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L S Goldstein

Publications and source records attributed to L S Goldstein.

At least 55 records · Page 3Linked to original sources
PubMed1999

Risk factors for an outbreak of multi-drug-resistant Acinetobacter nosocomial pneumonia among intubated patients.

INTRODUCTION: Acinetobacter baumanii is a Gram-negative coccobacillus that is normally a commensal pathogen but can be a nosocomial pathogen. An epidemiologic study was performed to investigate an outbreak of A baumanii that occurred in our medical intensive care unit (MICU) from March to September 1995. METHODS: A case-control study was performed by retrospective chart review, comparing case patients to randomly selected patients who were mechanically ventilated in the MICU for at least 1 week during the outbreak. A case patient was defined as any patient with an Acinetobacter infection in which the epidemic strain was considered to be a pathogen. The epidemic strain was defined by its antibiogram. Case patients and control patients were compared for age, gender, underlying disease, acute physiology and chronic health evaluation III score, length of MICU stay, prior antibiotic use, presence of fever, sepsis, type of pulmonary infiltrate, and outcome. Environmental and hand-washing studies also were performed during the period of the outbreak. Molecular typing was performed on available bloodstream isolates. RESULTS: There were 15 cases of A baumanii nosocomial pneumonia. Fifty percent were bacteremic; one chart was unavailable for review. Twenty-nine patients were identified as control patients. The mean age for case patients was 50 (range, 21 to 84). The mean duration of time from admission to the ICU to infection was 12.8 days (range, 4 to 40). Sepsis developed in 35% of the case patients. Forty-three percent of the case patients died during their hospitalization, with two of those deaths attributed to Acinetobacter infection. Univariate analysis showed that prior use of ceftazidime was associated with infection with Acinetobacter (11/14 case patients compared to 11/29 control patients; p < 0.01). Pulsed-field gel electrophoresis revealed two strains to be responsible for the outbreak. Hand washing was performed before patient contact by only 10% of health-care workers, and only 32% washed their hands after patient contact. CONCLUSION: The use of ceftazidime was associated with an increased risk of nosocomial pneumonia with resistant strains of Acinetobacter. Health-care workers need to improve compliance with hand-washing recommendations.

Acinetobacter Infections↗
PubMed1998

Chromosomal localization reveals three kinesin heavy chain genes in mouse.

Kinesin-related proteins constitute a superfamily of microtubule-dependent motors that play important roles in organelle transport and cell division. These molecules share a conserved motor region of approximately 340 amino acids, which is attached to diverse "tail" or cargo-binding domains. The kinesin superfamily was first defined by kinesin heavy chain, which is the principal component of "true" kinesin. Invertebrates appear to possess only a single gene encoding kinesin heavy chain. Mammals appear to have two or more genes encoding kinesin heavy chain, although the precise situation has been unclear. Here we definitively demonstrate that mouse has three kinesin heavy chain genes, Kif5a, Kif5b, and Kif5c. Kif5a, Kif5b, and Kif5c map to mouse chromosomes 10, 18, and 2; Kif5a and Kif5c appear to be expressed only in neuronal tissues by Northern blot analysis while Kif5b appears to be ubiquitous in its expression.

Animals↗
PubMed1998

Two kinesin light chain genes in mice. Identification and characterization of the encoded proteins.

Native kinesin consists of two light chains and two heavy chains in a 1:1 stoichiometric ratio. To date, only one gene for kinesin light chain has been characterized, while a second gene was identified in a genomic sequencing study but not analyzed biochemically. Here we describe new genes encoding kinesin light chains in mouse. One of these light chains is neuronally enriched, while another shows ubiquitous expression. The presence of multiple kinesin light chain genes in mice is especially interesting, since there are two kinesin heavy chain genes in humans (Niclas, J., Navone, F., Hom-Booher, N., and Vale, R. D. (1994) Neuron 12, 1059-1072). To assess the selectivity of kinesin light chain interaction with the heavy chains, we performed immunoprecipitation experiments. The data suggested that the light chains form homodimers with no specificity in their interaction with the two heavy chains. Immunofluorescence and biochemical subfractionation suggested differences in the subcellular localization of the two kinesin light chain gene products. Although both kinesin light chains are distributed throughout the central and peripheral nervous systems, there is enrichment of one in sciatic nerve axons, while the other shows elevated levels in olfactory bulb glomeruli. These results indicate that the mammalian nervous system contains multiple kinesin light chain gene products with potentially distinct functions.

