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PubMed1992

Expression, activity, and cellular accumulation of methyl jasmonate-responsive lipoxygenase in soybean seedlings.

Exposure of soybean (Glycine max) seedlings to low levels of atmospheric methyl jasmonate induced the expression and accumulation of one or more lipoxygenase(s) in the primary leaves, hypocotyls, epicotyls, and cotyledons. In the primary leaf, the major site of lipoxygenase accumulation in response to methyl jasmonate was in the vacuoles of paraveinal mesophyll cells. In the other organs, however, most of the methyl jasmonate-responsive lipoxygenase(s) were associated with both the epidermal and cortical cells and were present in both vacuoles and plastids. In plastids, the methyl jasmonate-responsive lipoxygenase was sequestered into protein inclusion bodies; no lipoxygenase was evident in either the thylakoids or the stroma. Both spectrophotometric measurement of conjugated diene formation and thin layer chromatography of lipoxygenase product formation indicated that methyl jasmonate caused an increase in the amount of lipoxygenase activity. Electron microscopy of the methyl jasmonate-responsive lipoxygenase protein in the vacuoles showed that it was arranged into a stellate, paracrystalline structure in various cell types other than the paraveinal mesophyll cells. The paracrystals appeared to be composed of tubular elements of between 5 and 8 nm in diameter, were of variable length, and were observed in most cell types of the seedling organs.

Journal Article↗

PubMed2005

Benefits and challenges brought by improved results from in vitro fertilization.

Abstract In vitro fertilization (IVF), in which preimplantation-stage embryos are produced after ovarian stimulation and retrieval of preovulatory oocytes, now accounts for almost 2% of all births in Australia. For clinics performing in the top quartile of national results, the chance of a live birth for a woman under 35 years from one round of egg retrieval and IVF treatment is greater than 50%, albeit still with a greater than 20% risk of twins or higher order multiple pregnancy. Similar or better live birth rates are now obtainable with the elective transfer of a single embryo at the stage of blastocyst (5-6 days in culture), a policy that if adopted for younger women can reduce the risk of twins in a clinic to less than 15%. Current developments centre around improvements to embryo culture and the testing of embryos for chromosomal normality and other genetic and epigenetic variables before transfer, made possible by licences for embryo research protocols now being issued under the Commonwealth's Research Involving Human Embryos Act 2002.

Abortion, Spontaneous↗

PubMed2001

Distinct phenotypes distinguish the molecular classes of Angelman syndrome.

BACKGROUND: Angelman syndrome (AS) is a severe neurobehavioural disorder caused by defects in the maternally derived imprinted domain located on 15q11-q13. Most patients acquire AS by one of five mechanisms: (1) a large interstitial deletion of 15q11-q13; (2) paternal uniparental disomy (UPD) of chromosome 15; (3) an imprinting defect (ID); (4) a mutation in the E3 ubiquitin protein ligase gene (UBE3A); or (5) unidentified mechanism(s). All classical patients from these classes exhibit four cardinal features, including severe developmental delay and/or mental retardation, profound speech impairment, a movement and balance disorder, and AS specific behaviour typified by an easily excitable personality with an inappropriately happy affect. In addition, patients can display other characteristics, including microcephaly, hypopigmentation, and seizures. METHODS: We restricted the present study to 104 patients (93 families) with a classical AS phenotype. All of our patients were evaluated for 22 clinical variables including growth parameters, acquisition of motor skills, and history of seizures. In addition, molecular and cytogenetic analyses were used to assign a molecular class (I-V) to each patient for genotype-phenotype correlations. RESULTS: In our patient repository, 22% of our families had normal DNA methylation analyses along 15q11-q13. Of these, 44% of sporadic patients had mutations within UBE3A, the largest percentage found to date. Our data indicate that the five molecular classes can be divided into four phenotypic groups: deletions, UPD and ID patients, UBE3A mutation patients, and subjects with unknown aetiology. Deletion patients are the most severely affected, while UPD and ID patients are the least. Differences in body mass index, head circumference, and seizure activity are the most pronounced among the classes. CONCLUSIONS: Clinically, we were unable to distinguish between UPD and ID patients, suggesting that 15q11-q13 contains the only significant maternally expressed imprinted genes on chromosome 15.

