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Separate modifiability, mental modules, and the use of pure and composite measures to reveal them.

How can we divide a complex mental process into meaningful parts? In this paper, I explore an approach in which processes are divided into parts that are modular in the sense of being separately modifiable. Evidence for separate modifiability is provided by an instance of selective influence: two factors F and G (usually experimental manipulations) such that part A is influenced by F but invariant with respect to G, while part B is influenced by G but invariant with respect to F. Such evidence also indicates that the modules are functionally distinct. If we have pure measures MA and MB, each of which reflects only one of the parts, we need to show that MA is influenced by F but not G, while MB is influenced by G but not F. If we have only a composite measure MAB of the entire process, we usually also need to confirm a combination rule for how the parts contribute to MAB. I present a taxonomy of separate-modifiability methods, discuss their inferential logic, and describe several examples in each category. The three categories involve measures that are derived pure (based on different transformations of the same data; example: separation of sensory and decision processes by signal detection theory), direct pure (based on different data; example: selective effects of adaptation on spatial-frequency thresholds), and composite (examples: the multiplicative-factor method for the analysis of response rate; the additive-factor method for the analysis of reaction time). Six of the examples concern behavioral measures and functional processes, while four concern brain measures and neural processes. They have been chosen for their interest and importance; their diversity of measures, species, and combination rules; their illustration of different ways of thinking about data; the questions they suggest about possibilities and limitations of the separate-modifiability approach; and the case they make for the fruitfulness of searching for mental modules.

Humans↗

Modified transposition procedure of the vertical recti in sixth nerve palsy.

PURPOSE: To report a modified transposition procedure of the vertical recti for severely limited abduction of the globe caused by sixth nerve palsy and to compare this with the Hummelsheim transposition procedure. METHODS: Retrospective study of 13 eyes of 12 patients that had Hummelsheim transposition procedure and 19 eyes of 17 patients that had modified transposition procedure of the vertical recti for severely limited abduction of the globe caused by sixth nerve palsy. The modified transposition procedure joins lateral strips of the vertical recti and sutures this junction to the lateral rectus muscle. Functional results of the Hummelsheim procedure are compared with functional results of the modified transposition procedure. RESULTS: Abductive capacity improved by 4.19 +/- 1.67 mm in the Hummelsheim group and 4.08 +/- 1.7 mm in the modification. The angle of squint changed from +22.33 +/- 6.74 degrees to -0.20 +/- 2.61 degrees in the Hummelsheim group and from +25.54 +/- 5.66 degrees to +0.95 +/- 5.26 degrees in the modification group. The functional results as to abductive capacity and postoperative angle of squint showed no significant difference between the two methods (P >.05, t test). The modification was less time consuming. CONCLUSIONS: A modification of the transposition techniques of eye muscles in sixth nerve palsy is introduced. Its functional results are comparable to the classic technique of Hummelsheim. Operative risk and trauma are reduced, because the technique avoids scleral stitches and was found to be less time consuming than the Hummelsheim procedure.

Abducens Nerve Diseases↗

Total en bloc excision: a modified vitrectomy technique for proliferative diabetic retinopathy.

PURPOSE: To report a modified vitrectomy technique for proliferative diabetic retinopathy. DESIGN: Interventional case series. METHODS: In the modified vitrectomy technique for proliferative diabetic retinopathy, core vitrectomy is performed, followed by separation of the glial ring from the optic disk using a hook or forceps. The posterior hyaloid membrane, including proliferative tissues, is lifted and peeled from the posterior to the peripheral retina without creating a window in the posterior hyaloid membrane. At any strong vitreoretinal adhesion site, the posterior hyaloid is partially removed, followed by membrane delamination. RESULTS: In the 18 eyes that underwent the modified technique, iatrogenic retinal breaks occurred less often compared with the 48 eyes that underwent the conventional technique. The difference was not statistically significant (P =.14), but the surgical time was significantly reduced (P =.0003). The glial ring and proliferative tissue arising from the optic disk can be readily separated, and other adhesion sites can be satisfactorily peeled after separating the posterior hyaloid membrane around the optic disk. CONCLUSIONS: This modified vitrectomy technique for proliferative diabetic retinopathy may be an alternative surgical technique to the conventional technique.

