Do infants have the horizontal bias?

A robust set of studies show that adults make more horizontal than vertical and oblique saccades, while scanning real-world scenes. In this paper we study the horizontal bias in infants. The directions of eye movements were calculated for 41 infants (M=8.40 months, SD=3.74, range=3.48-15.47) and 47 adults (M=21.74 years, SD=4.54, range=17.89-39.84) while viewing 28 real-world scenes. Saccade directions were binned to study the proportion of saccades in the horizontal, vertical and oblique directions. In addition, saccade directions were also modeled using a mixture of Von Mises distributions, to account for the relatively large amount of variance in infants data. Horizontal bias was replicated in adults and also found in infants, using both the binning and Von Mises approach. Moreover, a developmental pattern was observed in which older infants are more precise in targeting their saccades than younger infants. That infants have a horizontal bias is important in understanding infants' eye movements. Future studies should account for the horizontal bias in their designs and analyses.

Hepatic arterial spin labelling MRI: an initial evaluation in mice.

The development of strategies to combat hepatic disease and augment tissue regeneration has created a need for methods to assess regional liver function. Liver perfusion imaging has the potential to fulfil this need, across a range of hepatic diseases, alongside the assessment of therapeutic response. In this study, the feasibility of hepatic arterial spin labelling (HASL) was assessed for the first time in mice at 9.4 T, its variability and repeatability were evaluated, and it was applied to a model of colorectal liver metastasis. Data were acquired using flow-sensitive alternating inversion recovery-arterial spin labelling (FAIR-ASL) with a Look-Locker readout, and analysed using retrospective respiratory gating and a T1 -based quantification. This study shows that preclinical HASL is feasible and exhibits good repeatability and reproducibility. Mean estimated liver perfusion was 2.2 ± 0.8 mL/g/min (mean ± standard error, n = 10), which agrees well with previous measurements using invasive approaches. Estimates of the variation gave a within-session coefficient of variation (CVWS) of 7%, a between-session coefficient of variation (CVBS) of 9% and a between-animal coefficient of variation (CVA) of 15%. The within-session Bland-Altman repeatability coefficient (RCWS) was 18% and the between-session repeatability coefficient (RCBS) was 29%. Finally, the HASL method was applied to a mouse model of liver metastasis, in which significantly lower mean perfusion (1.1 ± 0.5 mL/g/min, n = 6) was measured within the tumours, as seen by fluorescence histology. These data indicate that precise and accurate liver perfusion estimates can be achieved using ASL techniques, and provide a platform for future studies investigating hepatic perfusion in mouse models of disease.

Atypical gaze following in autism: a comparison of three potential mechanisms.

In order to evaluate the following potential mechanisms underlying atypical gaze following in autism, impaired reflexive gaze following, difficulty integrating gaze and affect, or reduced understanding of the referential significance of gaze, we administered three paradigms to young children with autism (N = 21) and chronological (N = 21) and nonverbal mental age (N = 21) matched controls. Children with autism exhibited impaired reflexive gaze following. The absence of evidence of integration of gaze and affect, regardless of diagnosis, indicates ineffective measurement of this construct. Reduced gaze following was apparent among children with autism during eye-tracking and in-person assessments. Word learning from gaze cues was better explained by developmental level than autism. Thus, gaze following may traverse an atypical, rather than just delayed, trajectory in autism.

Association between vitamin D and diabetic neuropathy in a nationally representative sample: results from 2001-2004 NHANES.