Amino Acid Sequence↗
PubMed1998

Kinesin light chains are essential for axonal transport in Drosophila.

Kinesin is a heterotetramer composed of two 115-kD heavy chains and two 58-kD light chains. The microtubule motor activity of kinesin is performed by the heavy chains, but the functions of the light chains are poorly understood. Mutations were generated in the Drosophila gene Kinesin light chain (Klc), and the phenotypic consequences of loss of Klc function were analyzed at the behavioral and cellular levels. Loss of Klc function results in progressive lethargy, crawling defects, and paralysis followed by death at the end of the second larval instar. Klc mutant axons contain large aggregates of membranous organelles in segmental nerve axons. These aggregates, or organelle jams (Hurd, D.D., and W.M. Saxton. 1996. Genetics. 144: 1075-1085), contain synaptic vesicle precursors as well as organelles that may be transported by kinesin, kinesin-like protein 68D, and cytoplasmic dynein, thus providing evidence that the loss of Klc function blocks multiple pathways of axonal transport. The similarity of the Klc and Khc (. Cell 64:1093-1102; Hurd, D.D., and W.M. Saxton. 1996. Genetics 144: 1075-1085) mutant phenotypes indicates that KLC is essential for kinesin function, perhaps by tethering KHC to intracellular cargos or by activating the kinesin motor.

Animals↗
PubMed1998

A marine natural product inhibitor of kinesin motors.

Members of the kinesin superfamily of motor proteins are essential for mitotic and meiotic spindle organization, chromosome segregation, organelle and vesicle transport, and many other processes that require microtubule-based transport. A compound, adociasulfate-2, was isolated from a marine sponge, Haliclona (also known as Adocia) species, that inhibited kinesin activity by targeting its motor domain and mimicking the activity of the microtubule. Thus, the kinesin-microtubule interaction site could be a useful target for small molecule modulators, and adociasulfate-2 should serve as an archetype for specific inhibitors of kinesin functions.

Adenosine Diphosphate↗
PubMed1998

Characterization of the KIF3C neural kinesin-like motor from mouse.

Proteins of the kinesin superfamily define a class of microtubule-dependent motors that play crucial roles in cell division and intracellular transport. To study the molecular mechanism of axonal transport, a cDNA encoding a new kinesin-like protein called KIF3C was cloned from a mouse brain cDNA library. Sequence and secondary structure analysis revealed that KIF3C is a member of the KIF3 family. In contrast to KIF3A and KIF3B, Northern and Western analysis indicated that KIF3C expression is highly enriched in neural tissues such as brain, spinal cord, and retina. When anti-KIF3C antibodies were used to stain the cerebellum, the strongest signal came from the cell bodies and dendrites of Purkinje cells. In retina, anti-KIF3C mainly stains the ganglion cells. Immunolocalization showed that the KIF3C motor in spinal cord and sciatic nerve is mainly localized in cytoplasm. In spinal cord, the KIF3C staining was punctate; double labeling with anti-giantin and anti-KIF3C showed a clear concentration of the motor protein in the Golgi complex. Staining of ligated sciatic nerves demonstrated that the KIF3C motor accumulated at the proximal side of the ligated nerve, which suggests that KIF3C is an anterograde motor. Immunoprecipitation experiments revealed that KIF3C and KIF3A, but not KIF3B, were coprecipitated. These data, combined with previous data from other labs, indicate that KIF3C and KIF3B are "variable" subunits that associate with a common KIF3A subunit, but not with each other. Together these results suggest that KIF3 family members combinatorially associate to power anterograde axonal transport.

Amino Acid Sequence↗
PubMed1998

A comparison of the tumors induced by coal tar and benzo[a]pyrene in a 2-year bioassay.

The tumorigenicity of two coal tar mixtures was compared to that of benzo[a]pyrene after 2 years of feeding. Mixture 1, a composite of coal tar from seven coal gasification plant waste sites, was fed to female B6C3F1 mice (48 mice per group) for 2 years at doses of 0.0, 0.01, 0.03, 0.1, 0.3, 0.6 and 1.0%. Mixture 2, which was composed of coal tar from two of the seven waste sites and another site having a high benzo[a]pyrene content, was fed at doses of 0.0, 0.03, 0.1 and 0.3%. Additional groups of mice were fed 0, 5, 25 and 100 ppm benzo[a]pyrene. The coal tar diets induced a dose-related increase in hepatocellular adenomas and carcinomas, alveolar/bronchiolar adenomas and carcinomas, forestomach squamous epithelial papillomas and carcinomas, small intestine adenocarcinomas, histiocytic sarcomas, hemangiosarcomas in multiple organs and sarcomas. Benzo[a]pyrene treatment resulted in an increased incidence of papillomas and/or carcinomas of the forestomach, esophagus and tongue. A comparison of the results indicated that the benzo[a]pyrene in the coal tar diets could be responsible for the forestomach tumors. In contrast, the lung and liver tumors appeared to be due to other genotoxic components contained within the coal tar mixture, while the small intestine tumors resulted from chemically-induced cell proliferation that occurred at high doses of coal tar.