Adult↗

PubMed2005

Gait dynamics in mouse models of Parkinson's disease and Huntington's disease.

BACKGROUND: Gait is impaired in patients with Parkinson's disease (PD) and Huntington's disease (HD), but gait dynamics in mouse models of PD and HD have not been described. Here we quantified temporal and spatial indices of gait dynamics in a mouse model of PD and a mouse model of HD. METHODS: Gait indices were obtained in C57BL/6J mice treated with the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 30 mg/kg/day for 3 days) for PD, the mitochondrial toxin 3-nitropropionic acid (3NP, 75 mg/kg cumulative dose) for HD, or saline. We applied ventral plane videography to generate digital paw prints from which indices of gait and gait variability were determined. Mice walked on a transparent treadmill belt at a speed of 34 cm/s after treatments. RESULTS: Stride length was significantly shorter in MPTP-treated mice (6.6 +/- 0.1 cm vs. 7.1 +/- 0.1 cm, P < 0.05) and stride frequency was significantly increased (5.4 +/- 0.1 Hz vs. 5.0 +/- 0.1 Hz, P < 0.05) after 3 administrations of MPTP, compared to saline-treated mice. The inability of some mice treated with 3NP to exhibit coordinated gait was due to hind limb failure while forelimb gait dynamics remained intact. Stride-to-stride variability was significantly increased in MPTP-treated and 3NP-treated mice compared to saline-treated mice. To determine if gait disturbances due to MPTP and 3NP, drugs affecting the basal ganglia, were comparable to gait disturbances associated with motor neuron diseases, we also studied gait dynamics in a mouse model of amyotrophic lateral sclerosis (ALS). Gait variability was not increased in the SOD1 G93A transgenic model of ALS compared to wild-type control mice. CONCLUSION: The distinct characteristics of gait and gait variability in the MPTP model of Parkinson's disease and the 3NP model of Huntington's disease may reflect impairment of specific neural pathways involved.

Journal Article↗

PubMed1997

Two complementary bioassays for screening the estrogenic potency of xenobiotics: recombinant yeast for trout estrogen receptor and trout hepatocyte cultures.

A relation between the chemical structure of a xenobiotic and its steroidal action has not yet been clearly established. Thus, it is not possible to define the estrogenic potency of different xenobiotics. An assessment may be accomplished by the use of different bioassays. We have previously developed a yeast system highly and stably expressing rainbow trout estrogen receptor (rtER) in order to analyze the biological activity of the receptor. The recombinant yeast system appears to be a reliable, rapid and sensitive bioassay for the screening and determination of the direct interaction between ER and estrogenic compounds. This system was used in parallel with a more elaborate biological system, trout hepatocyte aggregate cultures, to examine the estrogenic potency of a wide spectrum of chemicals commonly found in the environment. In hepatocyte cultures, the vitellogenin gene whose expression is principally dependent upon estradiol was used as a biomarker. Moreover, competitive binding assays were performed to determine direct interaction between rtER and xenobiotics. In our study, 50% of the 49 chemical compounds tested exhibited estrogenic activity in the two bioassays: the herbicide diclofop-methyl; the fungicides biphenyl, dodemorph, and triadimefon; the insecticides lindane, methyl parathion, chlordecone, dieldrin, and endosulfan; polychlorinated biphenyl mixtures; the plasticizers or detergents alkylphenols and phthalates; and phytoestrogens. To investigate further biphenyl estrogenic activity, its principal metabolites were also tested in both bioassays. Among these estrogenic compounds, 70% were able to activate rtER in yeast and hepatocytes with variable induction levels according to the system. Nevertheless, 30% of these estrogenic compounds exhibited estrogenic activity in only one of the bioassays, suggesting the implication of metabolites or different pathways in the activation of gene transcription. This paper shows that it is important to combine in vivo bioassays with in vitro approaches to elucidate the mechanism of xenoestrogen actions.

Animals↗

PubMed1997

Role of nitric oxide in acute renal failure.

