Inflammation in arthritis induces expression of BMP3, an inhibitor of bone formation.

OBJECTIVES: Inflammation in diseases such as rheumatoid arthritis (RA) stimulates osteoclast-mediated articular bone erosion and inhibits osteoblast-mediated bone formation, leading to a net loss of bone. Pro-inflammatory cytokines and antagonists of the Wnt signalling pathway have been implicated in the inhibition of osteoblast differentiation and activity in RA, contributing to the erosive process and impairing erosion healing. Importantly, osteoblast differentiation and function are also regulated by the osteogenic bone morphogenetic protein (BMP) signalling pathway, which is antagonized by BMP3. We therefore examined the potential role of BMP3 in inflammatory arthritis. METHOD: Two murine models of RA, K/BxN serum transfer arthritis (STA) and antigen-induced arthritis (AIA), were used to establish the temporal expression of BMP3 and the cellular sources of BMP3 mRNA and protein in inflammatory arthritis. To determine the effects of inflammation on the expression of BMP3 in osteoblasts, murine calvarial osteoblasts were treated with pro-inflammatory cytokines and BMP3 expression was assessed. RESULTS: In both murine models of RA, BMP3 mRNA and protein are highly expressed by osteoblasts lining inflammation-bone interfaces late in the course of arthritis. Synovial tissues are not a significant source of BMP3. BMP3 expression is induced in osteocalcin-expressing osteoblasts in vitro following stimulation by tumour necrosis factor (TNF). CONCLUSIONS: These data implicate BMP3 as a novel factor that may act locally to contribute to the erosive process and inhibit the repair of articular bone in RA through inhibition of osteoblast differentiation and function.

Activated human T cells express alternative mRNA transcripts encoding a secreted form of RANKL.

Receptor activator of nuclear factor-kappaB-ligand (RANKL), encoded by the gene TNFSF11, is required for osteoclastogenesis, and its expression is upregulated in pathologic bone loss. Transcript variants of TNFSF11 messenger RNA (mRNA) have been described that encode a membrane-bound and a putative secreted form of RANKL. We identify a TNFSF11 transcript variant that extends the originally identified transcript encoding secreted RANKL. We demonstrate that this TNFSF11 transcript variant is expressed by the human osteosarcoma cell line, Saos-2, and by both primary human T cells and Jurkat T cells. Of relevance to the production of RANKL in pathologic bone loss, expression of this secreted TNFSF11 transcript is upregulated in Jurkat T cells and primary human T cells upon activation. Furthermore, this transcript can be translated and secreted in Jurkat T cells in vitro and is able to support osteoclast differentiation. Our data highlight the complexity of the TNFSF11 genomic locus, and demonstrate the potential for the expression of alternate mRNA transcripts encoding membrane-bound and secreted forms of RANKL. Implications of alternate mRNA transcripts encoding different RANKL protein isoforms should be carefully considered and specifically examined in future studies, particularly those implicating RANKL in pathologic bone loss.

The effect of speed-accuracy strategy on response interference control in Parkinson's disease.

Studies that used conflict paradigms such as the Eriksen Flanker task show that many individuals with Parkinson's disease (PD) have pronounced difficulty resolving the conflict that arises from the simultaneous activation of mutually exclusive responses. This finding fits well with contemporary views that postulate a key role for the basal ganglia in action selection. The present experiment aims to specify the cognitive processes that underlie action selection deficits among PD patients in the context of variations in speed-accuracy strategy. PD patients (n=28) and healthy controls (n=17) performed an arrow version of the flanker task under task instructions that either emphasized speed or accuracy of responses. Reaction time (RT) and accuracy rates decreased with speed compared to accuracy instructions, although to a lesser extent for the PD group. Differences in flanker interference effects among PD and healthy controls depended on speed-accuracy strategy. Compared to the healthy controls, PD patients showed larger flanker interference effects under speed stress. RT distribution analyses suggested that PD patients have greater difficulty suppressing incorrect response activation when pressing for speed. These initial findings point to an important interaction between strategic and computational aspects of interference control in accounting for cognitive impairments of PD. The results are also compatible with recent brain imaging studies that demonstrate basal ganglia activity to co-vary with speed-accuracy adjustments.

The effect of Parkinson's disease on interference control during action selection.