Adenoma↗
PubMed1998

Tumors and DNA adducts in mice exposed to benzo[a]pyrene and coal tars: implications for risk assessment.

Current methods to estimate the quantitative cancer risk of complex mixtures of polycyclic aromatic hydrocarbons (PAH) such as coal tar assume that overall potency can be derived from knowledge of the concentration of a few carcinogenic components such as benzo[a]pyrene (B[a]P). Genotoxic damage, such as DNA adducts, is thought to be an essential aspect of PAH-induced tumorigenesis and could be a biomarker for exposure useful for estimating risk. However, the role of B[a]P and the relationship of adduct formation in tumorigenesis have not been tested rigorously in models appropriate for human health risk assessment. Therefore, we directly compared tumor induction and adduct formation by B[a]P and coal tars in several experimental protocols, including one broadly accepted and used by regulators. We found that B[a]P content did not account for tumor incidences after exposure to coal tars. DNA adducts were found in both tumors and tumor-free tissue and tumor outcomes were not predicted by either quantitation of total DNA adducts or by the DNA adduct formed by B[a]P. These data suggest that risk assessments based on B[a]P content may not predict accurately risk to human health posed by environmental PAH.

Administration, Oral↗
PubMed1998

Pulmonary alveolar proteinosis: clinical features and outcomes.

INTRODUCTION: Pulmonary alveolar proteinosis (PAP) is a rare disease of unknown etiology and variable natural history. To date, the largest series from a single institution has consisted of 68 individuals. To extend the understanding of the clinical features and natural history of PAP, we present a series of 24 patients with PAP from a single institution. METHODS: Patients with PAP were identified by a review of The Cleveland Clinic Foundation discharge database from 1965 to 1995. After identification, a chart review of the 24 selected patients was conducted. Charts were abstracted for historical, diagnostic, and therapeutic features. Diagnosis was confirmed by a review of the lung biopsy, where it was available, by a lung pathologist. Follow-up by telephone was performed with 19 patients. RESULTS: Most patients (70%) were male, and smoking was common (75%; mean pack-years, 29) in the group. The mean age at initial evaluation was 43 years. Presenting symptoms were as follows: 19 patients (79%) reported dyspnea, 19 patients (79%) reported a cough, 4 patients (17%) reported hemoptysis, and 3 patients (13%) reported chest pain. The earliest available spirometry after presentation of symptoms showed a prediction of mean FEV1 of 74% (range, 45 to 99%) and a prediction of mean FVC of 76% (range, 41 to 99%). The diagnosis of PAP was established by transbronchial biopsy alone in 7 patients (29%) and by open-lung biopsy alone in 17 patients (71%). Whole lung lavage was deemed necessary in 13 patients (54%); 3 patients underwent lavage of one lung only, and 10 patients underwent bilateral whole lung lavage. Whole lung lavage was required only once in 46% of patients, and from two to four times in the remainder of patients. During the follow-up period (mean length of follow-up, 8.5 years; range, 5 months to 21 years), 25% of the patients died, but none as a result of sequelae of PAP. Half of the survivors reported persistent symptoms. CONCLUSIONS: In this series, which represents one of the largest single institutional experiences with PAP reported, the clinical features are largely consistent with previously reported cases. However, contrary to early reported experiences in which open-lung biopsy was frequently required to establish PAP and in which whole lung lavage was needed, transbronchial biopsy established the diagnosis in 29% of patients and whole lung lavage could be deferred in 46% of patients.

Adult↗
PubMed1998

Central nervous system complications after lung transplantation.