AIMS: To evaluate the association between vitamin D insufficiency and peripheral neuropathy in a nationally representative sample of adults with diagnosed diabetes. METHODS: Vitamin D concentrations, medical examination variables and questionnaire results from the 2001-2004 National Health and Nutrition Examination Survey were analysed for adults ≥ 40 years old with diagnosed diabetes (unweighted n = 591, weighted n = 8.82 million). Neuropathy was defined as self report of peripheral neuropathy symptoms of painful sensation, tingling, numbness or loss of feeling in hands or feet. Additionally, Semmes-Weinstein monofilament test results were used as an indicator of neuropathy. Insufficient vitamin D was characterized as < 30 ng/ml. RESULTS: In the weighted population, 81% of adults with diabetes had vitamin D insufficiency. Vitamin D insufficiency was more common among Hispanics (92%) and non-Hispanic black people (98%) than among non-Hispanic white people (76%). Within the 3 months preceding the questionnaire, 50% reported experiencing pain or numbness (paresthesia) in their hands or feet; 37% reported pain or tingling in hands or feet; and 38% reported numbness or loss of feeling in hands or feet. Eight per cent had 4-6 insensate areas on their feet as determined by the Semmes-Weinstein monofilament test. Logistic regressions demonstrate vitamin D insufficiency is associated with the adjusted composite paresthesia measure (odds ratio 2.12; 95% CI 1.17-3.85) and the adjusted numbness measure (odds ratio 2.04; 95% CI 1.18-3.52). CONCLUSIONS: Vitamin D insufficiency is associated with self-reported peripheral neuropathy symptoms even after adjusting for demographic factors, obesity, co-morbidities, use of medications for neuropathy and diabetes duration and control.

Bifunctional DNA alkylator 1,3-bis(2-chloroethyl)-1-nitrosourea activates the ATR-Chk1 pathway independently of the mismatch repair pathway.

The presence of DNA damage initiates signaling through the ataxia-telangiectasia mutated kinase (ATM) and the ATM- and the Rad3-related kinase (ATR), which phosphorylate, thus activating, the checkpoint kinases (Chk) 1 and 2, which leads to cell cycle arrest. The bifunctional DNA alkylator 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) is cytotoxic primarily by inducing DNA monoadducts and ultimately, interstrand cross-links, which block DNA replication. In this study, we investigated the activation of the ATR-Chk1 pathway in response to BCNU treatment and the dependence of this response on the DNA mismatch repair (MMR) capacity. Medulloblastoma cells were exposed to low and moderate doses of BCNU, and the effects on this DNA damage signaling pathway were examined. In response to BCNU, Chk1 was found to be phosphorylated at serine 345 and exhibited increased kinase activity. Caffeine and wortmannin, which are broad-spectrum inhibitors of ATM and ATR, reduced this phosphorylation. Cell cycle analysis further revealed an accumulation of cells in the S phase in response to BCNU, an effect that was attenuated by caffeine. Small interfering RNA knockdown of ATR also reduced Chk1 phosphorylation after exposure to BCNU. However, knockdown of ATM had no effect on the observed Chk1 phosphorylation, suggesting that ATR was primarily responsible for Chk1 activation. Analysis of Chk1 activation in cells deficient in MMR proteins MutLalpha or MutSalpha indicated that the DNA damage response induced by BCNU was independent of the MMR apparatus. This MMR-independent activation seems to be the result of DNA interstrand cross-link formation.

The gene expression profiles of medulloblastoma cell lines resistant to preactivated cyclophosphamide.

The total expression profiles of two medulloblastoma cell lines resistant to the preactivated form of cyclophosphamide (4-hydroperoxycyclophosphamide, 4-HC) were examined using the Affymetrix GeneChip U133A array. Our primary objective was to look for possible genes, other than the well-studied aldehyde dehydrogenases (ALDH) that may be involved in cyclophosphamide (CP) resistance in medulloblastomas. We present here the lists of the most highly upregulated [30 for D341 MED (4-HCR); 20 for D283 MED (4-HCR)] and downregulated [19 for D341 MED (4-HCR); 15 for D283 MED (4-HCR)] genes which may be involved in conferring CP-resistance to the two medullobalstoma cell lines. The lists of genes from the two sublines almost had no overlap, suggesting different mechanisms of CP-resistance. One of the most noteworthy upregulated gene is TAP1 [90-fold increase in D341 MED (4-HCR) relative to D341 MED]. TAP1, a protein belonging to the ABC transporter family is normally involved in major histocompatibility class I (MHC I) antigen processing. This suggests the possible role of multidrug resistance (MDR), albeit atypical (which means it does not involve the usual MDR1 and MRP glycoproteins), in medulloblastoma's CP-resistance. Apart from TAP1, a number of other genes involved in MHC1 processing were upregulated in D341 MED (4HCR). D341 MED (4-HCR) also had a 20-fold increase in the expression of the aldo-keto reductase gene, AKR1B10, which may deactivate the reactive cyclophosphamide metabolite, aldophosphamide. For D283 MED (4-HCR), the most notable increase in expression is that of ALDH1B1, a member of the aldehyde dehydrogenase (ALDH) family of proteins.