Nitric oxide synthase has been identified in several epithelial cells in the kidney, including proximal tubular cells, thick ascending limb, inner medullary collecting duct, and interstitial cells. Nitric oxide (NO) plays an important role in renal hemodynamics and sodium tubular transport. We have demonstrated that NO participates in hypoxia/reoxygenation (H/R) injury in isolated rat proximal tubules (PT) suspensions. In this in vitro model L-arginine addition enhanced H/R injury while L-NAME almost completely prevented injury. These effects were less intense in chronic supplemented rats with L-arginine and L-NAME, suggesting that NO synthase manipulation had interfered with PT susceptibility to H/R injury. In contrast, L-arginine protected IMCD cells in culture from hypercholesterolemic rats against hypoxia. Moreover, acute infusion of L-arginine before bilateral renal artery clamping was protective while L-arginine chronic administration and L-NAME were deleterious in this ARF model. The L-arginine protection was not observed in unilateral renal clamping plus contralateral nephrectomy in normal rats, but L-arginine was protective in hypercholesterolemic rats. Taken together, these results suggest that the net effect of NO stimulation is variable, and that it is the result of a balance between beneficial hemodynamic effects and cytotoxicity.

Acute Kidney Injury↗

PubMed1994

Clonal composition of human adrenocortical neoplasms.

The mechanisms of tumorigenesis of adrenocortical neoplasms are still not understood. Tumor formation may be the result of spontaneous transformation of adrenocortical cells by somatic mutations. Another factor stimulating adrenocortical cell growth and potentially associated with formation of adrenal adenomas and, less frequently, carcinomas is the chronic elevation of proopiomelanocortin-derived peptides in diseases like ACTH-dependent Cushing's syndrome and congenital adrenal hyperplasia. To further investigate the pathogenesis of adrenocortical neoplasms, we studied the clonal composition of such tumors using X-chromosome inactivation analysis of the highly polymorphic region Xcen-Xp11.4 with the hybridization probe M27 beta, which maps to a variable number of tandem repeats on the X-chromosome. In addition, polymerase chain reaction amplification of a phosphoglycerokinase gene polymorphism was performed. After DNA extraction from tumorous adrenal tissue and normal leukocytes in parallel, the active X-chromosome of each sample was digested with the methylation-sensitive restriction enzyme HpaII. A second digestion with an appropriate restriction enzyme revealed the polymorphism of the region Xcen-Xp11.4 and the phosphoglycerokinase locus. Whereas in normal polyclonal tissue both the paternal and maternal alleles are detected, a monoclonal tumor shows only one of the parental alleles. A total of 21 female patients with adrenal lesions were analyzed; 17 turned out to be heterozygous for at least one of the loci. Our results were as follows: diffuse (n = 4) and nodular (n = 1) adrenal hyperplasia in patients with ACTH-dependent Cushing's syndrome, polyclonal pattern; adrenocortical adenomas (n = 8), monoclonal (n = 7), as well as polyclonal (n = 1); adrenal carcinomas (n = 3), monoclonal pattern. One metastasis of an adrenocortical carcinoma showed a pattern most likely due to tumor-associated loss of methylation. In the special case of a patient with bilateral ACTH-independent macronodular hyperplasia, diffuse hyperplastic areas and a small nodule showed a polyclonal pattern, whereas a large nodule was monoclonal. We conclude that most adrenal adenomas and carcinomas are monoclonal, whereas diffuse and nodular adrenal hyperplasias are polyclonal. The clonal composition of ACTH-independent massive macronodular hyperplasia seems to be heterogeneous, consisting of polyclonal and monoclonal areas.

Adenoma↗

PubMed1996

Human thyroid epithelial cells cultured in monolayers. II. Influence of serum on thyroglobulin and cAMP production.