PURPOSE: This study describes the central nervous system (CNS) events after lung transplantation. METHODS: A chart review of all lung transplant recipients (LTR) to collect the clinical and neuroimaging data for CNS events defined as seizures, severe headaches, confusion, or stroke. RESULTS: Twenty-six patients of 100 LTRs from 1990 through 1995 had a CNS event; more than one event occurred in 5 patients for a total of 32 events. Severe headache was most common, occurring in 14 patients, followed by seizures in 10, stroke in 5, and confusion in 3. The CNS event was related to infection in three of the 26 patients. Of all evaluations performed, magnetic resonance imaging (MRI) identified the most abnormalities, the most common being white matter changes consistent with cyclosporine toxicity. Cyclosporine levels were elevated in slightly more than half of the patients. Hypomagnesemia was present in three of 10 patients with seizures. Prognosis for recovery from these complications was good, with only five patients having ongoing problems with headaches, one requiring long term anticonvulsant therapy, three having minor or no limitations from stroke and no long-term problems with confusion. One patient with seizures resulting from an aspergilloma died. CONCLUSION: CNS events occur commonly in LTRs, mostly related to cyclosporine toxicity or infection. MRI identifies more abnormalities than computed tomography. These events were not consistently associated with documented high cyclosporine levels and hypomagnesemia. In spite of significantly abnormal MRIs, the functional outcome is favorable.

Adolescent↗
PubMed1997

CENP-E is a plus end-directed kinetochore motor required for metaphase chromosome alignment.

Mitosis requires dynamic attachment of chromosomes to spindle microtubules. This interaction is mediated largely by kinetochores. During prometaphase, forces exerted at kinetochores, in combination with polar ejection forces, drive congression of chromosomes to the metaphase plate. A major question has been whether kinetochore-associated microtubule motors play an important role in congression. Using immunodepletion from and antibody addition to Xenopus egg extracts, we show that the kinetochore-associated kinesin-like motor protein CENP-E is essential for positioning chromosomes at the metaphase plate. We further demonstrate that CENP-E powers movement toward microtubule plus ends in vitro. These findings support a model in which CENP-E functions in congression to tether kinetochores to dynamic microtubule plus ends.

Amino Acid Sequence↗
PubMed1997

Identification, partial characterization, and genetic mapping of kinesin-like protein genes in mouse.

Microtubule-dependent motors of the kinesin superfamily have undergone structural and functional diversification during evolution and play crucial roles in cell division and intracellular transport. Degenerate oligonucleotides homologous to highly conserved regions of sequence within the motor domain were used in a polymerase chain reaction to isolate five new members (KIF3C, KIFC2, KIFC3, KIFC4, and KIF22) of the kinesin superfamily from a mouse brain cDNA library. Northern analysis showed that KIF3C and KIFC2 are expressed mainly in neural tissues, that KIFC4 and KIF22 are expressed primarily in proliferative tissues and cell lines, and that KIFC3 is apparently ubiquitous. To elucidate the organization of genes encoding kinesin-like motors in the mouse genome and to explore the potential associations of these genes with classical mouse mutations or human genetic diseases, these new genes as well as genes encoding the previously reported KIF3A and KIF3B motors were mapped to mouse chromosomes by using an interspecific backcross panel of DNAs from The Jackson Laboratory. The data indicate that the gene KIFC4 is present in three copies in the mouse genome on chromosomes 13 (KIFC4A), 10 (KIFC4B), and 17 (KIFC4C). The gene KIF22 is present in two copies on chromosomes 7 (KIF22A) and 1 (KIF22B). The genes KIF3A, KIF3B, KIF3C, KIFC2, and KIFC3 are each single loci and map to chromosomes 11, 2, 12, 15, and 8, respectively.

Amino Acid Sequence↗
PubMed1997

Probing the kinesin-microtubule interaction.

Kinesin is a mechanoenzyme that couples adenosine triphosphate hydrolysis to the generation of force and movement along microtubules. To gain insight into the interactions of kinesin and microtubules, cross-linking, mapping, and proteolysis experiments were executed. The motor domain of kinesin was consistently cross-linked to both alpha- and beta-tubulin subunits. Initial mapping of the cross-linked kinesin suggested that amino acids within the N- and C-terminal cyanogen bromide fragments of the motor domain formed cross-links to both alpha- and beta-tubulin subunits. Mapping of the cross-linked tubulin suggested that cross-linking to kinesin motors occurred within the negatively charged, C-terminal cyanogen bromide fragments of alpha- and beta-tubulin subunits. Treatment of microtubules with subtilisin, a protease that cleaves C-terminal fragments from alpha- and beta-tubulin, reduced their ability to be cross-linked to kinesin motors supporting the idea that C-terminal sequences of alpha- and beta-tubulin may interact with kinesin motors. Finally, of three synthetic peptides, a peptide consisting of the last 12 C-terminal amino acids of beta-tubulin competitively interfered with the microtubule-stimulated adenosine triphosphatase activity of the kinesin motor, further suggesting that C-terminal sequences of beta-tubulin may be involved in kinesin binding.

