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PubMed1992

Aldehyde dehydrogenases and their role in carcinogenesis.

Aldehydes are highly reactive molecules that may have a variety of effects on biological systems. They can be generated from a virtually limitless number of endogenous and exogenous sources. Although some aldehyde-mediated effects such as vision are beneficial, many effects are deleterious, including cytotoxicity, mutagenicity, and carcinogenicity. A variety of enzymes have evolved to metabolize aldehydes to less reactive forms. Among the most effective pathways for aldehyde metabolism is their oxidation to carboxylic acids by aldehyde dehydrogenases (ALDHs). ALDHs are a family of NADP-dependent enzymes with common structural and functional features that catalyze the oxidation of a broad spectrum of aliphatic and aromatic aldehydes. Based on primary sequence analysis, three major classes of mammalian ALDHs--1, 2, and 3--have been identified. Classes 1 and 3 contain both constitutively expressed and inducible cytosolic forms. Class 2 consists of constitutive mitochondrial enzymes. Each class appears to oxidize a variety of substrates that may be derived either from endogenous sources such as amino acid, biogenic amine, or lipid metabolism or from exogenous sources, including aldehydes derived from xenobiotic metabolism. Changes in ALDH activity have been observed during experimental liver and urinary bladder carcinogenesis and in a number of human tumors, including some liver, colon, and mammary cancers. Changes in ALDH define at least one population of preneoplastic cells having a high probability of progressing to overt neoplasms. The most common change is the appearance of class 3 ALDH dehydrogenase activity in tumors arising in tissues that normally do not express this form. The changes in enzyme activity occur early in tumorigenesis and are the result of permanent changes in ALDH gene expression. This review discusses several aspects of ALDH expression during carcinogenesis. A brief introduction examines the variety of sources of aldehydes. This is followed by a discussion of the mammalian ALDHs. Because the ALDHs are a relatively understudied family of enzymes, this section presents what is currently known about the general structural and functional properties of the enzymes and the interrelationships of the various forms. The remainder of the review discusses various aspects of the ALDHs in relation to tumorigenesis. The expression of ALDH during experimental carcinogenesis and what is known about the molecular mechanisms underlying those changes are discussed. This is followed by an extended discussion of the potential roles for ALDH in tumorigenesis. The role of ALDH in the metabolism of cyclophosphamidelike chemotherapeutic agents is described. This work suggests that modulation of ALDH activity may an important determinant of the effectiveness of certain chemotherapeutic agents.(ABSTRACT TRUNCATED AT 400 WORDS)

Aldehyde Dehydrogenase↗
PubMed1991

Lateral geniculate neurons in behaving primates. II. Encoding of visual information in the temporal shape of the response.

1. We used the Karhunen-Loève (K-L) transform to quantify the temporal distribution of spikes in the responses of lateral geniculate (LGN) neurons. The basis functions of the K-L transform are a set of waveforms called principal components, which are extracted from the data set. The coefficients of the principal components are uncorrelated with each other and can be used to quantify individual responses. The shapes of each of the first three principal components were very similar across neurons. 2. The coefficient of the first principal component was highly correlated with the spike count, but the other coefficients were not. Thus the coefficient of the first principal component reflects the strength of the response, whereas the coefficients of the other principal components reflect aspects of the temporal distribution of spikes in the response that are uncorrelated with the strength of the response. Statistical analysis revealed that the coefficients of up to 10 principal components were driven by the stimuli. Therefore stimuli govern the temporal distribution as well as the number of spikes in the response. 3. Through the application of information theory, we were able to compare the amount of stimulus-related information carried by LGN neurons when two codes were assumed: first, a univariate code based on response strength alone; and second, a multivariate temporal code based on the coefficients of the first three principal components. We found that LGN neurons were able to transmit an average of 1.5 times as much information using the three-component temporal code as they could using the strength code. 4. The stimulus set we used allowed us to calculate the amount of information each neuron could transmit about stimulus luminance, pattern, and contrast. All neurons transmitted the greatest amount of information about stimulus luminance, but they also transmitted significant amounts of information about stimulus pattern. This pattern information was not a reflection of the luminance or contrast of the pixel centered on the receptive field. 5. In addition to measuring the average amount of information each neuron transmitted about all stimuli, we also measured the amount of information each neuron transmitted about the individual stimuli with both the univariate spike count code and the multivariate temporal code. We then compared the amount of information transmitted per stimulus with the magnitudes of the responses to the individual stimuli. We found that the magnitudes of both the univariate and the multivariate responses to individual stimuli were poorly correlated with the information transmitted about the individual stimuli.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1992

[Postural control in the elderly].

In order to investigate postural control in the elderly, a stabilometric investigation including fast Fourier Transform (FFT) analysis was conducted in three different age groups. The oldest group was composed of 16 subjects who ranged in age from 75 to 86 years: another group consisted of eight 65 to 74 year olds; the control group was composed of 21 young students. The subject was instructed to stand and look for 30 seconds at a spot in a CRT 50 cm ahead of his eyes, and to control body sway as indicated by the gravitational spot in the CRT. The subject was then told to stand with eyes closed for 30 seconds. Next, a 100 Hz vibratory stimulation was applied to the bilateral Achilles tendon in each trial. The data was filtered with a 10 Hz high cut filter and digitized at 25 Hz, and subsequently analyzed by a microcomputer (PC9801 VM 2). Thus, statistical analysis was performed in terms of area, length, and total frequency spectra from 0.10 Hz to 10.0 Hz in both lateral and antero-posterior directions. Sixteen power spectra of 0.249 Hz step from 0.10 to 3.96 Hz were demonstrated in the CRT and were also compared with those of the young group. When standing naturally, significant increases in body sway were found in terms of area, length, and total frequency spectra in the most elderly group as compared with the other two groups. There was no significant change in Romberg ratio between the elderly and the young groups. However, FFT analysis confirmed the influence of visual cues. When vibration was applied, no increases in body sway with regard to these parameters were demonstrated in the elderly, whereas significant increases were found in the young control group. This was especially evident in the eyes-closed trials, as previously reported. There were few increased frequency ranges in either lateral or antero-posterior sway in the elderly. This might suggest that proprioceptive afferent information play a less important role in elderly than in young subjects. When the subject was requested to minimize his own sway by utilizing visual feedback, no difference was found in this parameter between the elderly and young groups. However, FFT analysis of the elderly group revealed an increase of the power spectra close to 1.0 Hz in both lateral and antero-posterior sway, whereas increases of approximately 1.0 and 2.0 Hz in the power spectra and a decrease in the power spectrum from 0.10 to 0.29 Hz were found in both directions in young subjects.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed2006