Diabetic Retinopathy↗

Influence of native and hypochlorite-modified low-density lipoprotein on gene expression in human proximal tubular epithelium.

Inflammatory infiltrates can modify (lipo)proteins via hypochlorous acid/hypochlorite (HOCl/OCl(-)) an oxidant formed by the myeloperoxidase-H(2)O(2)-halide system. These oxidatively modified proteins emerge in tubuli in some proteinuric and interstitial diseases. Human proximal tubular cells (HK-2) were used to confirm the hypothesis of detrimental and differential impact of HOCl-modified low density lipoprotein (HOCl-LDL), an in vivo occurring lipoprotein modification exerting proatherogenic and proinflammatory capacity. HOCl-LDL showed dose-dependent antiproliferative effects in HK-2 cells. Small dedicated cDNA macroarrays were used to identify differentially regulated genes. A rapid increase in the expression of genes involved in reactive oxygen species metabolism and cell stress, eg, heme oxygenase-1, thioredoxin reductase, cytochrome b5 reductase, Gadd 153, amino acid transporter E16, and HSP70 was found after HOCl-LDL treatment of HK-2 cells. In parallel, genes involved in tissue remodeling and inflammation eg, CTGF, VCAM-1, IL-1beta, MMP7, and VEGF were up-regulated. Quantitative RT-PCR verified differential expression of a subset of these genes in microdissected tubulointerstitia from patients with acute tubular damage, progressive proteinuric renal disease, and membranous glomerulonephritis (with declining renal function), but not in stable patients with proteinuria caused by minimal change disease. The demonstration of selective up-regulation of a subgroup of genes if proteinuria is accompanied by the presence of HOCl-modified (lipo)proteins support the potential pathophysiological role of the myeloperoxidase-H(2)O(2)-halide system and HOCl-LDL in renal disease.

Adult↗

The modified Konno procedure for complex left ventricular outflow tract obstruction.

BACKGROUND: Complex left ventricular outflow tract (LVOT) obstruction with normal aortic valve function requires aggressive resection in the subaortic region and preservation of the aortic valve. The modified Konno procedure allows generous exposure of the LVOT from the left ventricular apex to the inter leaflet trigones of the aortic valve. Widespread use of this procedure has been limited by concern over injury to the aortic valve, the conduction system, and possibility of residual ventricular septal defect (VSD). METHODS: Retrospective analysis of pertinent data for all patients undergoing the modified Konno procedure (1994 to 2001) at the University of Iowa were reviewed. RESULTS: The modified Konno procedure was used in 18 patients (age 1 to 31) for LVOT obstruction associated with diffuse narrowing of the LVOT (n = 7), a discrete fibrous ring (n = 7), or a fibrous ring associated with abnormal mitral attachments (n = 4). Eight patients had previously undergone LVOT resection. There were no perioperative deaths. Estimated LVOT peak gradients by echocardiogram were 70.4 +/- 24.2 mm Hg (preoperative) and 19.2 +/- 20.4 mm Hg (postoperative) at most recent followup (p < 0.001 vs preop). Aortic insufficiency was moderate in one patient (present preop) and mild or less in all other patients. There were no cases of permanent heart block. Small residual VSDs were present in five patients (28%). Median follow-up is 3.1 years. CONCLUSIONS: The modified Konno procedure can effectively relieve complex LVOT obstruction and preserve aortic valve function. Extension of this procedure for use in the initial presentation of LVOT may be appropriate in cases at increased risk of recurrent LVOT obstruction.

