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Biomedical subjects

T Herman

Publications and source records attributed to T Herman.

At least 19 recordsLinked to original sources
PubMed2005

Falls in outpatients with Parkinson's disease: frequency, impact and identifying factors.

Falls are one of the most serious complications of gait disturbances in patients with Parkinson's disease (PD). Among previous reports, the percentage of patients with PD who fall varies between 38% to 68%. We sought to determine the frequency of falls and the factors associated with falls in a group of patients with idiopathic PD who attended an outpatient, tertiary movement disorders clinic. 350 ambulatory, non-demented patients (230 males) were studied. Mean age was 69.7+/-10.6 years (range: 43-97 yrs) and mean duration of PD symptoms was 8.6+/- 6.2 years (range: 1-33 yrs). Assessments included characterization of demographics, disease duration, disease severity as measured by the Hoehn and Yahr Scale (H&Y), co-morbidities, the presence of depressive symptoms, the presence of urinary incontinence, use of anti-parkinsonian medications, and two performance-based tests of balance and gait (tandem standing and Timed Up & Go). Fall history was determined during three time periods: previous week, previous month, and previous year. Univariate and multivariate logistic regression models were applied to evaluate the relationship between the above-mentioned factors and falls. 46% of the subjects reported at least one fall in the previous year and 33% reported 2 or more falls and were classified as Fallers. Fallers had significantly more prolonged and advanced PD compared with Non-fallers (p=0.001 and p<0.001, respectively). Urinary incontinence was the factor most closely associated with falls (crude and adjusted OR were 1.95 and 5.89, respectively). Other factors significantly associated with fall status included increased Timed Up & Go times and increased PD duration. These findings confirm that falls are a common problem among patients with advanced PD and suggest easily measurable features that may be used to prospectively identify those PD patients with the greatest risk of falls.

Accidental Falls↗
PubMed2005

Clinical characteristics of elderly patients with a cautious gait of unknown origin.

OBJECTIVE: To evaluate and systematically characterize a group of older adults with disturbed gait of unknown origin. DESIGN: Cross-sectional study. SETTING: Outpatient clinic in a movement disorders unit. PARTICIPANTS: Twenty-five patients (mean age 78.4 years) with a disturbed gait of unknown origin were compared with twenty-eight age matched "healthy" controls (mean age 78.2). MEASUREMENT: Detailed medical history, geriatric and neurological assessments. RESULTS: Patients walked more slowly (P<0.0001) and with shorter strides (P<0.0001) compared with controls. Muscle strength was lower, and static and dynamic balance and gait performance were worse among the patients (P<0.0001). The patients also tended to be more depressed (P<0.0001),more anxious (P<0.002), had a greater fear of falling (P<0.0001) and had lower scores on the Mini-Mental State Examination (P<0.005). There was no difference in the frequency of cerebellar or pyramidal signs in the two groups. However, neurological testing revealed that extrapyramidal (P<0.0001) and frontal release signs (P<0.0001) were more common among the patients. Neuroradiological findings were rare among the patients and they did not explain the changes in gait speed or fear of falling. CONCLUSIONS: Older adults with a disturbed gait of unknown origin appear to share common characteristics. They walk more slowly than "healthy" controls with increased unsteadiness and with excessive fear of falling. The extrapyramidal, frontal lobe, and limbic systems apparently play an important role, to different degrees, in what can be viewed as a multisystem neurodegenerative syndrome clearly different from "aging."

Aged↗
PubMed2005

Gait instability and fractal dynamics of older adults with a "cautious" gait: why do certain older adults walk fearfully?

