Toll-like receptors and inflammation in metabolic neuropathy; a role in early versus late disease?

Neuropathy is a common, morbid complication of the metabolic syndrome, prediabetes, and diabetes. Recent studies have indicated a potential role for the immune system in the development of neuropathy. In particular, toll-like receptors (TLR) 2 and 4 have been linked to metabolic dysfunction, and blocking TLR4 is proposed as a treatment for neuropathic pain. In the current study, we investigated the role of the immune system, particularly TLRs 2 and 4, in the pathogenesis and progression of neuropathy. Sural or sciatic nerve gene expression arrays from humans and murine neuropathy models of prediabetes and diabetes were first analyzed to identify differentially expressed TLR2- and TLR4-associated genes within the KEGG (Kyoto Encyclopedia of Genes and Genomes) database. We observed that genes associated with TLRs 2 and 4, particularly lipopolysaccharide binding protein (LPB) and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta (PIK3CB), were dysregulated across species and across multiple murine models of prediabetic and diabetic neuropathy. To further understand the role of these pathways in vivo, TLR 2 and 4 global knockout mice placed on a 60% high fat diet (HFD-TLR2/4-/-) were compared with wild type (WT) mice on a high fat diet (HFD-WT) and WT controls on a standard diet (CON). Mice then underwent metabolic, neuropathic, and immunological phenotyping at two time points to assess the impact of TLR signaling on neuropathy and immunity during metabolic dysfunction over time. We found that HFD-TLR2/4-/- and HFD-WT mice weighed more than CON mice but did not have increased fasting blood glucose levels. Despite normal blood glucose levels, HFD-TLR2/4-/- mice eventually developed neuropathy at the later time point (28 wks of age) but were somewhat protected from neuropathy at the early time point (16 wks of age) as measured by shorter hind paw withdraw latencies. This is in contrast to HFD-WT mice which developed neuropathy within 11 wks of being placed on a high fat diet and were neuropathic by all measures at both the early and late time points. Finally, we immunophenotyped all three mouse groups at the later time point and found differences in the number of peripheral blood Ly6C-myeloid cells as well as F4/80+ expression. These results indicate that TLR signaling influences early development of neuropathy in sensory neurons, potentially via immune modulation and recruitment.

TODAM2: a model for the storage and retrieval of item, associative, and serial-order information.

This article presents an extended version of the convolution-correlation memory model TODAM (theory of distributed associative memory) that not only eliminates some of the inadequacies of previous versions but also provides a unified treatment of item, associative, and serial-order information. The chunking model extended the basic convolution-correlation formalism by using multiple convolutions, n-grams (multiple autoassociations of sums of item vectors), and chunks (sums of n-grams) to account for chunking and serial organization. TODAM2 extends the chunking model by including rn-grams (reduced n-grams), labels, and "lebals" (the involution or mirror image of a label) to provide a general model for episodic memory. For paired associates, it is assumed that subjects store only labeled n-grams and lebaled rn-grams. It is shown that the model is broadly consistent with a number of major empirical paired-associate and serial-order effects.

Prevention of catheter-associated urinary tract infection: a cost-benefit analysis.

A cost-benefit analysis was used to assess four strategies to prevent catheter-associated urinary tract infections in an acute care setting. Routine use of catheters with sealed collection junctions, selective use of these catheters, and oral antibiotic prophylaxis all result in fewer deaths, fewer infections, and lower overall costs than not using any of these. Routine use of sealed junction catheters results in fewer infections and deaths than does selective use. When the cost of a nosocomial urinary tract infection is +500, routine use of sealed junction catheters is also less expensive than selective use in many circumstances. Oral antibiotic prophylaxis would result in the lowest net cost and the fewest deaths and infections, if it were as effective as parenteral prophylaxis, if more than 72% of patients received it, and if important negative factors such as selection of antimicrobial resistance and adverse drug reactions are not considered. When there is no extra cost of sealed junction catheters, their use is less expensive than the oral prophylaxis strategy if the total cost of oral prophylaxis, including the cost of adverse reactions, is greater than +15. If the extra cost of sealed junction catheters is +4 per unit, their use is less expensive than oral prophylaxis when its cost exceeds +35. Prevention of catheter-associated urinary tract infection reduces the overall cost of patient care, even when the prevention itself incurs costs. This analysis supports the routine use of sealed junction catheters in most acute care situations that require indwelling catheter drainage. Currently, we do not recommend routine antibiotic prophylaxis.

The mirror effect and attention-likelihood theory: a reflective analysis.

The mirror effect refers to findings from studies of recognition memory consistent with the idea that the underlying "strength" distributions are symmetric around their midpoint separating studied and nonstudied items. Attention-likelihood theory assumes underlying binomial distributions of marked features and claims that old-item differences result from differential attention across conditions during study. The symmetry arises because subjects use the likelihood ratio as the basis for decision. The author analyzes the model and argues that one of the main criticisms (the complexity of the likelihood-ratio decision rule) is unwarranted. A further analysis shows that other distributions (the Poisson and the hypergeometric) can also produce a mirror effect. Even with the binomial distribution, a variety of parameter values can produce a mirror effect, and with the right combination of parameter values, differential attention across conditions is not necessary for a mirror effect to occur.