Adolescent↗

Effects of cardiopulmonary bypass and use of modified ultrafiltration.

BACKGROUND: Hemodilution is a prominent problem in cardiopulmonary bypass in a pediatric population. Ultrafiltration is a method used to reduce fluid volume and tissue edema and to increase hematocrit without the need for blood products. Modified ultrafiltration may offer advantages in comparison with conventional ultrafiltration. METHODS: This article reviews the technique of modified ultrafiltration and its use, results, complications, and safety in pediatric cardiopulmonary bypass. RESULTS: Modified ultrafiltration in pediatric cardiopulmonary bypass reduces total body water and serum levels of inflammatory mediators. It results in an elevated hematocrit without the need for transfusion, improved pulmonary compliance in the immediate postbypass period, and probably improved cerebral metabolic recovery after deep hypothermic circulatory arrest. CONCLUSIONS: Modified ultrafiltration can be performed safely in neonatal patients after cardiopulmonary bypass and offers advantages in comparison with conventional ultrafiltration.

Adolescent↗

Fusion between Jurkat cell and PEO-lipid modified liposome.

Direct fusion between Jurkat cell and a liposome modified with poly(ethylene oxide)-bearing lipid (PEO-lipid) was examined using diphtheria toxin fragment A (DTA) as the probe. Only the DTA-loaded liposome modified with PEO-lipid(n = 32) (n is the number of ethylene oxide units) exerted significant cytotoxicity against Jurkat cells, while liposomes lacking either the PEO-lipid or DTA did not. Liposomes modified by the PEO-lipid with shorter PEO chain(n = 5 or 15) did not show any cytotoxicity, irrespective of their DTA-loading. The cytotoxicity was observed even in the presence of cytochalasin B, an inhibitor of endocytosis. Judging from these results, we concluded that the PEO-lipid(n = 32)-modified liposome directly fused with plasma membrane of Jurkat cell.

Cell Survival↗

GATE-16 and GABARAP are authentic modifiers mediated by Apg7 and Apg3.

GATE-16, GABARAP, and LC3 are three mammalian counterparts of yeast Apg8p/Aut7p. Here, we show that GATE-16 and GABARAP are authentic modifiers, as is the case of LC3 modification. The C-terminal Phe(117) of proGATE-16 and the C-terminal Leu(117) of proGABARAP are post-translationally cleaved to expose an essential Gly(116) within GATE-16 and GABARAP, with the products designated GATE-16-I and GABARAP-I, respectively. The Gly(116) within GATE-16 and GABARAP are essential for further formation of the intermediates between them and Apg7p(C572S) and Apg3p(C264S). When Apg7p and Apg3p are expressed, GATE-16-I and GABARAP-I are modified to a secondary ubiquitin-like modified form, GATE-16-II and GABARAP-II, respectively. GATE-16-I and GABARAP-I, but not LC3-I, localize to membrane compartments before their modification. These results indicate that GATE-16 and GABARAP are authentic modifiers, but that they have different biochemical characteristics from those of LC3.

Adaptor Proteins, Signal Transducing↗

Ester synthesis catalyzed by polyethylene glycol-modified lipase in benzene.

Lipoprotein lipase, which catalyzes hydrolysis of emulsified triglycerides or water-insoluble esters, was modified with 2,4-bis(o-methoxy-polyethylene glycol)-6-chloro-s-triazine(activated PEG2). The modified lipase, in which 55% of the total amino groups in the lipase molecule, was soluble in organic solvents such as benzene, toluene, chloroform and dioxane. The modified lipase could catalyze ester synthesis reaction in benzene. When very hydrophobic substrates of lauryl alcohol and stearic acid were used, the ester synthesis reaction proceeded efficiently in the transparent benzene solution with the maximum activity of approximate 5.0 mumoles/min/mg of protein. Ester exchange and aminolysis reactions were also conducted with the modified lipase in benzene.

