High yielding synthesis of 2,2'-bipyridine macrocycles, versatile intermediates in the synthesis of rotaxanes.

We present an operationally simple approach to 2,2'-bipyridine macrocycles. Our method uses simple starting materials to produce these previously hard to access rotaxane precursors in remarkable yields (typically >65%) across a range of scales (0.1-5 mmol). All of the macrocycles reported are efficiently converted (>90%) to rotaxanes under AT-CuAAC conditions. With the requisite macrocycles finally available in sufficient quantities, we further demonstrate their long term utility through the first gram-scale synthesis of an AT-CuAAC [2]rotaxane and extend this powerful methodology to produce novel Sauvage-type molecular shuttles.

Correction: High yielding synthesis of 2,2'-bipyridine macrocycles, versatile intermediates in the synthesis of rotaxanes.

[This corrects the article DOI: 10.1039/C6SC00011H.].

Bilateral thalamic lesions affect recollection- and familiarity-based recognition memory judgments.

The contribution of the thalamus to different forms of explicit memory is poorly understood. In the current study, explicit memory performance was examined in a 40-year-old male (RG) with bilateral anterior and medial thalamic lesions. Standardized tests indicated that the patient exhibited more severe recall than recognition deficits and his performance was generally worse for verbal compared to nonverbal memory. Recognition memory tests using the remember-know (R/K) procedure and the confidence-based receiver operating characteristic (ROC) procedure were used to examine recollection- and familiarity-based recognition. These tests revealed that RG had deficits in recollection and smaller, but consistent deficits in familiarity. The results are in agreement with models indicating that the anteromedial thalamus is important for both recollection- and familiarity-based recognition memory.

Lag-sensitive repetition suppression effects in the anterior parahippocampal gyrus.

Single-unit recording studies of monkeys have shown that neurons in perirhinal and entorhinal cortex exhibit activity reductions following stimulus repetition, and some have suggested that these "repetition suppression" effects may represent neural signals that support recognition memory. Critically, repetition suppression effects are most pronounced at short intervals between stimulus repetitions. Here, we used event-related functional magnetic resonance imaging (fMRI) to identify repetition suppression effects in the human medial temporal lobe and determine whether these effects are sensitive to the length of the interval between repetitions. Twenty-one participants were scanned while performing a continuous recognition memory task in which the interval between item repetitions was parametrically varied from 2 to 32 intervening items. We found evidence of repetition suppression in the anterior parahippocampal gyrus, but only when the repetition interval was relatively short. Moreover, bilateral hippocampal regions showed lag-sensitive repetition effects. Our results demonstrate that activity in the human medial temporal cortex, like that of monkeys, exhibits repetition suppression effects that are sensitive to the length of the interval between repetitions.

Distinctiveness and the recognition mirror effect: evidence for an item-based criterion placement heuristic.

Superior detection and rejection of 1 versus another class of items during recognition is called the mirror effect. Some mirror effects may involve strategic criterion adjustments based on item distinctiveness and its relation to memorability. Three experiments demonstrated mirror effects for known versus unknown scenes and 1 suggested a similar pattern for faces. In opposition to preexperimental familiarity, lures from known and frequently encountered locations were confidently rejected more often than unknown lures. Forgetting and speeding recognition reversed this lure response pattern, suggesting abandonment of strategic adjustment in favor of a single fixed criterion. With sufficient response time and recent encoding, observers demand more evidence for conceptually distinctive items, perhaps because such items typically foster vivid recollection during retrieval.

Recall and recognition in mild hypoxia: using covariance structural modeling to test competing theories of explicit memory.

To test theories of explicit memory in amnesia, we examined the effect of hypoxia on memory performance in a group of 56 survivors of sudden cardiac arrest. Structural equation modeling revealed that a single-factor explanation of recall and recognition was insufficient to account for performance, thus contradicting single-process models of explicit memory. A dual-process model of recall in which two processes (e.g., declarative memory and controlled search) contribute to recall performance, whereas only one process (e.g., declarative memory) underlies recognition performance, also failed to explain the results adequately. In contrast, a dual-process model of recognition provided an acceptable account of the data. In this model, two processes--recollection and familiarity--underlie recognition memory, whereas only the recollection process contributes to free recall. The best-fitting model was one in which hypoxia and aging led to deficits in recollection, but left familiarity unaffected. Moreover, a controlled search process was correlated with recollection, but was not associated with familiarity or the severity of hypoxia. The results support models of explicit memory in which recollection depends on the hippocampus and frontal lobes, whereas familiarity-based recognition relies on other brain regions.

