MMP9-sensitive polymers mediate environmentally-responsive bivalirudin release and thrombin inhibition.

MMP9-responsive bivalirudin-HPMA copolymers were synthesized for direct, local administration in rat spinal cord contusion injury models. Polymer-conjugated bivalirudin peptides maintained activity while demonstrating enzyme-mediated release upon MMP9 exposure and prolonged release from hyaluronic acid/methylcellulose (HAMC) hydrogels compared to free bivalirudin peptide. Localized administration of bivalirudin copolymers in vivo at the site of rat spinal cord injury decreased cellular proliferation and astrogliosis, suggesting the bivalirudin copolymer and HAMC hydrogel system are a promising therapeutic intervention for reducing immediate inflammatory responses and long term scarring.

The use of intravitreal ranibizumab for choroidal neovascularization associated with vogt-koyanagi-harada syndrome.

Purpose. To describe the use of intravitreal ranibizumab for choroidal neovascular membrane (CNVM) secondary to Vogt-Koyanagi-Harada (VKH) syndrome. Methods. Interventional case report. Results. A 50-year-old woman presented with conjunctival injection and bilateral eye pain. Vision was 20/400 and 20/80 in the right and left eyes, respectively. Bilateral iritis, vitritis, and choroidal thickening were evident. Exudative retinal detachment was present in the left eye. Corticosteroid treatment improved vision to 20/40 bilaterally. Methotrexate (MTX) was initiated and vision remained stable for 3 months. After a 5-month loss to follow-up, vision in the left eye decreased to finger counting (CF) and a parafoveal CNVM was identified. After 3 intravitreal ranibizumab injections, vision improved to 20/40. Twelve months later, despite inflammation control, vision decrease to CF due to recurrent CNVM. A fourth ranibizumab injection was given. Twenty months later, best-corrected vision was 20/400, and an inactive CNVM was present in the left eye. Conclusion. After initial CNVM regression and visual acuity improvement due to ranibizumab, the CNVM recurred and became refractory to treatment. Despite control of inflammation and neovascularization, VKH chronicity lead to permanent vision loss in our patient. A combinational treatment approach may be required in such patients.

Human immunodeficiency virus-positive patients with posterior intracorneal precipitates.

PURPOSE: To describe an unusual and possibly new keratopathy in human immunodeficiency virus (HIV)-positive patients. DESIGN: Retrospective observational case series. PARTICIPANTS: : Six HIV-positive patients at four centers. METHODS: A complete medical history was obtained and a thorough ophthalmic examination was performed on each of the patients. RESULTS: Each patient had bilaterally symmetrical keratopathy consisting of variably pigmented round and reticular posterior intracorneal precipitates at the level of Descemet's membrane. The precipitates were diffuse, but larger and more prominent near the limbus and finer toward the central cornea. None of the eyes were inflamed, and all had normal vision. No patient had uveitis on presentation or any history of cytomegalovirus retinitis. CONCLUSION: These patients have a unique posterior keratopathy, which requires further investigation.

A modulatory role for clathrin light chain phosphorylation in Golgi membrane protein localization during vegetative growth and during the mating response of Saccharomyces cerevisiae.

The role of clathrin light chain phosphorylation in regulating clathrin function has been examined in Saccharomyces cerevisiae. The phosphorylation state of yeast clathrin light chain (Clc1p) in vivo was monitored by [32P]phosphate labeling and immunoprecipitation. Clc1p was phosphorylated in growing cells and also hyperphosphorylated upon activation of the mating response signal transduction pathway. Mating pheromone-stimulated hyperphosphorylation of Clc1p was dependent on the mating response signal transduction pathway MAP kinase Fus3p. Both basal and stimulated phosphorylation occurred exclusively on serines. Mutagenesis of Clc1p was used to map major phosphorylation sites to serines 52 and 112, but conversion of all 14 serines in Clc1p to alanines [S(all)A] was necessary to eliminate phosphorylation. Cells expressing the S(all)A mutant Clc1p displayed no defects in Clc1p binding to clathrin heavy chain, clathrin trimer stability, sorting of a soluble vacuolar protein, or receptor-mediated endocytosis of mating pheromone. However, the trans-Golgi network membrane protein Kex2p was not optimally localized in mutant cells. Furthermore, pheromone treatment exacerbated the Kex2p localization defect and caused a corresponding defect in Kex2p-mediated maturation of the alpha-factor precursor. The results reveal a novel requirement for clathrin during the mating response and suggest that phosphorylation of the light chain subunit modulates the activity of clathrin at the trans-Golgi network.