Benzene↗

Recognition of DNA modified by antitumor cisplatin by "latent" and "active" protein p53.

Tumor suppressor protein p53 possesses two DNA-binding sites. One that is located within its core domain is responsible for sequence-specific DNA binding of the protein, non-specific binding to internal segments of single- or double-stranded DNA, and to certain kinds of non-B DNA structures. The other that is contained in the C-terminus of the protein binds to damaged DNA. Binding of active, latent, and in vitro-activated p53 protein to DNA fragments modified by antitumor cisplatin was studied using electrophoretic mobility shift assay in agarose gels and immunoblotting analysis. We found that both latent and active p53 forms bound to random sequences of DNA globally modified by cisplatin with a higher affinity than to unmodified DNA. Interestingly, the latent form exhibited a more pronounced selectivity for platinated DNA than the active p53. Consistently with this observation, the preference of the latent form for platinated DNA decreased as a consequence of the activation of latent p53 by phosphorylation at the protein kinase C site within its C-terminus or by binding of the monoclonal antibody Bp53-10.1. Competition experiments involving a 20-bp consensus sequence of p53 suggested that the p53 core domain was a primary binding site of the active p53 when it bound to DNA fragments lacking consensus sequence, but modified by cisplatin. In addition, the latent protein was found to selectively interact with DNA modified by cisplatin probably via its C-terminus.

Animals↗

Chronic ethanol consumption impairs receptor-mediated endocytosis of MAA-modified albumin by liver endothelial cells.

Alcoholic liver disease has been associated with abnormalities in receptor-mediated endocytosis (RME) which results in abnormal degradation of metabolically altered proteins. Model systems using formaldehyde-modified albumin (f-Alb) have shown an impairment in RME following chronic alcohol consumption utilizing both in situ perfused rat livers and isolated rat liver endothelial cells (LECs). The discovery that alcohol metabolite derived aldehydes can modify proteins prompted a study to determine if malondialdehyde-acetaldehyde-modified albumin (MAA-Alb) would be degraded similar to that reported for f-Alb, and whether ethanol-fed rats would demonstrate an impaired RME with respect to this ligand which occurs as a consequence of chronic ethanol consumption. MAA-Alb was degraded slightly more than f-Alb in both in situ perfused livers and at the single cell level. This degradation was completely inhibited with 100x unlabeled f-Alb, which suggests the use of a similar receptor. Following alcohol consumption there was a 50-60% decrease in MAA-Alb degradation in whole livers and isolated LECs. Utilizing isolated LECs it was determined that impairment in internalization was the most likely mechanism for the decrease in the amount of MAA-Alb that was degraded. These data show that chronic alcohol consumption by rats does in fact impair RME of alcohol metabolite-derived adducted proteins, and this impairment is due to a defect in the post-internalization step rather than the binding or degradation of the modified protein.

Acetaldehyde↗

Studies on the reactivity of acyl glucuronides--VIII. Generation of an antiserum for the detection of diflunisal-modified proteins in diflunisal-dosed rats.

Acyl glucuronide metabolites of carboxylic drugs such as the salicylate derivative diflunisal (DF) have been shown to react with proteins to produce covalent adducts. To aid in the study of the formation and distribution of these adducts in both humans and rats, we raised an antiserum against human serum albumin modified by covalent attachment of DF via an amide bond, using a carbodiimide reagent. This antiserum had wide reactivity, reacting with all types of DF-modified proteins tested and with free DF (albeit at a lower affinity). It did not cross-react with other salicylates or other non-steroidal anti-inflammatory drugs. The antiserum has been used in immunoblotting to detect proteins covalently modified by DF in the plasma and livers of rats treated with the drug for 7 days. Although some cross-reactivity was apparent on the blots, a series of DF-modified proteins was found in cytosolic, mitochondrial and mixed membrane fractions of hepatocytes, with molecular weights ranging from 28 to 130 kDa.

