrome

OBJECTIVE: To report asymptomatic optic disc edema in a patient with Churg-Strauss syndrome. DESIGN: Retrospective, observational case report. METHODS: Neuro-ophthalmic examination, sural nerve biopsy, and laboratory evaluation. MAIN OUTCOME MEASURES: Visual acuity, funduscopy, automated perimetry, and histopathology of sural nerve biopsy. CONCLUSIONS: Churg-Strauss syndrome may be associated with optic neuropathy. Careful ophthalmic evaluation may reveal signs of optic neuropathy before the development of symptomatic vision loss.     

Late visual and auditory toxicity of radiotherapy for nasopharyngeal carcinoma

AIMS AND BACKGROUND: Classical irradiation of carcinoma of the nasopharynx involves large fields and high doses; therefore, significant late toxicity and late side effects are to be expected. Given the fact that nasopharyngeal carcinoma (NPC) is a relatively radiosensitive disease and a significant proportion of patients are long-term survivors, late visual and auditory complications of treatment are of utmost concern for patients and radiation oncologists. The aim of this study was to evaluate the long-term visual and auditory toxicity in patients treated with radiotherapy for NPC. METHODS AND STUDY DESIGN: Forty-three long-term survivors (including 11 children), following definitive radiotherapy for NPC, underwent a thorough visual and auditory evaluation 2-22 years after their treatment. Ophthalmological examination consisted of anamnesis of dry eye syndrome and visual acuity, visual acuity testing, slit-lamp examination, Schirmer test, fundus examination, and intraocular pressure measurement, as well as fluorescein angiography in patients with pathological vascular findings in the fundus examination. Audiological evaluation included anamnesis of hearing loss, tinnitus or vertigo, examination of the ears and nasopharynx, audiogram, and tympanogram. RESULTS: Radiation retinopathy was found in 16% of patients by fundus examination, with one patient (2.3%) developing blindness. Severe dry eye syndrome was present in 26%. Fifty-six percent had some degree of hearing impairment, with 74% showing severe sensorineural hearing loss. Fifty-eight percent of patients reported tinnitus and 26% reported suffering from dizziness. Radiation retinopathy as well as all manifestations of auditory toxicity were found to bear a direct correlation with dose per fraction. CONCLUSIONS: Unless there is tumor involvement, the orbital contents should be completely excluded from the target volume. Auditory toxicity is significant when treating NPC with two-dimensional techniques.     

A phase I trial of immunotherapy with intratumoral adenovirus-interferon-gamma (TG1041) in patients with malignant melanoma

AIMS: Interferon-gamma (IFN-gamma) has been shown to upregulate MHC class I and II expression, and to promote generation of specific antitumor immune responses. We hypothesized that intratumoral administration of an IFN-gamma gene transfer vector facilitates its enhanced local production and may activate effector cells locally. We conducted a phase I dose-escalation study of a replication-deficient adenovirus-interferon-gamma construct (TG1041) to determine safety and tolerability of intratumoral administration, in advanced or locally recurrent melanoma. METHODS: Patients were enrolled at four successive dose levels: 10(7) infectious units (iu) (n=3), 10(8) iu (n=3), 10(9) iu (n=3), and 10(10) iu (n=2) per injection per week for 3 weeks. TG1041 was injected in the same tumor nodule weekly in each patient. Safety, toxicity, local and distant tumor responses and biologic correlates were evaluated. RESULTS: A total of 11 patients were enrolled and received the planned three injections per cycle. One patient with stable disease received a second cycle of treatment. A maximum tolerated dose was not reached in this study. No grade 4 toxicities were observed. Two grade 3 toxicities, fever and deep venous thrombosis were observed in one patient. The most frequently reported toxicities were grade 1 pain and redness at the injected site (n=8), and grade 1 fatigue (n=5) patients. Clinical changes observed at the local injected tumor site included erythema (n=5), a minor decrease in size of the injected lesion (n=5) and significant central necrosis by histopathology (n=1). Systemic effects included stable disease in one patient. Correlative studies did not reveal evidence of immunologic activity. CONCLUSION: Weekly intratumoral administration of TG1041 appears to be safe and well tolerated in patients with advanced melanoma.     