Patients as peer preceptors for orthopedic oncology rehabilitation patients.

This article describes a peer preceptor program that trains patients who have experienced limb preservation surgeries and managed long-term rehabilitative therapy to support and teach newly diagnosed patients through their rehabilitation. This preceptor program was designed to complement the professional counseling and support that rehabilitation staff provide to patients and their families. Training includes communication techniques, practice sessions using videotaped scenes of patients and their families, as well as role-playing. Experienced patients who became preceptors as a result of this program were orthopedic oncology patients who had completed limb preservation surgery, chemotherapy, grafting, and physical therapies. After their training, preceptors exhibited improved communication skills in terms of empathy, listening, and voice expressions. Initiatives designed to make the preceptor program self-sustaining by having staff nurses manage the training still have to be tested.

Developing TODAM: three models for serial-order information.

TODAM2, a theory of distributed associative memory, shows how item and associative information can be considered special cases of serial-order information. Consequently, it is important to get the right model for serial-order information. Here, we analyze and compare three distributed-memory models for serial-order information that use TODAM's convolution-correlation formalism. These models are the chaining model, the chunking model, and a new model, the power-set model. The chaining model associates each item with its predecessor; the chunking model uses multiple convolutions and n-grams to form chunks; and the power-set model interassociates all items in a set in a particular way to form a chunk. The models are compared in terms of their performance on seven basic tests of serial-order information--namely, serial recall, backward recall, recall of missing items, sequential probe tests, positional probe tests, serial-to-paired-associate transfer, and item recognition. The strengths and weaknesses of each model are discussed.

Sensory stores and high-speed scanning.

A model of scanning based on separate sensory and short-term stores was suggested and tested. The experiment used a probe recognition method, with set size varied from 1 to 8 and a fast presentation rate. A masking procedure was used to vary the number of items available in a possible sensory store. Although conditions were such as to maximize the chances of detecting an effect, none was found: the possible size of the sensory store had no effect on reaction time whatsoever. Other aspects of the data lent little support to a serial exhaustive scanning model, but a previously proposed parallel processing model fared better. Finally, not only was the function for positive probes steeper than that for negative probes but also there was a crossover effect as well. This crossover is not without precedent and may indicate the need for consideration of both accuracy and latency in high-speed scanning studies.

The role of auditory features in memory span for words.

In two experiments on the effects of modality on memory span for words, conventional measures of span were supplemented by analyses of serial position curves and by analyses of the principal auditory features of intrusion errors. Auditory presentation led not only to better recall of the terminal words in each stimulus list but also to better recall of word order given correct item recall. Intrusion errors were found to share a number of auditory features with the corresponding omissions, even when the lists had been presented visually. The most salient or the best-retained word features were the syllabic stress pattern and the identity of the stressed vowel phoneme. The data provide evidence for a partial retention of auditory features of stimulus words in short-term memory tasks and are taken to support attribute rather than unit models of short-term memory.

The effect of a subsidiary task on iconic memory.

Using a subsidiary task technique, Doest and Turvey (1971) concluded that iconic memory was independent of the central processing system. However, they did not control the timing between the short-term memory and the iconic-memory tasks in their first experiment and they used a rather long stimulus duration in their second experiment. These procedural difficulties were rectified here in Experiments I and II. It was found that memory load reduced partial report at all interstimulus intervals and there was no interaction. The results of Experiment I were replicated with auditory presentation in Experiment III, ruling out a masking interpretation. Experiment IV ruled out an interpretation in terms of rehearsal or response competition. It was concluded that iconic memory, like short-term memory, is dependent on the central processing system in the sense that it will suffer in a subsidiary-task situation. The locus of the interference effect appears to be in the encoding stage.

Output and retrieval interference in the missing-number task.

Three experiments are reported that represent a reexamination of the missing-number method (Buschke, 1963b) of estimating short-term memory span. The missing-number task involved presenting a random sequence of all but one of the numbers of a known reference set and asking subjects to identify the missing number. Experiment 1 introduced a modified missing-number task that included two missing items and two choices made by the subject. With a large decline in performance for the second choice relative to the first, it is possible that only the second choice was subject to output or retrieval interference. An alternative explanation is that subjects output the number with the weakest memory representation as their first response. By postcuing subjects to report their two choices in a forward or backward sequence, Experiment 2 provided evidence against the importance of output interference and support either for the importance of retrieval interference or for the "weakest-first" hypothesis. However, with a paradigm that replaced only correctly identified missing numbers, a prediction that subjects would select the number with the weakest memory representation as their first response was not confirmed in Experiment 3. Instead, retrieval interference was implicated to explain the first-choice superiority found in Experiments 1 and 3. The results were interpreted in terms of the TODAM model of Murdock (1982, 1987, in press).