Dissociating familiarity from recollection using rote rehearsal.

Recollection-based recognition memory judgments benefit greatly from effortful elaborative encoding, whereas familiarity-based judgments are much less sensitive to such manipulations. In this study, we have examined whether rote rehearsal under divided attention might produce the opposite dissociation, benefiting familiarity more than recollection. Subjects rehearsed word pairs during the "distractor" phase of a working memory span task, and were then given a surprise memory test for the distractor items at the end of the experiment. Experiment 1 demonstrated that increasing rehearsal elevated the recognition rate for intact and rearranged pairs, but neither associative recognition accuracy nor implicit fragment completion benefited from rehearsal. The results suggest that rote rehearsal leads to a greater increase in familiarity than in recollection, and that the increase in observed familiarity cannot be attributed to effects of repetition priming. In Experiment 2, we tested item recognition with the remember/know procedure, and the results supported the conclusions of Experiment 1. Moreover, a signal detection model of remember/know performance systematically overpredicted rehearsal increases in remember rates, and this worsened when high-rehearsal items were assumed to be more variable in strength. The results suggest that rote rehearsal can dissociate familiarity from recollection at the time of encoding and that item recognition cannot be fully accommodated within a one-dimensional signal detection model.

Recognition memory for source and occurrence: the importance of recollection.

Previous recognition memory studies indicate that when both recollection and familiarity are expected to contribute to recognition performance (e.g., discriminating studied items from nonstudied items) the dual-process and the unequal-variance signal detection models provide comparable accounts of performance. When familiarity is not expected to be useful (e.g., when items from two equally familiar sources are discriminated between), the dual-process model provides a significantly better account of performance. In the present study, source recognition was tested under conditions in which familiarity could have been used to perform a list-discrimination task; participants were required to discriminate between strong studied items, weak studied items, and new items. The dual-process model provided a better account of performance than did the unequal-variance model. Moreover, the results indicated that the unequal-variance assumption in a single-process signal detection model was not a valid substitution for recollection and that recollection was used to make recognition judgments even when assessments of familiarity were useful.

Effects of extensive temporal lobe damage or mild hypoxia on recollection and familiarity.

Memory for past events can be based on recollection or on assessments of familiarity. These two forms of human memory have been studied extensively by philosophers and psychologists, but their neuroanatomical substrates are largely unknown. Here we examined the brain regions that are involved in these two forms of memory by studying patients with damage to different temporal lobe regions. Our results come from (i) structural covariance modeling of recall and recognition, (ii) introspective reports during recognition and (iii) analysis of receiver operating characteristics. In sum, we found that the regions disrupted in mild hypoxia, such as the hippocampus, are centrally involved in conscious recollection, whereas the surrounding temporal lobe supports familiarity-based memory discrimination.

Separating sensitivity from response bias: implications of comparisons of yes-no and forced-choice tests for models and measures of recognition memory.

A fundamental challenge to psychological research is the measurement of cognitive processes uncontaminated by response strategies resulting from different testing procedures. Test-free estimates of ability are vital when comparing the performance of different groups or different conditions. The current study applied several sets of measurement models to both forced-choice and yes-no recognition memory tests and concluded that the traditional signal-detection model resulted in distorted estimates of accuracy. Two-factor models were necessary to separate memory sensitivity from response bias. These models indicated that (a) memory accuracy did not differ across the tests and (b) the tests relied on the same underlying memory processes. The results illustrate the pitfalls of using a single-component model to measure accuracy in tasks that reflect 2 or more underlying processes.

Steatorrhea: a common manifestation in patients with HIV/AIDS.