Rickettsia africae, a tick-borne pathogen in travelers to sub-Saharan Africa

BACKGROUND: African tick-bite fever occurs after contact with ticks that carry Rickettsia africae and that parasitize cattle and game. Sporadic reports suggest that this infection has specific clinical and epidemiologic features. METHODS: We studied patients who were tested for a rickettsial disease after returning from a visit to Africa or Guadeloupe. To assess the value of the microimmunofluorescence assay, Western blotting, and cross-adsorption assays, we compared the results of these tests in 39 patients in whom African tick-bite fever had been confirmed by the polymerase-chain reaction assay, cell culture, or both; 50 patients with documented R. conorii infection; and 50 blood donors. These diagnostic criteria were then applied to 376 additional patients who had returned from southern Africa and 2 who had returned from Guadeloupe and whose serum was being tested for rickettsial disease. RESULTS: In the 39 patients with direct evidence of R. africae infection, the combination of microimmunofluorescence assay, Western blotting, and cross-adsorption assays showing antibodies specific for R. africae had a sensitivity of 0.56; however, each test had a positive predictive value and a specificity of 1.0. An additional 80 patients were found to have an R. africae infection on the basis of these serologic criteria. Infections with R. africae were acquired by visitors to 11 African countries and Guadeloupe. The illness was generally mild and was characterized by a rash in 46 percent of the patients; the rash was usually maculopapular or vesicular and rarely purpuric. Ninety-five percent of patients had an inoculation eschar or eschars, and 54 percent of these patients had multiple eschars, a finding that is unusual in patients with rickettsial infection. CONCLUSIONS: In this series, R. africae was the cause of nearly all cases of tick-bite rickettsiosis in patients who became ill after a trip to sub-Saharan Africa.     

Predictors of neuropathological severity in 100 patients with Huntington's disease

Subjects were followed in the Longitudinal Core Study of the Baltimore Huntington's Disease Center and given annual neurological, cognitive, and psychiatric examinations. Postmortem neuropathological grade was assigned using the system of Vonsattel and colleagues. We examined the correlations between the neuropathological grade and scores on the Quantified Neurological Examination (QNE) and its chorea and motor impairment subscales, the Mini-Mental State Examination (MMSE), the HD Activities of Daily Living (ADL) Scale, and a number of demographic variables (CAG number, age of onset, age at death, disease duration) in 100 subjects who had been examined within 1,000 days of death. All measures showed significant correlation with Vonsattel score except for chorea. The strongest effect was that of motor impairment score (r(2) = 0.351, p < 0.0001). In a stepwise correlation of clinical variables, motor impairment remained significant. The largest effect for a demographic variable was for age of onset (r(2) = 0.226, p < 0.0001) A partial correlation was significant between CAG number and Vonsattel grade, controlling for age at death or disease duration. Motor impairment appears to be a good clinical measure of neuronal cell loss, at least late in the course of HD and therefore may prove useful in observational and treatment studies.     

A disorder similar to Huntington's disease is associated with a novel CAG repeat expansion

Huntington's disease (HD) is an autosomal dominant disorder characterized by abnormalities of movement, cognition, and emotion and selective atrophy of the striatum and cerebral cortex. While the etiology of HD is known to be a CAG trinucleotide repeat expansion, the pathways by which this mutation causes HD pathology remain unclear. We now report a large pedigree with an autosomal dominant disorder that is clinically similar to HD and that arises from a different CAG expansion mutation. The disorder is characterized by onset in the fourth decade, involuntary movements and abnormalities of voluntary movement, psychiatric symptoms, weight loss, dementia, and a relentless course with death about 20 years after disease onset. Brain magnetic resonance imaging scans and an autopsy revealed marked striatal atrophy and moderate cortical atrophy, with striatal neurodegeneration in a dorsal to ventral gradient and occasional intranuclear inclusions. All tested affected individuals, and no tested unaffecteds, have a CAG trinucleotide repeat expansion of 50 to 60 triplets, as determined by the repeat expansion detection assay. Tests for the HD expansion, for all other known CAG expansion mutations, and for linkage to chromosomes 20p and 4p were negative, indicating that this mutation is novel. Cloning the causative CAG expansion mutation for this new disease, which we have termed Huntington's disease-like 2, may yield valuable insight into the pathogenesis of HD and related disorders.