The effects of visual presentation method on single-trial free recall.

In two experiments four different conditions of visual presentation were studied with the purpose of furthering our understanding of the role of temporal and spatial factors underlying modality effects in single-trial free recall. Enriching spatial factors in the visual presentation did not produce a higher performance in the recency part of the serial-position curve, and it was therefore concluded that the modality effect could not be due to any visual handicap. A lag distribution measure was suggested and applied to the data to characterize output order (the order of recall) in single-trial free recall. The two experiments carried out used a within-subjects and a between-subjects design, respectively, and illustrate the importance of the methodological difference between these two designs.

Mortality associated with nosocomial urinary-tract infection.

In a prospective study, 131 of 1458 patients acquired 136 urinary-tract infections (defined as greater than 10(5) colony-forming units per milliliter) during 1474 indwelling bladder catheterizations. Seventy-six patients (25 infected and 51 noninfected) died during hospitalization; death rates were 19 per cent in infected patients and 4 per cent in noninfected patients. Multiple logistic regression analysis demonstrated that seven of 21 prospectively monitored variables were associated with mortality among the catheterized patients. The adjusted odds ratio for mortality between those who acquired infection and those who did not was 2.8 (95 per cent confidence limits, 1.5 to 5.1). The acquisition of infection as not associated with the severity of underlying disease; among patients who died, infections occurred in 38 per cent of those classified as having nonfatal underlying disease (15 of 39) and in 27 per cent of those classified as having fatal disease (10 of 37). Twelve deaths may have been caused by acquired urinary-tract infections. Two patients had urinary-tract pathogens in premortem blood cultures. Another 10 died with clinical pictures compatible with serious infection, but no diagnostic cultures were performed. We conclude that the acquisition of urinary-tract infection during indwelling bladder catheterization is associated with nearly a threefold increase in mortality among hospitalized patients, but the reason for this association is not yet clear.

Reduction of mortality associated with nosocomial urinary tract infection.

A randomised controlled trial was conducted to assess whether bladder catheters with preconnected sealed junctions were associated with a lower risk of urinary-tract infection than were catheters without such junctions, and to determine whether prevention of catheter-associated infection would be accompanied by a reduction of mortality. Among those not taking systemic antibiotics, patients assigned sealed junction catheters had fewer infections and deaths. Before they received antibiotics, the risk of infection among those assigned unsealed catheters was 2.7 times that of patients assigned sealed catheters (95% confidence interval=1.3-5 . 4, p=0 . 007). Among the 220 patients who received no antibiotics, 14% (15/108) of those assigned unsealed catheters and 4% (4/112) of those assigned sealed catheters died. Stratification by important risk factors for mortality yielded an adjusted risk ratio for death of 3.4 (95% CI=1.1-10.7, p=0.03). Among patients who received systemic antibiotic the use of sealed catheters did not affect infection rates (RR=0.9, 95% CI=0.5-1.5, p=0.68) or deaths (RR=1.2, 95% CI=0.6-2.2, p=0.62). These data indicate how the rates of infection and mortality can be reduced in hospital. Since the degree of reduction in mortality corresponded with the degree of reduction of infection, measures to prevent catheter-associated nosocomial urinary tract infection should be implemented.

Risk factors for nosocomial urinary tract infection.

In a prospective study carried out in June 1979-April 1981, 134 of 1,458 adult inpatients at New England Deaconess Hospital, Boston, Massachusetts, acquired 136 urinary tract infections during 1,474 indwelling bladder catheterizations. Multiple logistic regression analysis identified nine factors that were significantly associated with acquisition of infection: duration of catheterization, lack of systemic antibiotic during short catheter courses, lack of urinemeter drainage, female sex, diabetes mellitus, microbial colonization of the drainage bag, serum creatinine greater than 2 mg/dl at the time of catheterization, the reason for catheterization, and the use of catheters with sealed collection junctions when no antibiotic was administered. When potential risk factors were considered individually, without adjusting for the influence of other factors, infection was also significantly associated with 11 other factors, including several that have been previously reported as risk factors for catheter-associated urinary tract infections; however, these associations were no longer significant after adjustment for one or more of the nine factors noted above. These findings suggest approaches to surveillance, prevention, and research activities. They also strongly support the widely-held but poorly documented belief that persons with diabetes are more susceptible to urinary tract infection than are persons without diabetes.

Home care for children dependent on medical technology: the family perspective.

Children who are dependent on medical technology present unique challenges to families and professionals who attempt to care for them at home. This longitudinal, exploratory study examines the placement threatening crises experienced over an eighteen-month period by four such families in Minnesota. The findings encourage development of a family support model of placement prevention for this population, as opposed to a crisis intervention model.