Basal ganglia structures comprise a portion of the neural circuitry that is hypothesized to coordinate the selection and suppression of competing responses. Parkinson's disease (PD) may produce a dysfunction in these structures that alters this capacity, making it difficult for patients with PD to suppress interference arising from the automatic activation of salient or overlearned responses. Empirical observations thus far have confirmed this assumption in some studies, but not in others, due presumably to considerable inter-individual variability among PD patients. In an attempt to help resolve this controversy, we measured the performance of 50 PD patients and 25 healthy controls on an arrow version of the Eriksen flanker task in which participants were required to select a response based on the direction of a target arrow that was flanked by arrows pointing in the same (congruent) or opposite (incongruent) direction. Consistent with previous findings, reaction time (RT) increased with incongruent flankers compared to congruent or neutral flankers, and this cost of incongruence was greater among PD patients. Two novel findings are reported. First, distributional analyses, guided by dual-process models of conflict effects and the activation-suppression hypothesis, revealed that PD patients are less efficient at suppressing the activation of conflicting responses, even when matched to healthy controls on RT in a neutral condition. Second, this reduced efficiency was apparent in half of the PD patients, whereas the remaining patients were as efficient as healthy controls. These findings suggest that although poor suppression of conflicting responses is an important feature of PD, it is not evident in all medicated patients.

Inefficient response inhibition in individuals with mild cognitive impairment.

Individuals diagnosed with mild cognitive impairment (MCI) show primary deficits in memory and are at increased risk for developing Alzheimer's disease (AD). In light of recent evidence that executive cognitive deficits are common in AD and may be detectable in individuals diagnosed with MCI, we extend these findings to the investigation of response inhibition, an essential aspect of executive cognitive control. Twenty MCI patients and 20 healthy controls (HC) completed an arrow version of the flanker task [Eriksen, B. A., & Eriksen, C. W. (1974). Effects of noise letters upon the identification of target letters in a non-search task. Perception & Psychophysics, 16, 143-149] in which participants responded to a target arrow surrounded by distractors (i.e., flankers) that signaled a same (congruent) or a conflicting (incongruent) response. Reaction time (RT) increased in both groups when flankers signaled an incongruent response, but more so among MCI patients. MCI patients taking a cholinesterase inhibitor showed smaller flanker interference effects than those not taking this medication. Analysis of the flanker effect as a function of the entire RT distribution indicated that MCI patients show increasing interference at the slowest segments of the distribution, a finding that implicates deficient inhibition of the incongruent response [Ridderinkhof, K. R. (2002). Activation and suppression in conflict tasks: Empirical clarification through distributional analyses. In W. Prinz & B. Hommel (Eds.), Common mechanisms in perception and action. Attention & performance, Vol. XIX (pp. 494-519). Oxford: Oxford University Press]. These results suggest that deficits in response inhibition are detectable in MCI patients and merit further investigation as to whether these changes aid prediction of which MCI patients convert to AD.

On-line anosognosia: unawareness for chorea in real time but not on videotape delay.

In hemiplegics, anosognosia (unawareness of deficit) rests on a mismatch between expected and actual movement: a feedback hypothesis emphasizes sensory deficits or neglect, a feedforward hypothesis postulates impaired intention to move. Anosognosia for other problems is less studied. The authors report a man without sensory deficits who was unaware of choreiform movements, except on videotape delay. The authors believe that a feed-forward mechanism underlies his "on-line" unawareness.

Glucose enhancement of 24-h memory retrieval in healthy elderly humans.

When administered soon before or after training, glucose facilitates memory in rodents and in several populations of humans, including healthy elderly people. Thus, glucose appears to enhance memory formation in a time- and dose-dependent manner. By assessing the effects of glucose at the time of memory tests, the present experiment examined the role of glucose on memory retrieval in healthy elderly people. On four sessions separated by a week, glucose or saccharin were administered immediately before hearing a narrative prose passage, as in previous experiments, or immediately before being tested for recall of the passage (24 h after training). Subjects recalled significantly more information after glucose ingestion than after saccharin ingestion whether the glucose was given before acquisition or memory tests. In addition, recall was significantly better in the preacquisition glucose condition relative to recall in the retrieval glucose condition. These findings provide evidence that glucose enhances both memory storage and retrieval.

Glucose effects on cognition in adults with Down's syndrome.