The light chain subunit is required for clathrin function in Saccharomyces cerevisiae.

Clathrin, a multimeric protein involved in intracellular protein trafficking, is composed of three heavy chains (Chc) and three light chains (Clc). Upon disruption (clc1Delta) of the single Clc-encoding gene (CLC1) in yeast, the steady state protein levels of Chc decreased 5-10-fold compared with wild type cells; consequently, phenotypes exhibited by clc1Delta cells may result indirectly from the loss of Chc as opposed to the absence of Clc. As an approach to directly examine Clc function, clc1Delta strains were generated that carry a multicopy plasmid containing the clathrin heavy chain gene (CHC1), resulting in levels of Chc 5-10-fold elevated over wild-type levels. As with deletion of CHC1, deletion of CLC1 results in defects in growth, receptor-mediated endocytosis, and maturation of the mating pheromone alpha-factor. However, elevated Chc expression in clc1Delta cells partially suppresses the growth and alpha-factor maturation defects displayed by clc1Delta cells alone. Biochemical analyses indicate that trimerization and assembly of Chc are perturbed in the absence of Clc, resulting in vesiculation defects. Our results demonstrate that the light chain subunit of clathrin is required for efficient Chc trimerization, proper formation of clathrin coats, and the generation of clathrin-coated vesicles.

The Saccharomyces cerevisiae APS1 gene encodes a homolog of the small subunit of the mammalian clathrin AP-1 complex: evidence for functional interaction with clathrin at the Golgi complex.

Clathrin-associated protein (AP) complexes have been implicated in the assembly of clathrin coats and the selectivity of clathrin-mediated protein transport processes. We have identified a yeast gene, APS1, encoding a homolog of the small (referred to herein as sigma) subunits of the mammalian AP-1 complex. Sequence comparisons have shown that Aps1p is more similar to the sigma subunit of the Golgi-localized mammalian AP-1 complex than Aps2p, which is more related to the plasma membrane AP-2 sigma subunit. Like their mammalian counterparts, Aps1p and Aps2p are components of distinct, large (> 200 kDa) complexes and a significant portion of the Aps proteins co-fractionate with clathrin-coated vesicles during gel filtration chromatography. Unexpectedly, even though the evolutionary conservation of AP small subunits is substantial (50% identity between mammalian and yeast proteins), disruptions of APS1 (aps1 delta) and APS2 (aps2 delta), individually or in combination, elicit no detectable mutant phenotypes. These data indicate that the Aps proteins are not absolutely required for clathrin-mediated selective protein transport in cells expressing wild type clathrin. However, aps1 delta accentuated the slow growth and alpha-factor pheromone maturation defect of cells carrying a temperature-sensitive allele of clathrin heavy chain (Chc) (chc1-ts). In contrast, aps1 delta did not influence the effects of chc1-ts on vacuolar protein sorting or receptor-mediated endocytosis. The aps2 delta mutation resulted in a slight effect on chc1-ts cell growth but had no additional effects. The growth defect of cells completely lacking Chc was compounded by aps1 delta but not aps2 delta. These results comprise evidence that Aps1p is involved in a subset of clathrin functions at the Golgi apparatus. The effect of aps1 delta on cells devoid of clathrin function suggests that Aps1p also participates in clathrin-independent processes.

Demography, population growth, and population policy in China: a brief history from 1940 to the present.

PIP: For some 3 decades after the founding of the People's Republic of China, Chinese studies have had to life with the paradoxical situation in which the abundance of population on the mainland, ever increasing in number predictably and inexorably, was couples with a scarcity of data about the nature and patterns of demographic change, ever harder to come by. As increasing amounts of new demographic data from China, sometimes produced jointly between Chinese and foreign researchers, become available, it is clear that previous methods, technics, and styles of analyses habituated by 3 decades of minimal data from China will become inadequate and obsolete. In 1957 Ma Yinchu put forth 3 main proposals for population control: 1) to conduct another national census to gain more demographic statistics, 2) to advocate widespread public education to inform people of the importance and practical knowledge of birth control combined with propaganda on the disadvantages of early marriages and the benefits of late marriage, and 3) family planning, by popular use of contraception, is the most effective method for population control. It is argued that 1) the years 1950-1958 consisted of a period of fermentation and preparation, 2) the post-leap years, 1959-1965, constituted a period of trial implementation of emerging policies, 3) 1966-1971 was an uncontrolled period, and 4) only the years after 1971 may be viewed as a period during which serious implementation took place. Overall, the selections in this volume are intended to inform both China scholars and social scientists interested in recent developments in Chinese population studies.^ieng

Physician's extenders' performance in Air Force clinics.

