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K Josephson

Publications and source records attributed to K Josephson.

13 recordsLinked to original sources
PubMed2001

Purification, crystallization and preliminary X-ray diffraction of a complex between IL-10 and soluble IL-10R1.

A complex between interleukin-10 and the extracellular domain of its high-affinity receptor (sIL-10R1) has been crystallized from polyethylene glycol solutions. Crystals suitable for diffraction analysis required the modification of the NXS/T glycosylation sites on sIL-10R1 by site-directed mutagenesis and inclusion of the detergent cyclohexyl-methyl-beta-D-maltopyranoside in the crystallization experiments. The crystals belong to space group P3(2)12 or its enantimorph P3(1)12, with unit-cell parameters a = b = 46.23, c = 307.78 A, alpha = beta = 90, gamma = 120 degrees, and diffract X-rays to approximately 2.9 A. The IL-10 dimer is positioned on a crystallographic twofold, resulting in one IL-10 chain and one sIL-10R1 chain in the asymmetric unit, which corresponds to a solvent content of approximately 44%.

Animals↗
PubMed2001

Crystal structure of the IL-10/IL-10R1 complex reveals a shared receptor binding site.

Interleukin 10 (IL-10) is a dimeric cytokine that plays a central role in suppressing inflammatory responses. These activities are dependent on the interaction of IL-10 with its high-affinity receptor (IL-10R1). This intermediate complex must subsequently recruit the low-affinity IL-10R2 chain before cell signaling can occur. Here we report the 2.9 A crystal structure of IL-10 bound to a soluble form of IL-10R1 (sIL-10R1). The complex consists of two IL-10s and four sIL-10R1 molecules. Several residues in the IL-10/sIL-10R1 interface are conserved in all IL-10 homologs and their receptors. The data suggests that formation of the active IL-10 signaling complex occurs by a novel molecular recognition paradigm where IL-10R1 and IL-10R2 both recognize the same binding site on IL-10.

Amino Acid Sequence↗
PubMed2000

Design and analysis of an engineered human interleukin-10 monomer.

A monomeric form of human interleukin 10 (IL-10M1) has been engineered for detailed structure-function studies on IL-10 and its receptor complexes. Wild type IL-10 (wtIL-10) is a domain swapped dimer whose structural integrity depends on the intertwining of two peptide chains. wtIL-10 was converted to a monomeric isomer by inserting 6 amino acids into the loop connecting the swapped secondary structural elements. Characterization of IL-10M1 by mass spectroscopy, size exclusion chromatography, cross-linking, and circular dichroism shows that IL-10M1 is a stable alpha-helical monomer at physiological pH whose three-dimensional structure closely resembles one domain of wtIL-10. As previously reported, incubation of wtIL-10 with a soluble form of the IL-10Ralpha (sIL-10Ralpha) generates a complex that consists of 2 wtIL-10 molecules and 4 sIL-10Ralphas. In contrast, IL-10M1 forms a 1:1 complex with the sIL-10Ralpha. Characterization of the interaction using isothermal titration calorimetry confirmed the 1:1 stoichiometry and yielded a dissociation constant of 30 nm with an apparent binding enthalpy of -12.2 kcal/mol. Despite forming a 1:1 complex, IL-10M1 is biologically active in cellular proliferation assays. These results indicate that the 1:1 interaction between IL-10M1 and IL-10Ralpha is sufficient for recruiting the signal transducing receptor chain (IL-10Rbeta) into the signaling complex and eliciting IL-10 cellular responses.

Amino Acid Sequence↗
PubMed2000

Pressure ulcers among patients admitted to home care.