Amoxicillin pharmacokinetics in harbor seals (Phoca vitulina) and northern elephant seals (Mirounga angustirostris) following single dose intravenous administration: implications for interspecific dose scaling.

The pharmacokinetics of sodium amoxicillin after a single intravenous dose of 20 mg/kg were determined in ten harbor seals (Phoca vitulina) and ten northern elephant seals (Mirounga angustirostris). The seals ranged in age from 1 to 6 months and the mean weights were 11.7 kg (range, 9.5-18.5 kg) for harbor seals and 47.1 kg (range, 39.5-61.4 kg) for elephant seals. The median half-life of amoxicillin (quartiles) in harbor seals, 1.5 (1.0-3.1) h. was not statistically different from that of elephant seals, 2.0 (1.4-3.8) h, nor were the differences between the terminal elimination rate constants between the two species. The only statistically significant differences between species were for area-under-the-curve (AUC), and total systemic clearance. The lack of statistical significance for differences in the volume of distribution at steady-state (Vss) may have been due to minor differences in the time frame of data collection and dose administered between the two groups. A true physiologic difference in drug handling, possibly related to renal perfusion or tubal secretory efficiency could affect amoxicillin kinetics in these species, and longer administration intervals may be appropriate for elephant seals as compared to harbor seals when administering multiple dose amoxicillin therapy at 20 mg/kg.

Radiolabeled guanine derivatives for the in vivo mapping of O(6)-alkylguanine-DNA alkyltransferase: 6-(4-[(18)F]Fluoro-benzyloxy)-9H-purin-2-ylamine and 6-(3-[(131)I]Iodo-benzyloxy)-9H-purin-2-ylamine.

Two radiolabeled analogues of 6-benzyloxy-9H-purin-2-ylamine (O(6)-benzylguanine; BG) potentially useful in the in vivo mapping of O(6)-alkylguanine-DNA alkyltransferase (AGT) were synthesized. Fluorine-18 labeling of the known 6-(4-fluoro-benzyloxy)-9H-purin-2-ylamine (FBG; 6) was accomplished by the condensation of 4-[(18)F]fluorobenzyl alcohol with 2-aminopurin-6-yltrimethylammonium chloride (4) or 2-amino-6-chloropurine in average decay-corrected radiochemical yields of 40 and 25%, respectively. Unlabeled 6-(3-iodo-benzyloxy)-9H-purin-2-ylamine (IBG; 7) was prepared from 4 and 3-iodobenzyl alcohol. Radioiodination of 9, prepared from 7 in two steps, and subsequent deprotection gave [(131)I]7 in about 70% overall radiochemical yield. The IC(50) values for the inactivation of AGT from CHO cells transfected with pCMV-AGT were 15 nM for IBG and 50 nM for FBG. The binding of [(18)F]6 and [(131)I]7 to purified AGT was specific and saturable with both exhibiting similar IC(50) values (5-6 microM).

Infants' perception of transparency.

Four- and 7-month-old infants' perception of transparency was investigated with computer-generated achromatic or color displays depicting a semitransparent box occluding the center of a rod. Following habituation, infants viewed test displays consisting of either a two-color rod (corresponding to the habituation display's proximal characteristics) or a solid rod (corresponding to the distal characteristics of the event depicted by the habituation display). Looking-time results from 4-month-olds suggested perception of transparency in color displays but not in an achromatic display. An additional condition indicated that transparency perception may rely on the visibility of background texture through the transparent surface. Seven-month-olds, in contrast, provided some evidence of transparency perception in the achromatic display. Implications for the development of infants' responses to object properties and perceptual segregation are discussed.

Schedule-dependent activity of temozolomide plus CPT-11 against a human central nervous system tumor-derived xenograft.