We evaluated the quality of care of physician's extenders (PEs: 23 physician's assistants, 7 primary care nurse practitioners) in Air Force primary medicine clinics, as part of an evaluation of PEs' assuming a considerable portion of the care, formerly provided by physicians in the military medical system. Physician's assistants performed at least as well as physicians on 25 out of 28 nonredundant process-of-care criteria; nurse practitioners met the physicians' standard on 14 of 19 criteria. In a comparison of physician's assistants with nurse practitioners, the two groups' performance was not significantly different. No major differences were found in PEs' and physicians' use of ancillary services (laboratory, x-ray, physical therapy) or orders for further care. As expected, PEs consulted physicians infrequently, but more often for serious complaints and at rates similar to those found in a civilian HMO setting. We conclude that the Air Force can deliver the same quality of care when PEs treat a sizable proportion of patients formerly treated by physicians.

Should-hand syndrome: importance of early diagnosis and treatment.

If the shoulder-hand syndrome is left without special care, it may lead to severe painful disabilities of the upper extremity. Early recognition of the clinical signs and symptoms and aggressive total care are essential for successful treatment and for the prevention of severe flexion contractures of the hand and shoulder, especially in patients whose symptoms have developed after a cerebrovascular accident. An outline is given of the treatment modalities (corticosteroids, physiotherapy and mechanical devices) used at the Institute for Rehabilitation Medicine (NYU) for obtaining maximum function of the involved upper extremity.

Phenol block of the tibial nerve in the hemiplegic patient.

Selective blocks of the tibial nerve with aqueous solution of 5% phenol, after localization of the nerve by electrical stimulation, were performed in 30 patients with acquired hemiplegia for treatment of severe spasticity of the foot plantar flexors and ankle clonus. Ankle clonus disappeared in all patients and resistance to passive stretch was reduced substantially immediately after the procedure; orthotic fitting and ambulation training then were possible. Longterm followup (averaging 12.9 months) showed the gait to be improved and spasticity decreased in all patients; there were no indications for further treatment of plantar flexor spasticity. Fixed equinus deformity was prevented in all cases. The only significant complication was the development of paresthesias in eight patients (26.6%) The simplicity of the procedure, the functional results observed immediately, its longlasting effect, and the lack of serious complications, warrant its more widespread use in the treatment and prevention of deformities in the spastic foot of the hemiplegic patient. However, there should be further study about prevention of paresthesias, which occurred in a significant percentage of patients in this study.

Autonomic hyperreflexia and its differentiation from pheochromocytoma.

Conceivably pheochromocytoma may have to be differentiated from autonomic hyperreflexia as the cause of paroxysmal hypertension. Elevated urinary catecholamine metabolites may occur in both conditions. However, marked elevations of serum dopamine-beta-hydroxylase (DBH) accompanied by relatively slight elevations of plasma catecholamines are observed during hypertensive paroxysms in patients with autonomic hyperreflexia, while marked elevations of plasma catecholamines with little if any change in serum DBH concentration are characteristic of hypertensive paroxysms caused by pheochromocytoma.

Shoulder-hand syndrome in a hemiplegic population: a 5-year retrospective study.

From 1969 through 1973, 68 (12.5%) of 540 rehabilitation inpatients with hemiplegia were diagnosed as having shoulder-hand syndrome. Care was used to distinguish these patients from those with other shoulder pathologic conditions and pain syndromes. Patients were evaluated with respect to side of hemiplegia, dates of onset of hemiplegia and of pain, age, sex, handedness, sensory losses, associated medical diseases and treatment response. All patients became pain-free within three weeks with a therapeutic regimen of low doses of steroids orally, passive range of motion to pain tolerance, use of a hemiplegia sling and the application of physical modalities for symptomatic relief. Losses of range of motion in the affected extremity responded less well to treatment. No complications or side effects attributable to steroids were observed. The full syndrome recurred in six patients, all of whom responded to a second course of treatment.

Lower-limb amputation for occlusive vascular disease.

A small series of 58 patients who required amputation because of gangrene of the lower limb with nonreconstructable arteries at New York University Medical Center illustrates the manner in which application of some of these principles achieved primary healing of 78% in below-knee amputation and rehabilitation rate of as high as 90% using simple nonrigid dressings.