Many older adults walk with a cautious and impaired gait of unknown origin, however, the relationship between fear of falling and the observed gait changes is not well understood. To better understand the "cautious" gait of the elderly, we tested the hypothesis that temporal gait variability, putatively a marker of intrinsic walking unsteadiness, is increased among older adults with a cautious gait and a higher-level gait disorder (HLGD), an altered gait that cannot be attributed to a well-defined cause. Twenty-five older adults (mean age: 78 years) with a HLGD were compared to healthy controls of similar age and sex (n=28). The clinical characteristics (e.g., neurological status, fear of falling), the magnitude of the stride-to-stride variations in gait cycle timing (a measure of temporal gait variability), and a fractal index of gait (a measure of the stride dynamics independent of the magnitude of the variability) were studied in both groups. Gait variability was significantly increased (P<0.0001) in HLGD subjects (52+/-26 ms) compared to controls (27+/-9 ms). Changes in frontal lobe and extra-pyramidal function were also found in the patient group. Among HLGD subjects, gait variability was not associated (P>0.05) with age, gender, MMSE score, muscle strength, # of co-morbidities, balance, cerebellar signs, or pyramidal signs, but was significantly associated with scores on the Geriatric Depression Scale (r=0.46, P<0.02) and fear of falling (r=0.69, P<0.0001). Among HLGD subjects, only a fractal index was significantly different in fallers and non-fallers. These findings underscore the idea that the gait changes in older adults who walk with fear may be an appropriate response to unsteadiness, are likely a marker of underlying pathology, and are not simply a physiological or psychological consequence of normal aging.

Accidental Falls↗
PubMed2005

Presence and titer of methyl palmitate in the Medfly (Ceratitis capitata) during reproductive maturation.

The relative amounts of methyl palmitate (MP) during the first 10 days post-eclosion were determined in whole-body extracts of adult female Ceratitis capitata by SIM monitoring of the 74 m/z fragment. MP peaks in receptive 3-day-old virgin females coincide with previously reported production of Juvenile Hormone (JH) by the corpus allatum (CA). Mating in the Medfly induces female non-receptivity. Indirect evidence suggests that the mevalonate pathway to sesquiterpene biosynthesis is underdeveloped in newly eclosed females. We propose that the pathway leading to synthesis of JH is markedly diverted in non-receptive virgin females to fatty acid synthesis, and partly so-in non-receptive mated females, leading to production of palmitic acid, presumably methylated thereafter. MP is depressed and remains marginal thereafter for the 7 days examined in the virgin female but goes through an apparent second cycle in the mated female. This contrasts with the consistent increase of allatal biosynthesis of MP of virgin and mated females previously reported and suggests additional control mechanisms in vivo. During the period of reduced receptivity following the first mating a second apparent peak of MP is observed. MP is a metabolic default metabolite of reproductively immature females whose putative role in reproductive physiology remains to be defined.

Animals↗
PubMed2002

Survival of patients with newly diagnosed glioblastoma multiforme treated with RSR13 and radiotherapy: results of a phase II new approaches to brain tumor therapy CNS consortium safety and efficacy study.

PURPOSE: The objectives of this phase II study were to determine survival, safety, pharmacokinetics (PK), and pharmacodynamics (PD) of 2,4-[[(3,5-dimethylanilino)carbonyl]methyl]phenoxy]-2-methylpropionic acid (RSR13, efaproxiral) 100 mg/kg per day administered with standard cranial radiotherapy (RT) for the treatment of glioblastoma multiforme (GBM). RSR13, a synthetic allosteric modifier of hemoglobin, is a radiation-enhancing agent that noncovalently binds to hemoglobin, reduces oxygen-binding affinity, and increases oxygen unloading to hypoxic tissue. PATIENTS AND METHODS: Fifty patients with newly diagnosed GBM (Karnofsky performance status >or= 60) were enrolled onto this multicenter phase II study. Patients received daily RSR13 100 mg/kg intravenously infused for 30 minutes immediately before cranial RT (60 Gy in 30 fractions). Supplemental oxygen was given during RSR13 infusion and continued until after the RT treatment was completed. RT was given within 30 minutes of the end of RSR13 infusion. PK and PD determinations were performed. RESULTS: The median survival for the RSR13-treated patients was 12.3 months with 1-year and 18-month survival rates of 54% and 24%, respectively. Twenty-four percent of patients had greater than grade 2 toxicity, which was generally transient and self-limited. A significant PD effect on hemoglobin-oxygen binding affinity was demonstrated for most patients. CONCLUSION: RSR13 (100 mg/kg) administered immediately before cranial RT is well tolerated and is pharmacodynamically active. Median survival in excess of 1 year is favorable.

Adult↗
PubMed2001

Drosophila LAR regulates R1-R6 and R7 target specificity in the visual system.