Temozolomide, an imidazole tetrazinone, and CPT-11, a camptothecin derivative, have previously been shown to have anti-central nervous system tumor activity in laboratory and clinical studies. The current experiments were designed to evaluate the activity of temozolomide plus CPT-11 against a malignant glioma-derived xenograft, D-54 MG, growing s.c. in athymic nude mice. The initial schedule of i.p. drug administration was temozolomide at 0.1 LD10 on day 1 and CPT-11 at 0.1 LD10 on days 1-5 and 8-14. The combination of these two agents produced greater than additive activity against D-54 MG. This enhanced activity was maintained when the initial administration of CPT-11 was delayed to day 3 or day 5. However, when CPT-11 was administered first on day 1 using 0.5 LD10 (for the single dose schedule) followed by temozolomide (0.1 LD10) 5 h, 3 days, or 5 days later, the enhancement of activity was substantially reduced. These results demonstrate that the combination of temozolomide plus CPT-11 displays a schedule-dependent enhancement of antitumor activity, suggest a mechanistic explanation for the enhanced activity, and provide the rationale for a Phase I trial of this regimen.

The role of good form in young Infants' perception of partly occluded objects.

Young infants have been reported to perceive the unity of a center-occluded object when the visible ends of the object undergo common motion, but not on the basis of stationary information (e.g., P. J. Kellman & E. S. Spelke, 1983). We investigated the possibility that 4-month-old infants will attend to and utilize the global configuration (i.e., the "good form") of a partly occluded, moving object to perceive its unity and coherence behind the occluder. In the first experiment, infants viewed a partly occluded circle or cross that translated laterally. Infants who habituated in the minimum number of trials ("fast habituators") showed a reliable posthabituation preference for a broken object over a complete object, indicating perception of unity in the habituation display. Slow habituators exhibited no posthabituation preference. In the second experiment, infants were presented with small ring and cross displays, and the infants looked longer at the broken object. There were no reliable differences in performance between fast and slow habituators. A control group demonstrated no reliable posthabituation preference. In three additional conditions, infants viewed either a partly occluded half ring or a display in which two rod parts were either relatable and nonaligned or nonrelatable. The results indicated that curvature per se provided information in support of completion, in addition to global configuration and motion. Implications for theories of infants' visual development are discussed.

Schedule-dependent activity of irinotecan plus BCNU against malignant glioma xenografts.

PURPOSE: To further evaluate the activity of irinotecan (CPT-11) plus 1,3-bis-(chloroethyl)-1-nitrosourea (BCNU) in the treatment of central nervous system tumor-derived xenografts in athymic nude mice. METHODS: We report studies evaluating the schedule-dependence of this regimen in the treatment of the malignant glioma xenograft D-54 MG. RESULTS: The combination of BCNU and CPT-11 showed the highest enhancement index (2.0-3.3) when BCNU was given on day 1 and CPT-11 was given on days 1-5 and 8-12. Delay of CPT-11 administration to day 3 or day 5 substantially decreased activity with enhancement indices of 1.6-1.8 and 0.6-1.0, respectively. Delay of BCNU administration to day 8 also reduced the CPT-11 activity with enhancement indices of 1.2-1.4. CONCLUSIONS: These results suggest that the presence of a BCNU-induced adduct or possibly crosslink prior to administration of CPT-11 is critical for enhanced activity. Although the mechanism of this enhancement is not currently known, a phase I trial of CPT-11 plus BCNU for adults with recurrent malignant glioma based on these results is in progress.

Synchronous change and perception of object unity: evidence from adults and infants.

Adults and infants display a robust ability to perceive the unity of a center-occluded object when the visible ends of the object undergo common motion (e.g. Kellman, P.J., Spelke, E.S., 1983. Perception of partly occluded objects in infancy. Cognitive Psychology 15, 483-524). Ecologically oriented accounts of this ability focus on the primary of motion in the perception of segregated objects, but Gestalt theory suggests a broader possibility: observers may perceive object unity by detecting patterns of synchronous change, of which common motion is a special case. We investigated this possibility with observations of adults and 4-month-old infants. Participants viewed a center-occluded object whose visible surfaces were either misaligned or aligned, stationary or moving, and unchanging or synchronously changing in color or brightness in various temporal patterns (e.g. flashing). Both alignment and common motion contributed to adults' perception of object unity, but synchronous color changes did not. For infants, motion was an important determinant of object unity, but other synchronous changes and edge alignment were not. When a stationary object with aligned edges underwent synchronous changes in color or brightness, infants showed high levels of attention to the object, but their perception of its unity appeared to be indeterminate. An inherent preference for fast over slow flash rates, and a novelty preference elicited by a change in rate, both indicated that infants detected the synchronous changes, although they failed to use them as information for object unity. These findings favor ecologically oriented accounts of object perception in which surface motion plays a privileged role.