An in vitro system of secondary cultures of human thyroid follicular epithelial cells in monolayer is described. The 72-h influence of serum and six supplements (thyrotropin, insulin, somatostatin, transferrin, hydrocortisone, glycyl-histidyl-lysine acetate) on growth and function in presence of 3-isobutyl-L-methyl-xanthine (IBMX) was investigated. The function of the cells was evaluated by production of the second messenger adenylate cyclase (cAMP) and the end product thyroglobulin (Tg). Growth was measured as the 3H-thymidine uptake of the cells. Three days of TSH-depletion preceeded the experiments. In presence of IBMX TSH stimulated cAMP production, while stimulation of Tg was only present in some cultures. In absence of IBMX TSH always stimulated the Tg production. The stimulation was independent of the presence of the other five investigated nutritional factors in physiological concentrations. TSH in concentrations from 0.1-10 U/1 stimulated the 72ih 3H-thymidine uptake of the cells. The TSH-stimulated production of Tg and cAMP decreased significantly with increasing concentrations of fetal calf serum (0-10%), (tau = 0.49, P < 0.001, n = 6-29 and tau = 0.75, P < 0.001, n = 6-29, respectively). Thus, serum as a complex, variable and not fully characterized mixture of hormones and growth factors was crucial to the attachment of the cells to the substrate, but inhibited differentiated functions of the human thyroid cells.

1-Methyl-3-isobutylxanthine↗

PubMed2001

Role of DNA minor groove interactions in substrate recognition by the M.SinI and M.EcoRII DNA (cytosine-5) methyltransferases.

The SinI and EcoRII DNA methyltransferases recognize sequences (GG(A)/(T)CC and CC(A)/(T)GG, respectively), which are characterized by an (A)/(T) ambiguity. Recognition of the A.T and T.A base pair was studied by in vitro methyltransferase assays using oligonucleotide substrates containing a hypoxanthine.C base pair in the central position of the recognition sequence. Both enzymes methylated the substituted oligonucleotide with an efficiency that was comparable to methylation of the canonical substrate. These observations indicate that M.SinI and M.EcoRII discriminate between their canonical recognition site and the site containing a G.C or a C.G base pair in the center of the recognition sequence (GG(G)/(C)CC and CC(G)/(C)GG, respectively) by interaction(s) in the DNA minor groove. M.SinI mutants displaying a decreased capacity to discriminate between the GG(A)/(T)CC and GG(G)/(C)CC sequences were isolated by random mutagenesis and selection for the relaxed specificity phenotype. These mutations led to amino acid substitutions outside the variable region, previously thought to be the sole determinant of sequence specificity. These observations indicate that (A)/(T) versus (G)/(C) discrimination is mediated by interactions between the large domain of the methyltransferase and the minor groove surface of the DNA.

Amino Acid Sequence↗

PubMed2000

Deoxycorticosterone suppresses the effects of losartan in nitric oxide-deficient hypertensive rats.

Chronic inhibition of the renin angiotensin system prevents increased BP and renal injury in N(G)-nitro-L-arginine methyl ester (L-NAME) hypertension. However, a relationship between plasma renin activity and the protective effect of chronic angiotensin II (Ang II) blockade has not been established. With this background, this study was undertaken to evaluate how the chronic administration of deoxycortisone acetate (DOCA) modifies the effects of losartan on BP, renal injury, and other variables in L-NAME hypertensive rats. The following groups were used: Control, DOCA, L-NAME, L-NAME + losartan, L-NAME + DOCA, and L-NAME + DOCA + losartan. Tail systolic BP was measured twice a week. After 4-wk evolution, mean arterial pressure and metabolic, morphologic, and renal variables were measured. The final mean arterial pressure values were 116 +/- 6 mmHg for control, 107 +/- 2 mmHg for DOCA, 151 +/- 5 mmHg for L-NAME, 123 +/- 2 mmHg for L-NAME + losartan, 170 +/- 3 mmHg for L-NAME + DOCA, and 171 +/- 5.5 mmHg for L-NAME + DOCA + losartan. Losartan prevented microalbuminuria, hyaline arteriopathy, and glomerulosclerosis of L-NAME hypertension but was ineffective in L-NAME + DOCA-treated rats. Plasma protein was significantly reduced in the L-NAME + DOCA group when compared with control and L-NAME groups, whereas no significant differences were observed in the other groups. Plasma renin activity was suppressed in the DOCA (0.55 +/- 0.2) and L-NAME + DOCA (0.60 +/- 10.2) groups but unsuppressed in the L-NAME + DOCA + losartan group (5.8 +/- 1). The conclusion is that DOCA blocks the preventive effect of losartan on the increased BP and renal injury of L-NAME hypertension, which suggests that DOCA transforms L-NAME hypertension into an Ang II-independent model of hypertension. These data also suggest that losartan prevents L-NAME hypertension by blocking the activity of systemic Ang II.