Different classes of photoreceptor neurons (R cells) in the Drosophila compound eye connect to specific targets in the optic lobe. Using a behavioral screen, we identified LAR, a receptor tyrosine phosphatase, as being required for R cell target specificity. In LAR mutant mosaic eyes, R1-R6 cells target to the lamina correctly, but fail to choose the correct pattern of target neurons. Although mutant R7 axons initially project to the correct layer of the medulla, they retract into inappropriate layers. Using single cell mosaics, we demonstrate that LAR controls targeting of R1-R6 and R7 in a cell-autonomous fashion. The phenotypes of LAR mutant R cells are strikingly similar to those seen in N-cadherin mutants.

Animals↗
PubMed2001

Tbx19, a tissue-selective regulator of POMC gene expression.

Pituitary cell types arise in a temporally and spatially specific fashion, in response to combinatorial actions of transcription factors induced by transient signaling gradients. The critical transcriptional determinants of the two pituitary cell types that express the pro-opiomelanocortin (POMC) gene, the anterior lobe corticotropes, producing adrenocorticotropin, and the intermediate lobe melanotropes, producing melanocyte-stimulating hormone (MSH alpha), have remained unknown. Here, we report that a member of the T-box gene family, Tbx19, which is expressed only in the rostral ventral diencephalon and pituitary gland, commencing on e11.5, marks pituitary cells that will subsequently express the POMC gene and is capable of altering progression of ventral cell types and inducing adrenocorticotropin in rostral tip cells. It is suggested that Tbx19, depending on the presence of synergizing transcription factors, can activate POMC gene expression and repress the alpha glycoprotein subunit and thyroid-stimulating hormone beta promoters.

Amino Acid Sequence↗
PubMed2001

N-cadherin regulates target specificity in the Drosophila visual system.

Using visual behavioral screens in Drosophila, we identified multiple alleles of N-cadherin. Removal of N-cadherin selectively from photoreceptor neurons (R cells) causes deficits in specific visual behaviors that correlate with disruptions in R cell connectivity. These defects include disruptions in the pattern of neuronal connections made by all three classes of R cells (R1-R6, R7, and R8). N-cadherin is expressed in both R cell axons and their targets. By inducing mitotic recombination in a subclass of eye progenitors, we generated mutant R7 axons surrounded by largely wild-type R cell axons and a wild-type target. R7 axons lacking N-cadherin mistarget to the R8 recipient layer. We consider the implications of these findings in the context of the proposed role for cadherins in target specificity.

Animals↗
PubMed2001

Fulminant radiation-induced necrosis after stereotactic radiation therapy to the posterior fossa. Case report and review of the literature.

The problem of radiation-induced necrosis of normal brain surrounding the target area has been a major catalyst for the development of stereotactically focused radiation therapy. According to current opinion, the effects of stereotactic irradiation are confined to the region targeted. The authors present a case in which the administration of a conventional dose of stereotactically focused irradiation for treatment of a pilocytic astrocytoma produced fulminant necrosis that necessitated a combination of intensive surgical and medical management, after which the patient improved over the course of 1 year. Concomitant with his improvement, the initially remarkable findings on magnetic resonance imaging gradually resolved. In this presentation the authors emphasize the need to evaluate alternatives carefully before a decision is made to administer therapeutic irradiation. Furthermore, they explore the roles that target, host, and dosage factors play in hypersensitivity to radiation injury, the detection of these factors before treatment, and the administration of radioprotective agents. With the growing use of stereotactically focused irradiation as a primary treatment modality for a variety of neurosurgical conditions, it is important to be cognizant of its uncommon but potentially lethal side effects. A cooperative multicenter database in which the outcomes and morbidity following stereotactic irradiation are recorded is essential to the detection of relatively uncommon but severe complications such as those observed in this case.

Adult↗
PubMed2000

Regulation of somatic growth by the p160 coactivator p/CIP.

A family of p160 coactivators was initially identified based on ligand-dependent interactions with nuclear receptors and thought to function, in part, by recruiting CREB-binding protein/p300 to several classes of transcription factors. One of the p160 factors, p/CIP/AIB1, often amplified and overexpressed in breast cancer, also exhibits particularly strong interaction with CREB-binding protein/p300. In this manuscript, we report that p/CIP, which exhibits regulated transfer from cytoplasm to nucleus, is required for normal somatic growth from embryonic day 13.5 through maturity. Our data suggest that a short stature phenotype of p/CIP gene-deleted mice reflect both altered regulation of insulin-like growth factor-1 (IGF-1) gene expression in specific tissues and a cell-autonomous defect of response to IGF-1, including ineffective transcriptional activities by several classes of regulated transcription factors under specific conditions. The actions of p/CIP are therefore required for full expression of a subset of genes critical for regulating physiological patterns of somatic growth in mammals.