Acute arterial occlusions of the small vessels of the hand and forearm: treatment with regional urokinase therapy.

PURPOSE: Arterial occlusions of the small vessels of the forearm and hand may have the same consequences as arterial occlusions in the distal lower extremity. There is limited reported experience with the regional thrombolytic therapy in this setting. The authors reviewed their experience with thrombolytic therapy in acute and subacute arterial occlusions of the distal upper extremity to further clarify its role. MATERIALS AND METHODS: Twelve patients with acute or subacute arterial occlusions of the forearm and hand who had ischemic digits and were treated with regional urokinase infusion were identified retrospectively. Their medical and radiology records were reviewed. RESULTS: All 12 patients demonstrated angiographic improvement and 11 patients demonstrated clinical improvement after treatment. Tissue necrosis in four patients led to partial amputation of one digit in two patients and three digits in two patients. Three of these patients had category III ischemia at presentation. The level of resulting amputation was altered in all but one patient. Vasospasm was noted frequently but responded to vasodilators. No significant complications occurred. CONCLUSIONS: When therapeutic alternatives are limited to anticoagulation and expectant amputation, regional urokinase infusion can optimize distal runoff, obviate or improve the options for distal surgical bypass, and limit tissue loss.

Multiple DNA repair mechanisms and alkylator resistance in the human medulloblastoma cell line D-283 Med (4-HCR).

PURPOSE: We have previously reported preferential repair of DNA interstrand crosslinks in the 4-hydroperoxycyclophosphamide-resistant human medulloblastoma cell line D-283 Med (4-HCR). We now report further studies that explored the potential mechanisms underlying this repair. METHODS: Limiting dilution assays and Western, Southern, and Northern blots were used to compare specific differences between D-283 Med (4-HCR) and its parental line D-283 Med. RESULTS: D-283 Med (4-HCR) was cross-resistant to melphalan and 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), with O6-alkylguanine-DNA alkyltransferase (AGT) levels of 466+/-164 fmol/mg protein; AGT levels in the parental line, D-283 Med, were 76+/-96 fmol/mg. The increase in AGT activity was not a result of gene amplification. Depleting AGT with O6-benzylguanine partially restored sensitivity to BCNU. Both cell lines were deficient in the human mismatch protein MutLalpha. ERCC4 mRNA and poly(ADP-ribose) polymerase levels were similar in both cell lines, and ERCC1 mRNA levels were 2- to 2.5-fold lower in D-283 Med (4-HCR). Topoisomerase I levels were 2- to 2.5-fold higher in D-283 Med compared with D-283 Med (4-HCR). CONCLUSION: These results, while illustrating the multiple differences between D-283 Med and D-283 Med (4-HCR), do not explain the enhanced DNA interstrand crosslink repair seen in D-283 Med (4-HCR).

Modulation of cyclophosphamide activity by O6-alkylguanine-DNA alkyltransferase.

PURPOSE: The human medulloblastoma cell line D283 Med (4-HCR), a line resistant to 4-hydroperoxycyclophosphamide (4-HC), displays enhanced repair of DNA interstrand crosslinks induced by phosphoramide mustard. D283 Med (4-HCR) cells are cross-resistant to 1,3-bis(2-chloroethyl)- -nitrosourea, but partial sensitivity is restored after elevated levels of O6-alkylguanine-DNA alkyltransferase (AGT) are depleted by O6-benzylguanine (O6-BG). Studies were conducted to define the activity of 4-HC and 4-hydroperoxydidechlorocyclophosphamide against D283 Med (4-HCR) after AGT is depleted by O6-BG. METHODS: Limiting dilution and xenograft studies were conducted to define the activity of 4-HC and 4-hydroperoxydidechlorocyclophosphamide with or without O6-BG. RESULTS: The activity of 4-HC and 4-hydroperoxydidechlorocyclophosphamide against D283 Med (4-HCR) was increased after AGT depletion by O6-BG preincubation. Similar studies with Chinese hamster ovary cells, with or without stable transfection with a plasmid expressing the human AGT protein, revealed that the AGT-expressing cells were significantly less sensitive to 4-HC and 4-hydroperoxydidechlorocyclophosphamide. Reaction of DNA with 4-HC, phosphoramide mustard, or acrolein revealed that only 4-HC and acrolein caused a decrease in AGT levels. CONCLUSIONS: We propose that a small but potentially significant part of the cellular toxicity of cyclophosphamide in these cells is due to acrolein, and that this toxicity is abrogated by removal of the acrolein adduct from DNA by AGT.