Albuminuria↗

PubMed2002

[EFfect of quinazolone-alkyl-carboxylic acid derivatives on the transmembrane Ca2+ ion flux mediated by AMPA receptors].

The excitatory neurotransmitter, Glu, plays a crucial role in many sensory and motor functions as well as in brain development, learning and memory and it is also involved in the pathogenesis of a number of neurological disorders, including epilepsy, Alzheimer's and Parkinson's diseases. Therefore, the study of Glu receptors (GluRs) is of therapeutical importance. We showed here by fluorescence monitoring of transmembrane Ca2+ ion fluxes in response to (S)-alpha-amino-3-hidroxi-5-metil-4-izoxazol propionic acid ((S)-AMPA) on the time scale of 0.00004-10 s that Ca2+ ion influx proceeds through faster and slower desensitizing receptors. Pharmacological isolation of the slower and faster desensitizing AMPA receptor was possible by fluorescence monitoring of Ca2+ ion translocation in response to (S)-AMPA in the presence and absence of various 2-methyl-4-oxo-3H-quinazoline-3-alkyl-carboxilic acid derivatives (Qxs): the acetic acid Q1 inhibits the slower desensitizing receptor response specifically, while the acetyl-piperidine Q5 is a more potent inhibitor of the faster desensitizing receptor response. In addition, spontaneous interictal activity, as induced by high [K+] conditions in hippocampal slices, was reduced significantly by Q5, suggesting a possible anticonvulsant property of Q5. Substitutions of Qxs into the GluR2 S1S2 binding core were consistent with their effect by causing variable degree of S1S2 bridging interaction as one of the main determinants of AMPA receptor agonist activity. The exploitation of differences between similar receptors will be important in the development and use of drugs with high pharmacological specificity.

Alkylation↗

PubMed1996

Variable expression of p16 protein in patients with acute myeloid leukemia without gross rearrangements at the DNA level.

The p16 protein is an inhibitor of cyclin-dependent kinases (cdk) 4 and 6. Both cdk4 and cdk6 phosphorylate the retinoblastoma protein (pRb) and are thought to be required for cell proliferation. Mutations and homozygous deletions in the p16 gene have been found in a number of cell lines but the incidence of abnormalities in primary tumours is controversial. We have studied the p16 gene in 76 cases of acute myeloid leukemia (AML) and 18 hematologically normal controls by quantitative Southern blotting. No deletions or rearrangements were detected. Twenty-five cases also showed no abnormal band patterns by RT-PCR-SSCP analysis of the coding sequence. We analyzed 60 AML samples for p16 protein expression by Western blot analysis. A reduced level of p16 was observed in six cases, however, none of them showed methylation of the 5'-CpG island. Over-expression of p16 protein was detected in six cases. Studies in cell lines have suggested a feedback loop between p16 and pRb with a futile overproduction of p16 protein in cells containing abnormal pRb. In accordance with these findings, four of the AML cases with high levels of p16 had abnormal pRb (two alteration in band size, two absent). From our data we suggest that gross abnormalities in the p16 gene are rare in AML, but that p16 levels are variable and high levels are associated with pRb abnormalities in a subset of cases.

Acute Disease↗

PubMed2003

The role of nitric oxide on fetal cardiovascular control during normoxia and acute hypoxia in 0.75 gestation sheep.