Animals↗
PubMed1999

sqv mutants of Caenorhabditis elegans are defective in vulval epithelial invagination.

By screening for mutations that perturb the invagination of the vulva of the Caenorhabditis elegans hermaphrodite, we have isolated 25 mutations that define eight genes. We have named these genes sqv-1 to sqv-8 (squashed vulva). All 25 mutations cause the same vulval defect, an apparent partial collapse of the vulval invagination and an elongation of the central vulval cells. Most sqv mutations also cause an oocyte or somatic gonad defect that results in hermaphrodite sterility, and some sqv mutations cause maternal-effect lethality. We propose that the sqv genes affect a pathway common to vulval invagination, oocyte development, and embryogenesis.

Alleles↗
PubMed1999

Three proteins involved in Caenorhabditis elegans vulval invagination are similar to components of a glycosylation pathway.

We have molecularly analyzed three genes, sqv-3, sqv-7, and sqv-8, that are required for wild-type vulval invagination in Caenorhabditis elegans. The predicted SQV-8 protein is similar in sequence to two mammalian beta(1,3)-glucuronyltransferases, one of which adds glucuronic acid to protein-linked galactose-beta(1, 4)-N-acetylglucosamine. SQV-3 is similar to a family of glycosyltransferases that includes vertebrate beta(1, 4)-galactosyltransferases, which create galactose-beta(1, 4)-N-acetylglucosamine linkages. One model is therefore that SQV-8 uses a SQV-3 product as a substrate. SQV-7 is similar to members of a family of nucleotide-sugar transporters. The sqv genes therefore are likely to encode components of a conserved glycosylation pathway that assembles a C. elegans carbohydrate moiety, the absence of which perturbs vulval invagination.

Amino Acid Sequence↗
PubMed1999

The mechanism of delayed selfing in Collinsia verna (Scrophulariaceae).

Collinsia verna, blue-eyed Mary, has floral attributes of an outcrossing species, yet most flowers readily self-pollinate under greenhouse conditions. Here we describe the mechanism of self-pollination in C. verna via changes in relative positions of the stigma and anthers and late timing of receptivity, resulting in delayed selfing. Each flower contains four anthers that dehisce sequentially over ∼1 wk. Pollen that is not collected by pollinators accumulates in the keel petal and retains high viability (>80% pollen germination) up to the time of corolla abscission. The stigmatic surface does not become receptive until after the third anther dehisces. This overlap in the sexual phases is concurrent with a change in herkogamy during floral development. In most flowers (70%), the stigma has moved to the front of the keel and is positioned near the anthers when the third anther dehisces. Under field conditions, fruiting success of plants within pollinator exclosures was ∼75% of the fruiting success in open-pollinated plants (33% fruiting success via autogamy vs. 44% fruiting success, respectively). Collinsia verna plants in pollinator exclosures exhibit variation in autogamy rates within natural populations (range 0-80%). In addition, only half of naturally pollinated, receptive flowers examined had pollen tubes growing in their styles. In contrast, shortly after corolla abscission, nearly all flowers examined (96%) had pollen tubes in their styles. Thus we find that in C. verna, autogamy occurs late in floral development, which has the potential to provide substantial reproductive assurance, and that individuals vary in their ability to set fruit through this mechanism. We suggest that delayed selfing mechanisms may be overlooked in other species and that variable pollinator availability may play a significant role in the maintenance of mixed mating in species with delayed selfing, such as C. verna.

Journal Article↗
PubMed1998

Germ cell nuclear factor is a response element-specific repressor of transcription.

We have shown that the orphan receptor Germ Cell Nuclear Factor (GCNF) binds to a direct repeat of the sequence AGGTCA with zero base pair spacing (DR0). Here, we further characterize the binding characteristics of GCNF. We demonstrate that GCNF binds specifically to DR0s as a homodimer, and does not bind with high affinity to DR1-DR6 sequences. GCNF is the first nuclear receptor shown to bind specifically to DR0s. The wild type GCNF is unable to transactivate the reporter plasmid DR0(2)tkCAT. Lacking a ligand to activate GCNF, we fused the activation domain from the viral protein VP16 to GCNF, and observed activation of DR0(2)tkCAT. This activation is specifc to DR0s, and is not observed when that sequence is replaced by DR1-DR6 sequences. In addition GCNF does not transactivate through an SF-1 response element. At increasing concentrations, wild type GCNF is able to repress basal transcription. Repression is again specific to DR0s. The preference of GCNF for the DR0 sequence both in vitro and in transfections suggests that GCNF defines a novel nuclear receptor signaling pathway.