Antimicrobial susceptibility of bacteria isolated from pinnipeds stranded in central and northern California.

Over a 2-yr period (1994-1995), the antimicrobial susceptibilities of 129 bacterial isolates recovered from live stranded California sea lions (Zalophus californianus), harbor seals (Phoca vitulina), and northern elephant seals (Mirounga angustirostris) were studied. Nineteen genera of bacteria were isolated from various sites of inflammation; abscesses and umbilici were the most common sites. Seventy-two percent of the bacterial isolated were gram negative, and the Enterobacteriaceae (Escherichia coli, Proteus spp., Klebsiella spp., Salmonella spp.) accounted for 75% of the gram-negative isolates. All of the gram-positive isolates were either Enterococcus spp. or Staphylococcus aureus. Multiple drug resistance was present in all but one of the bacterial isolates. The gram-positive bacteria were most susceptible to amoxicillin-clavulanic acid (77% of 36 isolates) and least susceptible to lincomycin (18% of 11 isolates). The gram-negative bacteria were most susceptible to amikacin (91% of 91 isolates) and least susceptible to clindamycin (3% of 109 isolates).

Effect of anatomic distribution of pulmonary emboli on interobserver agreement in the interpretation of pulmonary angiography.

OBJECTIVE: This study examines the anatomic distribution of emboli on pulmonary angiography and attempts to determine the relationship of vessel size to interobserver agreement, two factors having important implications in comparing pulmonary angiography with cross-sectional imaging for pulmonary embolism. MATERIALS AND METHODS: One hundred twenty-five consecutive pulmonary angiograms were reviewed retrospectively by three interventional radiologists. Initial interpretations were recorded and compared to determine interobserver agreement on a per-patient and per-embolus basis. Discordant interpretations were reviewed by all radiologists for a consensus interpretation. RESULTS: Unanimous per-patient agreement occurred in 91% (114/125) of initial interpretations. The largest artery containing acute pulmonary embolism was segmental or larger in 24 patients (83% of patients with acute positive findings, 19% of all patients) and subsegmental in only five patients (17% and 4%, respectively). On a per-patient basis, initial interobserver agreement averaged 45% and unanimous consensus agreement was achieved for 79% of patients having isolated subsegmental pulmonary embolism. Consensus readings altered initial per-patient interpretations for 30% of patients having only subsegmental pulmonary embolism; per-embolus interpretations were altered for 37% of all subsegmental emboli. CONCLUSION: Subsegmental emboli occurring as isolated findings are relatively rare. Approximately one third of subsegmental emboli and one third of patients having isolated subsegmental emboli may be initially misdiagnosed on pulmonary angiography. Objections to cross-sectional imaging for pulmonary embolism based on the inability to detect subsegmental pulmonary embolism when compared with pulmonary angiography should be reexamined with this data in mind.

Young infants' perception of illusory contours in dynamic displays.

Ninety-six 4-month-old infants were habituated to one of three computer-generated displays depicting two rod parts above and below an occluding box. In the first display, the surfaces and boundaries of the rod and box were specified by dense surface texture. Their depth segregation was specified by accretion and deletion of background texture and motion shear. In the second display, the unity of the rod parts and box, and their depth segregation, were specified only by illusory contours. In the third display, the boundaries of the rod and box were specified by illusory contours, perceptible only via spatiotemporal integration of accretion and deletion of sparse-background-texture elements. Infants appeared to perceive object unity, and segregate the rod and box surfaces, in all three displays, indicating use of illusory contours to perceive bounded surfaces in depth. The results suggest a cognitive contribution to perception of some illusory contours, abilities which seem to be present by at least 4 months of age.