CONTEXT: Pressure ulcers are an understudied problem in home care. OBJECTIVE: To determine the prevalence of pressure ulcers among patients admitted to home care services, describe the demographic and health characteristics associated with pressure ulcers in this setting, and identify the percentage of these patients at risk for developing pressure ulcers. DESIGN: Cross-sectional survey of patients on admission to home care agencies. SETTING: Forty-one home care agencies in 14 states. PATIENTS: A consecutive sample of 3,048 patients admitted March 1 through April 30, 1996 (86% of all admissions). Subjects had a mean age of 75 years; 63% were female and 85% white. MAIN OUTCOME MEASURES: Demographic, social, and clinical characteristics, functional status (Katz activities of daily living scale and Lawton instrumental activities of daily living scale), mental status (Katzman Short Memory-Orientation-Concentration test), pressure ulcer risk (Braden Scale), pressure ulcer status (Bates-Jensen Pressure Ulcer Status Tool), and a checklist of pressure-reducing devices and wound care products being used. RESULTS: In the total sample of 3,048 patients, 9.12% had pressure injuries: 37.4% had more than one ulcer and 14.0% had three or more ulcers. Considering the worst ulcer for each subject, 40.3% had Stage II and 27% had Stage III or IV injuries. Characteristics associated with pressure ulcers included recent institutional discharge, functional impairment, incontinence, and having had a previous ulcer. About 30% of subjects were at risk for new pressure ulcers. Pressure-relieving devices and other wound care strategies appeared to be underutilized and often indiscriminately applied. CONCLUSIONS: There is substantial need for pressure ulcer prevention and treatment in home care settings.

Activities of Daily Living↗
PubMed1999

Doxorubicin does not spread systemically following a local injection into the eyelids of rabbits.

PURPOSE: An experimental treatment for benign essential blepharospasm and hemifacial spasm involves the direct injection of doxorubicin into the eyelids to permanently kill muscle. This study examined the extent of local and systemic spread of doxorubicin after localized injections of low doses into the eyelid and determined the length of time doxorubicin was retained in the eyelid after injection. METHODS: Two mg doxorubicin was injected subcutaneously into the lower eyelids of rabbits. After various time periods, the eyelids were removed and dissected into three separate specimens consisting of skin, subcutaneous connective tissue including orbicularis oculi muscle, or palpebral conjunctiva. Nearby tissues were also collected, including facial muscles and extraocular muscles. Urine, blood, kidney, spleen, heart and liver samples were collected. All tissues were prepared for HPLC determination of doxorubicin concentration. RESULTS: Doxorubicin was detected in all three eyelid specimens for the first 4 days after injection, although by the fourth day the level of doxorubicin was greatly reduced. On and after the seventh day, there was no detectable doxorubicin in the treated eyelid tissues. There were no detectable levels of doxorubicin in the urine or any other body tissue at any of the post-injection intervals examined. There was no long term retention in any of the eyelid tissues examined. CONCLUSIONS: The well described array of serious systemic side effects caused by the use of high systemic doses of doxorubicin as a chemotherapeutic agent made it critical to ascertain how long doxorubicin remained within the injected eyelids, and to determine to what extent and with what time course local injections of chemically intact doxorubicin might spread systemically. The short retention of the active or unmetabolized drug at the injection site is important, since more than one set of injections has been required for satisfactory amelioration of muscle spasms in blepharospasm and hemifacial spasm patients. The lack of detectable systemic spread of the drug distant from the local site of injection as well as the lack of long term retention of the locally injected doxorubicin lends support for the safety of doxorubicin administered in this manner to blepharospasm and hemifacial spasm patients.

Animals↗
PubMed1994

Investigation of thermoregulatory characteristics in patients with Prader-Willi syndrome.

A survey instrument is used to assess temperature regulation characteristics in children with Prader-Willi syndrome (PWS) compared to 3 control groups: sibs of PWS patients (SIB), neurodevelopmentally handicapped children (ND), and age and gender matched well children (WC). Significant differences were found between PWS patients, SIB controls, and WC controls in the prevalence of febrile convulsions, fever-associated symptoms, and temperature less than 94 degrees F. No differences were noted in any variable between the PWS patients and the ND controls, suggesting that these abnormalities are not unique to PWS, but can occur in any neurodevelopmentally handicapped individual, further suggesting these do not necessarily reflect syndrome-specific hypothalamic abnormalities.

Body Temperature Regulation↗
PubMed1994

An in-home preventive assessment program for independent older adults: a randomized controlled trial.