OBJECTIVE: The role of nitric oxide in control of fetal cardiovascular functions and of cerebral blood flow during normoxia and acute hypoxia is only partially known. We studied the effects of nitric oxide synthase inhibition on the distribution of cardiac output in preterm sheep using N(omega)-nitro-L-arginine methyl ester (L-NAME). METHODS: Thirteen fetal sheep were instrumented at a gestational age of 107 days. Three days later fetuses received L-NAME (n = 7) or vehicle infusion (n = 6). At 0 minutes, acute hypoxia was induced by occlusion of the maternal aorta for 2 minutes. Organ blood flows (microsphere method) and physiologic variables (fetal heart rate, mean arterial pressure [MAP], oxygen saturation, and pH) were measured at -75, -1, +2, +4, and +30 minutes. RESULTS: L-NAME caused bradycardia and an increase in MAP. A significant decrease in cardiac output by 32% occurred in the control group during the control period, which was consequently reflected in organ blood flows. L-NAME injection reduced cardiac output by 64% during normoxia. Blood flow to the fetal body, placenta, and cerebrum decreased by 62%, 66%, and 55%, respectively. During acute hypoxia, L-NAME did not change the redistribution of cardiac output toward the central organs. In the L-NAME group MAP increased, and fetal heart rate was maintained; in contrast, in controls MAP initially decreased and then returned to control values while fetal heart rate decreased. After hypoxia L-NAME delayed the recovery of cardiac output and blunted the increase in blood flow to the brain and heart. CONCLUSIONS: Although influenced by fetal stress after extensive instrumentation, the results of this study indicate that nitric oxide plays a role in fetal cardiovascular control during normoxia and acute hypoxia. Nitric oxide also mediates the increase in blood flow to the brain and heart immediately after hypoxia.

Animals↗

PubMed1984

Regulation of Na+,K+-ATPase activity in MDCK kidney epithelial cell cultures: role of growth state, cyclic AMP, and chemical inducers of dome formation and differentiation.

Na+,K+-ATPase activity was monitored in MDCK kidney epithelial cell monolayers and in cell extracts as a function of cell density, cAMP elevation, and exposure to hexamethylene bisacetamide (HMBA) and dimethylsulfoxide (Me2SO). Ouabain-sensitive Na+,K+-ATPase and 86Rb+ uptake activities, and the number of [3H]-ouabain binding sites were maximal in subconfluent cultures and decreased accompanying the development of a confluent monolayer. A sodium pump density of 8 X 10(7) pumps/cell was estimated for subconfluent cultures, declining to 9 X 10(5) pumps/cell at confluence. Previous studies have shown that dibutyryl cyclic AMP (Bt2cAMP), 1-methyl-3-isobutylxanthine (IBMX), or the differentiation inducers HMBA and Me2SO, which also caused cAMP elevation, all stimulated dome formation, a visible manifestation of active transepithelial Na+ and water transport (Lever, 1979). In the present study, all of these inducers were found to elevate intracellular Na+ content, implicating this variable in control of induction of dome formation. Operationally, inducers could be divided into two classes. HMBA and Me2SO partially inhibited ouabain-sensitive 86Rb+ influx. Ouabain, at a concentration that caused partial sodium pump inhibition and increased intracellular Na+ content, was also effective as an inducer. The second class, exemplified by IBMX and Bt2cAMP caused a furosemide-sensitive increase in intracellular Na+ content. This class of inducers stimulated ouabain-sensitive 86Rb+ uptake, presumably by substrate effects due to increased Na+ levels. The Na+ or ATP activation of Na+,K+-ATPase activity assayed in cell-free extracts, the affinity of the transport system for Rb+ in intact cells and intracellular ATP levels were unchanged by inducer treatment. Elevation of intracellular Na+ concentration, either by cAMP-stimulated, furosemide-sensitive mechanisms or by partial inhibition of the sodium pump may stimulate the induction of dome formation in MDCK cells.

Acetamides↗

PubMed1996

The burst-like firing of spinal neurons in rats with peripheral inflammation is reduced by an antagonist of N-methyl-D-aspartate.

Ankle inflammation was induced in rats by subcutaneous injection of complete Freund's adjuvant and the firing properties of spinal neurons receiving afferent input from the inflamed areas were studied four to six days later. Comparable neurons in normal rats were also studied. In normal animals the response of neurons to ankle compression consisted of a brief burst of action potentials followed by sustained firing during stimulus application. On cessation of the stimulus there was no prolonged afterdischarge. In rats with an inflamed ankle, compression of the ankle produced firing while the stimulus was applied, but with 17 of 22 neurons there was a prolonged (219 +/- 55 s) post-stimulus afterdischarge. All neurons studied in rats with peripheral inflammation fired with intermittent bursts of action potentials, particularly during the afterdischarge and spontaneous firing. The N-methyl-D-aspartate receptor antagonist DL-2-amino-5-phosphonopentanoate was ejected microiontophoretically near the cells studied. The major effect was a near abolition of bursts present in spontaneous firing and post-stimulus afterdischarges with a lesser reduction in firing during stimulus application. Effects on afterdischarge duration were variable. Since firing in bursts is known to increase transmitter release at some sites in the brain, it is proposed that when the relevant spinal neurons fire in bursts, additional intraspinal pathways are recruited and this contributes to the expanded receptive fields of neurons and possibly to the enhanced pain experienced by manipulation of inflamed peripheral tissues.