Glucose enhances memory in a variety of individuals, including people with Alzheimer's disease. By 35 years of age, adults with Down's syndrome (DS) develop the characteristic plaques and tangles found in Alzheimer's disease, despite findings indicating that not all older DS individuals meet criteria for dementia. To examine the possibility that glucose enhances memory in adults with DS (mean age = 35 years, range = 19-55 years), adults with DS were given a battery of tests specifically designed for individuals with DS in glucose and control conditions. No participant met criteria for dementia, regardless of age. Glucose enhanced performance on tests requiring both long-term memory and auditory processing. In addition, increased age was associated with poorer performance on the majority of tests in the control condition, indicating that cognitive decline with aging may be more prevalent in DS than previously believed.

Comparison of portable automated keratometry and manual keratometry for IOL calculation.

PURPOSE: To compare the accuracy of portable automated keratometry (PAK) with that of manual keratometry (MK) in measuring corneal power for intraocular lens calculations. SETTING: Wilford Hall Medical Center, San Antonio, Texas, USA. METHODS: In Part 1 of the study, five ophthalmic technicians performed keratometric analysis in 20 eyes in 10 volunteers using both manual and automated methods to determine the relative accuracy and reproducibility of each instrument. In Part 2, both MK and PAK were prospectively performed in 11 patients having cataract surgery to compare the accuracy of each instrument in predicting postoperative refractive outcome. RESULTS: The difference between instruments in determining the average corneal power in all eyes was less than 0.10 diopter (D) (MK = 43.84 D, PAK = 43.93 D). Portable keratometry demonstrated less variability in measurements in each eye (average standard deviation, MK = 0.30 D, PAK = 0.11 D; average range, MK = 1.08 D, PAK = 0.44 D). The mean absolute refractive error (difference between the actual refractive outcome and predicted refractive outcome) was 0.37 D +/- 0.30 (SD) using MK values and 0.45 +/- 0.19 D using PAK values. CONCLUSIONS: Portable automated keratometry is a simple keratometric technique that appeared to be as accurate as but with less variability than manual keratometry in determining corneal power for cataract surgery.

Age-related differences in an ecologically based study of route learning.

Spatial learning abilities in younger adults and in healthy elderly adults were examined in 2 tasks. In the first task, participants were tested for their ability to recall relevant route information as well as to recognize and to order temporally landmark information observed along the route. Older participants had relatively greater difficulty retracing the route and temporospatially ordering landmarks but were equally good at recognition of landmarks occurring on the route. In the second task, participants memorized a 2-dimensional representation of a route and subsequently navigated the route from memory. Older participants had greater difficulty memorizing the route and navigating it. Errors of omission, commission, wrong, and forced choice were analyzed. Group differences in the pattern of errors differed by task.

Intraoperative mitomycin in primary pterygium excision. A prospective, randomized trial.

PURPOSE: Conjunctival autograft transplantation and postoperative mitomycin therapy are two adjuvant treatment methods shown to lessen the high pterygium recurrence rate seen with simple excision alone. The authors conducted a prospective, randomized study comparing these two techniques with a relatively new treatment method using intraoperative mitomycin application. METHODS: Fifty patients with 56 primary pterygia were randomized to 1 of 3 treatment groups: conjunctival autograft (group 1), postoperative mitomycin 0.2 mg/ml four times a day x 7 days (group 2), and intraoperative mitomycin 0.4 mg/ml x 3 minutes (group 3). The mean follow-up time was 16 months (range, 6 to 28 months). RESULTS: Recurrences developed in 4 (22.2%) of 18 eyes in group 1, 4 (21.1%) of 19 eyes in group 2, and 2 (10.5%) of 19 eyes in group 3. Complications developed in two, patients from group 2, scleral thinning managed successfully with a scleral patch graft, and epithelial toxicity that resolved on discontinuation of mitomycin on postoperative day 6. There were no complications in the other two groups. CONCLUSIONS: Intraoperative mitomycin is a simple and effective alternative to postoperative mitomycin therapy, showing the lowest recurrence rate in their series with no toxicity during the study period. If the decision is made to use adjunctive mitomycin, the authors recommend intraoperative application over postoperative administration.

Functions of external cues in prospective memory.