OBJECTIVE: To evaluate the effectiveness of in-home geriatric assessments as a means of providing preventive health care and improving health and functional status of community-living elderly veterans. DESIGN: Randomized controlled trial with 1-year follow-up. SETTING: Home visits performed in a suburb of Los Angeles. PARTICIPANTS: Community-living veterans 70 years and older not currently receiving health care at the Sepulveda VA Medical Center (n = 131 intervention; 123 controls). INTERVENTION: A home visit by a physician's assistant or nurse, to screen for medical, functional and psychosocial problems, followed by a letter describing findings and recommendations, and follow-up visits by trained volunteers at 4-month intervals for 1 year. Controls received only telephone interviews at 4-month intervals to collect outcome data. MEASUREMENTS: Compliance with recommendations was studied for the intervention group. Outcome comparisons between the two groups included: mortality, medication usage, functional status, immunization rates, and nursing home and hospital utilization. MAIN RESULTS: A mean of four new or suboptimally treated problems was identified for intervention subjects. Subjects complied with 76% of recommendations to see a physician or initiate a specific health practice. At 12-month follow-up, intervention subjects had significantly increased their immunization rates (P < 0.001) and had a significantly increased likelihood of having a primary care physician (P < 0.05). Twelve-month functional status (IADL) scores were significantly higher for intervention subjects than for controls; intervention subjects maintained their functional status, while controls experienced significant decline during the follow-up year (P < 0.05). Non-prescription drug use increased significantly among controls, but not among intervention subjects (P < 0.05). CONCLUSIONS: A brief geriatric screening assessment performed in the home can detect unrecognized and treatable problems, even among relatively healthy older adults. The use of trained volunteers is a feasible strategy for providing health education and follow-up contacts. These results support the concept that preventive gerontological approaches can help maintain important aspects of health and function.

Activities of Daily Living↗
PubMed1991

Effects of aging on the neuroglial cells and pericytes within area 17 of the rhesus monkey cerebral cortex.

An electron microscopic analysis has been carried out to compare the neuroglial cells and pericytes within the primary visual cortex, area 17, of young (5-6 years) and old (25-35 years) rhesus monkeys. All of the neuroglial cell types accumulate inclusions within their cytoplasm as they age, and the inclusions within the astrocytes and oligodendrocytes are essentially characteristic of those cell types. The astrocytes probably acquire their inclusions by phagocytosis, and it is suggested that the inclusions in the oligodendrocytes are caused by an age-related degeneration of the myelin sheaths they produce. The inclusions within the microglia are very heterogeneous. They are more massive than in the other neuroglial cells, so that their inclusions may almost fill the microglia. Pericytes also accumulate inclusions with age and there is evidence to suggest that they empty the contents of their inclusions vacuoles directly into the capillaries. On the basis of counts of the numbers of profiles of neuroglial cells displaying nuclei in thin sections, the only cells to increase in number with age are the microglia. They show an increase of about 44% when the cortices of young and old monkeys are compared.

Aging↗
PubMed1990

Transcallosal non-pyramidal cell projections from visual cortex in the cat.

Non-pyramidal cells with transcallosal projections were identified in the area 17/18 border region of the cat by retrograde transport of horseradish peroxidase injected into border region of the opposite hemisphere. From several hundred neurons filled with a Golgi-like diaminobenzidine (DAB) reaction product, seven cells were identified by their radially oriented smooth dendrites as possible non-pyramidal cells. Following thin-sectioning and examination with the electron microscope, four of the neurons proved to be layer IV spiny stellate cells with incompletely filled dendritic spines, and two proved to be layer III pyramidal cells with an incompletely labelled apical dendrite and dendritic spines. The remaining neuron was a non-pyramidal cell whose essentially smooth dendrites were covered with synapses, and whose cell body formed both symmetric and asymmetric synapses with presynaptic terminals. To better assess how many non-pyramidal cells might be labelled, thin sections of the area 17/18 border were surveyed using material processed with tetramethylbenzidine (TMB), and another five labelled non-pyramidal cells with transcallosal projections were identified by the needle-like crystals of TMB reaction product they contained. During the study it became evident that both the DAB and TMB reaction products in the lightly labelled neurons tended to be associated with granules that are 0.5 microns or larger in diameter and that had the characteristics of lysosomes. These granules are also visible in the light microscope as dark puncta. The numbers of puncta in profiles of pyramidal and of non-pyramidal cells in layers II/III and IVa of the area 17/18 border region and in the control acallosal region of area 17 were counted and compared. These comparisons revealed that labelled transcallosally projecting non-pyramidal cells may constitute 10-32% of the non-pyramidal cell population at the area 17/18 border region. Similar values were also obtained for pyramidal cells in this region. Consequently, it is concluded that significant numbers of non-pyramidal cells have axons that project through the corpus callosum to the contralateral hemisphere.