Animals↗
PubMed1997

Mitochondrial association of a plus end-directed microtubule motor expressed during mitosis in Drosophila.

The kinesin superfamily is a large group of proteins (kinesin-like proteins [KLPs]) that share sequence similarity with the microtubule (MT) motor kinesin. Several members of this superfamily have been implicated in various stages of mitosis and meiosis. Here we report our studies on KLP67A of Drosophila. DNA sequence analysis of KLP67A predicts an MT motor protein with an amino-terminal motor domain. To prove this directly, KLP67A expressed in Escherichia coli was shown in an in vitro motility assay to move MTs in the plus direction. We also report expression analyses at both the mRNA and protein level, which implicate KLP67A in the localization of mitochondria in undifferentiated cell types. In situ hybridization studies of the KLP67A mRNA during embryogenesis and larval central nervous system development indicate a proliferation-specific expression pattern. Furthermore, when affinity-purified anti-KLP67A antisera are used to stain blastoderm embryos, mitochondria in the region of the spindle asters are labeled. These data suggest that KLP67A is a mitotic motor of Drosophila that may have the unique role of positioning mitochondria near the spindle.

Amino Acid Sequence↗
PubMed1997

Characterization of KIFC2, a neuronal kinesin superfamily member in mouse.

Members of the kinesin superfamily of microtubule-associated proteins are involved in a variety of intracellular processes including cell division and organelle transport. In the case of axonal transport, all kinesin superfamily members reported thus far appear to play a role in anterograde transport, while a different type of microtubule motor, dynein, appears to function in retrograde transport. To better understand the role of kinesins in axonal transport, we cloned and characterized KIFC2, a novel kinesin superfamily member from mouse brain. KIFC2 encodes a 792 amino acid protein, which contains the conserved motor domain at the C-terminal end of the protein and is most similar to members of the KAR3 family involved in cell division. However, expression analysis localized KIFC2 mRNA to nonproliferative neuronal cells in the central nervous system, and immunolocalization studies demonstrated that KIFC2 is present in axons and dendrites of neurons in the central and peripheral nervous systems. Immunolocalization and biochemical fractionation studies suggest that KIFC2 localizes with some, but not all, axonally transported organelles. Finally, ligation of mouse peripheral nerves showed that KIFC2 accumulates at the proximal and distal sides of an axonal ligature. Taken together, the data suggest that, unlike other C-terminal motor proteins that appear to be involved in cell division, KIFC2 may play a role in retrograde axonal transport.

Amino Acid Sequence↗
PubMed1997

Carcinogenicity of benzo[a]pyrene and manufactured gas plant residues in infant mice.

The present study determined tumorigenicity, tumor classification and DNA damage induced in infant mice by benzo[a]pyrene (B[a]P) or Manufactured Gas Plant (MGP) residues after a single exposure. Male and female B6C3F1 mice were exposed to B[a]P or MGP residue from a single environmental site (MGP-4) and males were also exposed to MGP residue composite from seven different sites (MGP-M7). At 26, 39 and 52 weeks after exposure tumorigenesis was assessed in lung, forestomach and liver. Formation and persistence of DNA adducts were quantified by 32P-postlabeling. Exposure of males to B[a]P induced liver tumors in a dose and time dependent manner. MGP induced more advanced tumors than B[a]P. Only a single liver tumor was found in MGP-4 treated females. No forestomach and few pulmonary adenomas were induced in males or females. MGP-4, MGP-M7 or B[a]P induced DNA adducts in males and females. Adducts in liver, lung and forestomach peaked on different days and decreased at different rates. At 24 h post-exposure, no significant differences in initial DNA adduct levels occurred in males and females exposed to MGP-4 or B[a]P. Lack of DNA damage (adducted DNA) did not account for non-responsiveness of lung and forestomach in B6C3F1 genders as well as in liver in females. MGP tumorigenicity could not be accounted for solely by B[a]P content nor did it reflect additivity of B[a]P and other carcinogenic polycyclic aromatic hydrocarbons (PAHs) in MGP. Synergy among MGP-PAHs, presence of unidentified carcinogens and/or promoters in MGP may account for MGP potency. The B6C3F1 infant male model is a convenient and rapid assay for assessing MGP liver tumorigenicity and potency.

Animals↗