DNA-Binding Proteins↗
PubMed1998

Trinucleotide insertions, deletions, and point mutations in glucose transporters confer K+ uptake in Saccharomyces cerevisiae.

Deletion of TRK1 and TRK2 abolishes high-affinity K+ uptake in Saccharomyces cerevisiae, resulting in the inability to grow on typical synthetic growth medium unless it is supplemented with very high concentrations of potassium. Selection for spontaneous suppressors that restored growth of trk1delta trk2delta cells on K+-limiting medium led to the isolation of cells with unusual gain-of-function mutations in the glucose transporter genes HXT1 and HXT3 and the glucose/galactose transporter gene GAL2. 86Rb uptake assays demonstrated that the suppressor mutations conferred increased uptake of the ion. In addition to K+, the mutant hexose transporters also conferred permeation of other cations, including Na+. Because the selection strategy required such gain of function, mutations that disrupted transporter maturation or localization to the plasma membrane were avoided. Thus, the importance of specific sites in glucose transport could be independently assessed by testing for the ability of the mutant transporter to restore glucose-dependent growth to cells containing null alleles of all of the known functional glucose transporter genes. Twelve sites, most of which are conserved among eukaryotic hexose transporters, were revealed to be essential for glucose transport. Four of these have previously been shown to be essential for glucose transport by animal or plant transporters. Eight represented sites not previously known to be crucial for glucose uptake. Each suppressor mutant harbored a single mutation that altered an amino acid(s) within or immediately adjacent to a putative transmembrane domain of the transporter. Seven of 38 independent suppressor mutations consisted of in-frame insertions or deletions. The nature of the insertions and deletions revealed a striking DNA template dependency: each insertion generated a trinucleotide repeat, and each deletion involved the removal of a repeated nucleotide sequence.

Alleles↗
PubMed1997

Use of a two-hybrid system to identify mutations in Max that confer increased affinity for Myc.

A yeast two-hybrid system was used to identify mutants of Max that exhibit an increased affinity for Myc. Truncated forms of the Max helix-loop-helix/leucine zipper motif (HLH/Zip) were first expressed in a two- hybrid system in which the bait protein was the HLH/Zip motif of Myc. Deletion of amino acids both amino-terminal and carboxy-terminal to the leucine zipper of Max reduced Myc/Max heterodimer formation as evidenced by a 160-fold reduction in the expression of the lacZ gene. A library of partially randomized sequences encoding this minimal leucine zipper of Max was then screened using the two-hybrid system. Mutant forms of the Max leucine zipper were identified whose affinities for Myc, as measured by beta-galactosidase activity in yeast lysates, were from 8- to 200-fold greater than the wild-type Max zipper. These Max mutants were shown to interact specifically with Myc and not with wild-type Max. Of 29 mutants analyzed, all had a unique amino acid sequence. This result illustrates the value of a genetic screen in the identification of a collection of mutant forms of the Max leucine zipper whose structures would not have been predicted based on principles of structure-based design.

Bacterial Proteins↗
PubMed1995

Linkage of preaxial polydactyly type 2 to 7q36.

We have characterized a 6-generation North American Caucasian kindred segregating one form of preaxial polydactyly type 2 (PPD-2). We demonstrate linkage to the 7q36 region and describe a submicroscopic telomeric chromosomal deletion in phase with the PPD-2 phenotype. Recently, several kindreds segregating triphalangeal thumb (TPT) with and without associated hand anomalies (syndactyly and/or postaxial polydactyly) have also been linked to the subtelomeric region of chromosome 7q [Heutink et al., 1994: Nat Genet 6:287-291; Tsukurov et al., 1994: Nat Genet 6:282-286]. We demonstrate by haplotype analysis that our North American pedigree represents a PPD allele that is independent of the founder PPD allele present in the previously described kindreds.

Base Sequence↗