Animals↗
PubMed1987

Geriatric assessment on a subacute hospital ward.

The authors collected data on all patients admitted to the Sepulveda Veterans Administration Geriatric Evaluation Unit (GEU) during its first 6 years of operation. Analysis of these data indicate several beneficial effects associated with this type of specialized geriatric care: improved diagnostic accuracy, reduced use of drugs, improved functional status, and improved placement location. The authors also analyzed additional data from a previously published, randomized controlled trial to compare better process of care between patients randomized to the GEU and those receiving usual services. During their initial hospitalizations, GEU patients received significantly more specialty evaluations than controls (4.9 versus 1.7, p less than .001), had longer lengths of stay (85.1 days versus 44.3 days, p less than .001), had more new diagnoses discovered (2.9 versus 0.6, p less than .001), and had more drugs discontinued from their regimens (4.6 versus 2.3 p less than .001). These process differences were probably related to the previously reported outcome differences: GEU patients were more likely than controls to show improvements in functional status, affect, placement location, use of institutional services, and survival.

Aged↗
PubMed1984

The Sepulveda VA Geriatric Evaluation Unit: data on four-year outcomes and predictors of improved patient outcomes.

Data from its first four operating years indicate that the Sepulveda VA Geriatric Evaluation Unit is having consistent beneficial effects on patient care. These benefits include improved diagnostic accuracy, reduced use of drugs, improved functional status, and improved placement location. However, not all patients benefit equally, and differences between patient responses highlight the need to select those who will benefit most from relatively costly Geriatric Evaluation Unit services. Discriminant and regression analyses were performed on 98 consecutive patients to determine which patients admitted to the Geriatric Evaluation Unit would show greatest improvement in terms of placement, functional status, one-year survival, and living location, and which patients would be treated most efficiently in terms of length of stay. Patient characteristics on admission significantly associated with discharge home included a relatively high functional and cognitive status, the absence of an unstable medical problem, and not being expected to need nursing home placement by the referring physician. The latter two factors alone predicted actual placement location on the next 101 patients admitted to the Geriatric Evaluation Unit with high predictive accuracy (88.5 per cent). Factors predictive of patients whose functional status would improve on the Geriatric Evaluation Unit included absence of an unstable medical problem and being over 75 years old (predictive accuracy was 82.5 per cent). Two major factors associated with long patient stays on the Geriatric Evaluation Unit were low functional status scores and not living in own home or with family. These analyses indicate criteria that may be useful in selecting patients for inpatient geriatric evaluation and rehabilitation programs.

Activities of Daily Living↗
PubMedDate not supplied

Occupational therapy for independent-living older adults. A randomized controlled trial.

CONTEXT: Preventive health programs may mitigate against the health risks of older adulthood. OBJECTIVE: To evaluate the effectiveness of preventive occupational therapy (OT) services specifically tailored for multiethnic, independent-living older adults. Design.-A randomized controlled trial. SETTING: Two government subsidized apartment complexes for independent-living older adults. SUBJECTS: A total of 361 culturally diverse volunteers aged 60 years or older. INTERVENTION: An OT group, a social activity control group, and a nontreatment control group. The period of treatment was 9 months. MAIN OUTCOME MEASURES: A battery of self-administered questionnaires designed to measure physical and social function, self-rated health, life satisfaction, and depressive symptoms. RESULTS: Benefit attributable to OT treatment was found for the quality of interaction scale on the Functional Status Questionnaire (P=.03), Life Satisfaction Index-Z (P=.03), Medical Outcomes Study Health Perception Survey (P=.05), and for 7 of 8 scales on the RAND 36-Item Health Status Survey, Short Form: bodily pain (P=.03), physical functioning (P=.008), role limitations attributable to health problems (P=.02), vitality (P=.004), social functioning (P=.05), role limitations attributable to emotional problems (P=.05), and general mental health (P=.02). CONCLUSIONS: Significant benefits for the OT preventive treatment group were found across various health, function, and quality-of-life domains. Because the control groups tended to decline over the study interval, our results suggest that preventive health programs based on OT may mitigate against the health risks of older adulthood.

Activities of Daily Living↗