A simulation of an air traffic control task was the setting for an investigation of the functions of external cues in prospective memory. External cues can support the triggering of an action or memory for the content of the action. We focused on memory for the content, and manipulated the temporal characteristics of the external cue to disentangle two possible functions the cue can support: (1) an external cue visible during a retention interval could support rehearsal of the to-be-performed action; (2) an external cue visible at the end of a retention interval could support retrieval of the to-be-performed action. Two experiments were conducted that converge on the same conclusion: the primary function of an external cue is to support retrieval. Implications for the design of a computer interface to present prospective cues are discussed.

The relationship between depression and cognition in older adults: a cross-validation study.

The relationship between depression and cognition in older adults has become a topic of extensive research and clinical interest. Results of previous research are limited, however, by sampling and methodological problems. Small sample sizes and the treatment of depression as a dichotomous variable may be major factors that limit data interpretation in previous studies. The present sample of 220 geriatric medical patients was split into a validation and a cross-validation sample specifically to test the hypothesis that depression is an independent predictor of cognition. Multiple regression analyses, controlling for the direct effects of demographic factors, found that Geriatric Depression Scale scores were consistently a significant predictor of Dementia Rating Scale and Logical Memory scores. Overall, GDS scores accounted for approximately 8% of unique variance for both measures of cognition. Demographic factors, particularly age and race, were also significant predictors of cognitive test scores. These data were interpreted as providing support for the hypothesis that level of depression predicts level of cognitive functioning.

Cognitive screening of nursing home residents: factor structures of the Mini-Mental State Examination.

OBJECTIVE: To examine factor structures of the Mini-Mental State Examination, attempting first to replicate any of previously proposed 2-factor solutions; and to explore, secondly, the presence of clinically more differentiated and statistically stable factor structures representing common neurocognitive dimensions. DESIGN: Factor analytic investigation of descriptive dataset collected on nursing home residents. Two factor analyses were performed, one in which the number of factors was fixed at 2 in an effort to replicate previous studies, and one in which the number of factors to retain was determined by the scree test. Both factor analyses used established methods for judging the adequacy of the correlation matrix and the significance of factor loadings, and both applied principal components analysis for initial factor extraction and the equamax criterion for orthogonal rotation. SETTING: Seven nursing homes with a total of 894 beds. PARTICIPANTS: 922 assessments on nursing home residents were performed, of which 892 were complete and entered into the factor analyses. The observation-to-variable ratio exceeded 81:1, assuring the statistical stability of factor solutions derived. MEASUREMENT: The Mini-Mental State Examination, with standardization of words to be recalled and the inverted spelling of "world" as the mental reversal task. MAIN RESULTS: Two factor structures were derived. A 2-factor solution, explaining 36.5% of the variance and statistically and conceptually different from those obtained in previous studies, distinguished between Perceptual-Organizational and Psychomotor skills. A 4-factor solution, which explained 56.1% of the variance, included a factor named Executing Psychomotor Commands, while also further differentiating the perceptual-organizational processes into the factors of Memory, Concentration, and Language. CONCLUSION: The 2-factor solution shows that, notwithstanding previous claims to the contrary, the MMSE can make stable and independent distinctions between psychomotor and perceptual-organizational processes. However, this solution is statistically and conceptually limited and, therefore, of limited clinical and scientific relevance. The 4-factor solution of the MMSE maps well onto commonly recognized dimensions of neurocognitive ability. It offers a stable, intuitively sound, and statistically supported framework for clinical differentiation of cognitive screening data into independent clinical dimensions of neurocognitive functioning. Thus, it offers clinicians and researchers a 4-dimensional framework for interpreting data obtained by means of the MMSE. Studies with other populations of cognitively impaired and intact elderly are recommended to validate and extend the present findings.

Multidisciplinary assessment of patients with Alzheimer's disease.

The complexity of AD necessitates that multiple disciplines interface effectively in the assessment of patient, caregiver, and family. This multidisciplinary effort should not be focused on the mere exchange of data. As this article emphasized, just from the perspective of nursing, it is critical that the various disciplines involved know about the purpose, focus, and process of assessment approaches used by each in the convergent effort to comprehensively evaluate the disease and its possible changes, as well as its impact on function, cognition, behavior, and emotion. From this article, it should be apparent that effective multidisciplinary assessment is not exchange of data but rather purposive interchange of clinical information to achieve the clinical goals of assessment, diagnosis, explanation, intervention, prognosis, and evaluation.