Animals↗

Modified retractor plication technique in lower lid entropion repair: a 4-year follow-up study.

BACKGROUND: Lower eyelid entropion is an eyelid malposition characterized by inward rotation of the eyelid margin associated with potentially significant discomfort and, occasionally, keratopathy. In this study we evaluated and compared the efficacy of two surgical techniques of retractor plication for involutional lower lid entropion repair. METHODS: Sixty-two consecutive patients (62 eyes) with involutional lower lid entropion were included. Of the 62, 34 underwent the Jones retractor plication technique, and 28 underwent a modification of this technique that simplifies the procedure. We evaluated horizontal lid laxity, medial canthal tendon laxity and lower lid excursion before and after surgery, and determined the rate of entropion recurrence in the two groups. All measures were obtained before and 1 month, 6 months, 1 year, 2 years, 3 years and 4 years after surgery. RESULTS: Preoperatively, there was no statistically significant difference between the two groups in any of the measures studied. Postoperatively, the mean amount of horizontal lid laxity was significantly less in the modified technique group than in the Jones technique group (6.86 mm [standard deviation (SD) 0.41 mm] vs. 7.30 mm [SD 0.64 mm]) (p < 0.05). Similarly, the mean amount of medial canthal tendon laxity in the resting position was significantly less in the modified technique group than in the Jones technique group (1.90 mm [SD 0.56 mm] vs. 1.25 mm [SD 0.43 mm]) (p < 0.05). The rate of entropion recurrence was significantly lower in the modified technique group (7.1%) than in the Jones technique group (14.7%) (p < 0.05). INTERPRETATION: The modified retractor plication technique showed encouraging results in terms of successful and long-lasting lower lid entropion repair.

Aged↗

Hypochlorite modified LDL are a stronger agonist for platelets than copper oxidized LDL.

Experimental low density lipoprotein (LDL) oxidation is usually performed using trace copper, although the in vivo relevance of this method has been called into question. Such LDL augment adenosine 5'-diphosphate (ADP) induced platelet aggregation, presumably by the action of lipid derived compounds. In striking contrast, we find that LDL oxidized to a comparable extent by hypochlorite, an in vivo occurring oxidant, reveal themselves to be potent promoters of platelet aggregation. Interestingly, hypochlorite modified LDL seem to mediate their influence on human platelets by means of the modified apolipoprotein B-100 (apoB) moiety. Also, the finding that hypochlorite modified albumin is able to trigger platelet aggregation suggests an essential role for hypochlorite modified protein(s) in the process of platelet activation.

Binding, Competitive↗

Modified low density lipoprotein delivers substrate for ceramide formation and stimulates the sphingomyelin-ceramide pathway in human macrophages.

Exposure of human blood monocytes derived macrophages to modified (oxidized or acetylated) LDL induced a approximately 40% elevation (60 pmol/10(6) cells) of the endogenous level of the sphingolipid ceramide. A rise of both neutral and acidic SMase activity was found after treatment with oxidized LDL (250 and 80%), while addition of acLDL stimulated only the neutral enzyme (280%). Sphingo(phospho)lipids from LDL were transferred to the cell membrane and distributed into intracellular compartments as observed with acLDL containing BODIPY-FL-C5-SM. Quantitation of ceramide after the addition of [3H-N-acetyl]- or BODIPY-FL-C5-SM-labeled modified LDL (27 microg/ml) to the cell culture medium indicated that approximately 210 pmol CA/10(6) cells was generated from exogenous (ox/acLDL) SM. These results demonstrate a stimulation of the sphingomyelin-ceramide pathway by modified LDL utilizing primarily exogenous (LDL-derived) substrate and suggest that the effects of modified LDL are at least partially due to an increased level of the messenger ceramide.

Boron Compounds↗

Temperature-dependent interaction of thermo-sensitive polymer-modified liposomes with CV1 cells.