Retinal nerve fiber layer analysis in the diagnosis of glaucoma.

PURPOSE OF REVIEW: The detection of optic disc and retinal nerve fiber layer damage and change is the cornerstone of glaucoma management. Assessment of the retinal nerve fiber layer for localized and diffuse damage has been traditionally based on clinical examination, with documentation of change primarily qualitative. With the latest improvements in optical imaging instruments, objective and quantitative measurements of the retinal nerve fiber layer are now possible. This review summarizes the results from recent cross-sectional studies evaluating the discriminating ability of automated retinal nerve fiber layer measurements to detect glaucoma, and from longitudinal studies assessing the ability to predict and monitor glaucomatous changes. RECENT FINDINGS: Numerous cross-sectional studies have documented good diagnostic accuracy of a scanning laser polarimeter (GDx VCC), the optical coherence tomograph (Stratus), and the Heidelberg Retina Tomograph retinal nerve fiber layer measurements for differentiating between healthy and glaucoma eyes. There are only limited data available on the ability of these retinal nerve fiber layer measurements to document change over time. SUMMARY: It is essential that the clinician understand the specific strengths and weaknesses of each technique so that only good quality retinal nerve fiber layer information will be used in conjunction with careful clinical examination and visual function testing for glaucoma management decisions. Longitudinal studies are needed to evaluate the ability of these instruments to document retinal nerve fiber layer change over time.

Diagnostic Imaging↗
PubMed2000

Gamma knife radiosurgery as a primary treatment for prolactinomas.

OBJECT: The purpose of this study was to estimate the efficacy of gamma knife radiosurgery (GKS) in controlling tumor growth and endocrinopathy associated with prolactinomas. METHODS: Between 1993 and 1997, 164 of 469 patients with pituitary adenomas treated by GKS harbored prolactinomas. The dose to the tumor margin ranged from 9 to 35 Gy (mean 31.2 Gy), and the visual pathways were exposed to a dose of less than 10 Gy. The mean tumor diameter was 13.4 mm. The mean follow-up time for 128 cases was 33.2 months (range 6-72 months). Tumor control was observed in all but two patients who underwent surgery 18 and 36 months, respectively, after GKS. Clinical cure was achieved in 67 cases. Clinical improvement was noted with a decrease in the hyperprolactinemia after GKS. Nonetheless, in 31 (29%) of 108 patients who were followed for more than 2 years no improvement in serum prolactin levels was demonstrated, although this could be normalized by bromocriptine administration after treatment. Nine infertile women became pregnant 2 to 13 months after GKS and all gave birth to normal children. There was no visual deterioration related to GKS. Five women experienced premature menopause. In these patients there was subtotal disappearance of the tumor and an empty sella developed. CONCLUSIONS: Gamma knife radiosurgery as a primary treatment for prolactinomas can be safe and effective both for controlling tumor growth and for normalization of prolactin hypersecretion. A higher margin dose (> or = 30 Gy) seemed to be associated with a better clinical outcome. Gamma knife radiosurgery may make prolactinomas more sensitive to the bromocriptine.

Humans↗
PubMed2002

Radiosurgery for residual or recurrent nonfunctioning pituitary adenoma.

OBJECT: Nonfunctioning pituitary adenomas comprise approximately 30% of all pituitary tumors. The purpose of this retrospective study is to evaluate the efficacy and role of gamma knife radiosurgery (GKS) in the management of residual or recurrent nonfunctioning pituitary adenomas. METHODS: A review was conducted of the data obtained in 42 patients who underwent adjuvant GKS at the University of Pittsburgh between 1987 and 2001. Prior treatments included transsphenoidal resection, craniotomy and resection, or conventional radiotherapy. Endocrinological, ophthalmological, and radiological responses were evaluated. The duration of follow-up review varied from 6 to 102 months (mean 31.2 months). Fifteen patients were observed for more than 40 months. The mean radiation dose to the tumor margin was 16 Gy. Conformal radiosurgery planning was used to restrict the dose to the optic nerve and chiasm. Tumor control after GKS was achieved in 100% of patients with microadenomas and 97% of patients with macroadenomas. Gamma knife radiosurgery was equally effective in controlling adenomas with cavernous sinus invasion and suprasellar extension. No patient developed a new endocrinological deficiency following GKS. One patient's tumor enlarged with an associated decline in visual function. Another patient experienced a deterioration of visual fields despite a decrease in tumor size. CONCLUSIONS: Gamma knife radiosurgery can achieve tumor control in virtually all residual or recurrent nonfunctioning pituitary adenomas. Dose sparing facilitates tumor management even when the adenoma is close to the optic apparatus or invades the cavernous sinus.

Adenoma↗