Glucose enhancement of memory in patients with probable senile dementia of the Alzheimer's type.

Attempts to attenuate the severe memory deficits in patients with SDAT have been largely unsuccessful, particularly in patients at advanced stages of the disease. Recent evidence indicates that glucose administration enhances memory in generally healthy aged rodents and humans. The present experiment demonstrates that glucose administration improves memory in moderately to severely demented patients with probable SDAT. Glucose ingestion significantly enhanced performance on several tests including orientation, word recognition and recall, narrative prose, and face recognition after glucose ingestion. Thus, the results extend enhancement of memory with glucose from generally healthy rodent and human populations to patients with probable SDAT.

Cloning, characterization, and expression of a human calcitonin receptor from an ovarian carcinoma cell line.

A human ovarian small cell carcinoma line (BIN-67) expresses abundant calcitonin (CT) receptors (CTR) (143,000 per cell) that are coupled, to adenylate cyclase. The dissociation constants (Kd) for the CTRs on these BIN-67 cells is approximately 0.42 nM for salmon CT and approximately 4.6 nM for human CT. To clone a human CTR (hCTR), a BIN-67 cDNA library was screened using a cDNA probe from a porcine renal CTR (pCTR) that we recently cloned. One positive clone of 3,588 bp was identified. Transfection of this cDNA into COS cells resulted in expression of receptors with high affinity for salmon CT (Kd = approximately 0.44 nM) and for human CT (Kd = approximately 5.4 nM). The expressed hCTR was coupled to adenylate cyclase. Northern analysis with the hCTR cDNA probe indicated a single transcript of approximately 4.2 kb. The cloned cDNA encodes a putative peptide of 490 amino acids with seven potential transmembrane domains. The amino acid sequence of the hCTR is 73% identical to the pCTR, although the hCTR contains an insert of 16 amino acids between transmembrane domain I and II. The structural differences may account for observed differences in binding affinity between the porcine renal and human ovarian CTRs. The CTRs are closely related to the receptors for parathyroid hormone-parathyroid hormone-related peptide and secretin; these receptors comprise a distinct family of G protein-coupled seven transmembrane domain receptors. Interestingly, the hCTR sequence is remotely related to the cAMP receptor of Dictyostelium discoideum (21% identical), but is not significantly related to other G protein-coupled receptor sequences now in the data bases.

Anterograde and retrograde enhancement of 24-h memory by glucose in elderly humans.

The present experiment examined anterograde and retrograde enhancement of memory storage by glucose in elderly humans. Glucose (50 g) or saccharin was administered shortly before or immediately after acquisition of a narrative prose passage. Recall was tested 24 h later. Glucose administration before or after presentation of the material to be learned significantly improved recall 24 h later compared to performance in the saccharin condition. These findings suggest that glucose retroactively enhances memory storage processing in elderly humans and that the enhancement of memory outlasts the transient elevations in blood glucose levels after glucose ingestion.

The regulation of p33 gene expression by insulin and calcium ionophores.

We have previously shown that insulin induces p33 transcription and mRNA levels in serum-deprived rat H4 hepatoma cells. In the current study, the effects of the calcium ionophores A23187 and ionomycin on the regulation of p33 gene expression were examined. When H4 cells were incubated with A23187 or ionomycin (1 microM) for 90-300 min, 700-900% and 400-600% increases in p33 mRNA levels were observed. The effects of ionophore and insulin together on p33 mRNA levels were not additive. Insulin-induced increases in p33 mRNA levels were diminished at low concentrations of extracellular calcium, but were unchanged by the calcium channel blocker verapamil. The chelation of intracellular calcium using 20 and 60 microM quin2-AM resulted in 50% and 90% reductions in insulin-induced p33 mRNA levels. When transcription assays were performed, A23187 treatment for 15-180 min increased p33 transcription 300-400%. The lesser effect of A23187 on transcription compared to that on mRNA levels was also true for insulin treatment. Similar results were obtained using ionomycin. Insulin- and A23187-induced p33 transcription was reduced by quin2-AM to below basal levels. These studies show that calcium ionophores stimulate p33 gene expression and suggest that changes in intracellular calcium can alter insulin's induction of this gene.