Egg yolk phosphatidylcholine liposomes modified with a copolymer of N-acryloylpyrrolidine and N-isopropylacrylamide having a lower critical solution temperature at ca. 40 degrees C were prepared and an effect of temperature on their interaction with CV1 cells was investigated. The unmodified liposomes were taken up by the cells approximately to the same extent after 3 h incubation at 37 and 42 degrees C. In contrast, uptake of the polymer-modified liposomes by CV1 cells decreased slightly at 37 degrees C but increased greatly at 42 degrees C, compared to the unmodified liposomes. Proliferation of the cells was partly prohibited by the incubation with the unmodified liposomes encapsulating methotrexate at 37 and 42 degrees C. The treatment with the polymer-modified liposomes containing methotrexate at 37 degrees C hardly effected the cell growth. However, the treatment at 42 degrees C inhibited the cell growth completely. It is considered that the highly hydrated polymer chains attached to the liposome surface suppressed the liposome-cell interaction below the lower critical solution temperature of the polymer but the dehydrated polymer chains enhanced the interaction above this temperature. Because interaction of the polymer-modified liposomes with cells can be controlled by the ambient temperature, these liposomes may have potential usefulness as efficient site-specific drug delivery systems.

Acrylic Resins↗

A simple method for preparing modified TES and Tris yolk buffer that is optically clear and membrane filterable.

OBJECTIVES: To determine whether modified TES and Tris (TEST) yolk buffer (TYB) made using a commercially available egg yolk extract would exhibit lab performance characteristics equal to the existing preparation made with whole egg yolk and to define the phospholipid content of the new modified TYB formulation. DESIGN: Divided ejaculates from 21 normozoospermic and 7 oligozoospermic males presenting for pre-IVF evaluation were stored at 0 to 4 degrees C for 42 hours using commercially available or modified TYB before analysis in the optimized sperm penetration assay (SPA). SETTING: A commercial tissue culture manufacturer and a clinical fertility reference laboratory. MAIN OUTCOME MEASURES: Sperm swim-up recoveries and average penetrations per ovum, determined by the SPA, were used as measures of sperm function. High-pressure liquid chromatography (HPLC) was used to profile the egg yolk extract. RESULTS: No significant differences in either sperm swim-up recovery rates or SPA results were found in normal or poor quality semen that was treated with modified or commercial TYB. The major constituent in commercial egg yolk extract is lecithin. CONCLUSIONS: Commercially available egg yolk extract passes easily through a 0.2-microns filter, is a rich source of lecithin, and can be substituted effectively for whole egg yolk in preparing TYB.

Chromatography, High Pressure Liquid↗

Vulvar vestibulitis treated by modified vestibulectomy.

OBJECTIVE: A prospective study to evaluate the success of a modified vestibulectomy in treating vulvar vestibulitis. METHODS: Fifty seven consecutive women with vulvar vestibulitis and suitable for surgery based on the criteria: superficial dyspareunia, erythematous vestibular region, positive Q-tip test, symptoms reduced with local anesthetic cream. A modified vestibulectomy with or without a modified Fentons procedure was performed. Response was based on return to normal coitus, 3 months after surgery. RESULTS: Most women suffered from chronic conditions (median duration of symptoms = 18 months). The median age was 28 years (range 18-53). Any infections were treated prior to surgery. All but 4 (7%) had histological abnormalities, mainly non-specific inflammation. In 18% of women who had cervical cytology some abnormality was detected. Mean follow-up time was 12 months (range 2-42). Three women were not evaluable. Complete response to surgery was achieved in 33 (61.1%) of the women, partial response was achieved in 15 (27.8%). Six (11.1%) had persistent symptoms, four of whom has psychosexual problems. CONCLUSION: Presently, surgery remains the most successful intervention for vulvar vestibulitis. Modified surgery which is less destructive seems to afford acceptable results. The completion of randomized studies are needed to recognise the optimum surgical procedure.

Adult↗