2-Amino-5-phosphonovalerate↗

PubMed2003

Development of a repeatedly adjustable intraocular lens.

PURPOSE: To provide a variable-focus intraocular lens (IOL) that is able to adjust repeatedly and reversibly. SETTING: University of Missouri-Rolla, Rolla, and Eggleston Adjustable Lens, St. Louis, Missouri, USA. METHODS: An adjustable IOL based on a mechanically adjustable design has been developed. Prototypes were fabricated from traditional Perspex CQ poly(methyl methacrylate) (PMMA) provided off the shelf by a current IOL manufacturer. The prototypes have undergone proof-of-concept testing per the requirements of National Institutes of Health grant 1 R41 EY13482-01, with specific attention to the feasibility and safety of continuing development of the lens with in vivo trials. The experimental results presented focus on operational force measurements. RESULTS: Prototype lenses were produced consistently. Operational force measurements indicated that use of the mechanical adjustment mechanism is viable for an adjustable IOL and provides repeated adjustments over time. Turning forces exhibited by the prototypes were low enough to suggest that operation of this adjustable IOL will not damage the capsular bag or ciliary body of the eye, a potential concern in using this design. Biocompatibility and optical quality of the prototype lenses are ensured by use of traditional Perspex CQ PMMA. CONCLUSIONS: The mechanically adjustable IOL provides a feasible and promising means of confronting postoperative refractive errors and the changing desires of patients. The viability of this IOL design has been proven, and results suggest that operation of the lens is safe enough to pursue in vivo trials. Evaluation of the biocompatibility of the lens architecture as well as the ultimate goal of noninvasive adjustment using this model are reported in a companion article.

Biocompatible Materials↗

PubMed1996

Genetic algorithm-based method for selecting wavelengths and model size for use with partial least-squares regression: application to near-infrared spectroscopy.

Genetic algorithms (GAs) are used to implement an automated wavelength selection procedure for use in building multivariate calibration models based on partial least-squares regression. The method also allows the number of latent variables used in constructing the calibration models to be optimized along with the selection of the wavelengths. The data used to test this methodology are derived from the determination of aqueous organic species by near-infrared spectroscopy. The three data sets employed focus on the determination of (1) methyl isobutyl ketone in water over the range of 1-160 ppm, (2) physiological levels of glucose in a phosphate buffer matrix containing bovine serum albumin and triacetin, and (3) glucose in a human serum matrix. These data sets feature analyte signals near the limit of detection and the presence of significant spectral interferences. Studies are performed to characterize the signal and noise characteristics of the spectral data, and optimal configurations for the GA are found for each data set through experimental design techniques. Despite the complexity of the spectral data, the GA procedure is found to perform well, leading to calibration models that significantly outperform those based on full spectrum analyses. In addition, a significant reduction in the number of spectral points required to build the models is realized.

Algorithms↗

PubMed2000

Palladium-catalyzed N-arylation of sulfoximines with aryl bromides and aryl iodides

Various N-arylated sulfoximines have been synthesized in high yield by a direct approach which is based on a palladium-catalyzed cross-coupling strategy. Aryl bromides of variable substitution pattern were found to be the most effective coupling partners, whereas aryl iodides showed a nonpredictable behavior requiring lithium or silver salts as additives to ensure product formation in acceptable yields. Coupling of (S)-2-(2'-bromophenyl)-4-tert-butyloxazoline with enantiomerically pure (-)-(RS)-S-methyl-S-phenylsulfoximine afforded the corresponding product in good yield as a single diastereomer, showing that the palladium-catalyzed arylation proceeds in a stereospecific manner. The reaction with dibromobenzenes yielded the monosulfonimidoyl arenes in all cases, suggesting that the introduction of the sulfonimidoyl moiety deactivates the arene, thus preventing a second coupling step.

Journal Article↗