Multiple infectious causes of diarrhea are known in patients with HIV/AIDS. Maldigestion and malabsorption have been reported in patients with HIV/AIDS and may be independent of infectious etiologies. Among ambulatory patients with HIV/AIDS, we examined the prevalence of fat malabsorption (steatorrhea). Sixty-one patients with unexplained diarrhea (defined as > 2 stools/d) and/or weight loss despite adequate caloric intake (and without clinical evidence of chronic pancreatitis) were evaluated in our outpatient Gastroenterology-Nutrition Clinic between March 1, 1993, and July 1994. Patients were instructed by a dietitian to follow a > or = 100 g/d fat diet for 24 h before submitting a stool sample for qualitative (or quantitative) fecal fat determination. Forty-five patients, 32 with ongoing diarrhea and 13 without diarrhea, submitted stool samples. Twenty-two of 45 patients (49%) had qualitative or quantitative steatorrhea, 16/32 with diarrhea (50%) and 6/13 patients without diarrhea (46%). Thirty of 32 patients with diarrhea had had extensive microbiologic and/or endoscopic evaluations. Only 9 patients had a detectable intestinal pathogen, 5 patients had cytomegalovirus (4 treated), 4 patients had cryptosporidia (3 treated), and 1 patient had microsporidia. Steatorrhea, as determined by abnormal qualitative fecal fat, is detectable in nearly 50% of patients with HIV/AIDS. Fat malabsorption appears to be a primary defect in these patients independent of detectable pathogens. Assessment of fat malabsorption should be considered in patients with unexplained weight loss or diarrhea before extensive evaluation for opportunistic infections.

Serum zinc and protein levels: lack of a correlation in hospitalized patients with AIDS.

Abnormally low serum zinc levels are associated with advanced states of malnutrition. Zinc levels are thought to parallel serum albumin, and repletion of zinc has reportedly led to increased albumin. We examined the correlation between zinc deficiency and serum proteins in hospitalized patients with AIDS. Over 500 inpatient consultations were performed by our Gastroenterology-Nutrition Consult Service from May 1992 to June 1994. We reviewed the medical records from all 228 AIDS patients in whom a serum zinc level was measured (by atomic absorption spectrophotometry). The correlation between serum zinc, albumin, prealbumin, and transferrin drawn on the same hospital day was analyzed by linear regression. The patients were stratified by the level of albumin, group A albumin < 2.0 g/dL, group B albumin 2.0-2.9 g/dL, and group C albumin > 3.0 g/dL, to allow comparison of the incidence of diarrhea and mean zinc level by chi square. Thirty-four patients had more than one serum zinc and albumin determination; the change over time was compared by linear regression. Serum zinc and albumin, prealbumin, and transferrin levels did not correlate strongly (r2 < or = 0.01). Furthermore, changes in zinc over time did not correlate with parallel changes in serum albumin (r2 < or = 0.01). In patients grouped by albumin, the proportion of patients with diarrhea did not differ significantly. The mean zinc levels were also not statistically significantly different. Serum zinc levels do not strongly correlate with serum proteins in hospitalized patients with AIDS. Serial measures of zinc over time also do not correlate strongly with changes in albumin. The incidence of diarrhea was not significantly different in patients with hypoalbuminemia or hypozincemia when compared with patients with near normal albumin or zinc. The relationship between zinc and serum proteins in AIDS patients is not linear. Zinc deficiency should be assessed in patients independent of the serum albumin.

Zinc levels and infections in hospitalized patients with AIDS.

Impaired cellular and humoral immunity and phagocytic function have been attributed to zinc deficiency. This study examined the association between low serum zinc concentration and opportunistic infections in hospitalized patients with the acquired immune deficiency syndrome (AIDS). We examined the records from all 505 inpatient consultations performed by our Nutrition Service from May 1992 through June 1994. The medical records from all 228 patients with AIDS with known serum zinc levels (determined by atomic absorption spectrophotometry) were reviewed. The length of HIV seropositivity, most recent CD4 count, presence of diarrhea, and degree of malnutrition were noted. The principal diagnosis accounting for the admission was grouped according to the type of infection: Pneumocystis carinii pneumonia (PCP), viral, fungal, bacterial, and other. Sixty-seven patients (29%) had abnormally low serum zinc levels (LSZ < 55 micrograms/dL), 49 patients (21%) had borderline low serum zinc (BSZ > or = 55 and < or = 65 microgram/dL), and 112 (49%) patients had normal serum zinc levels (NSZ > 65 micrograms/dL). There was no significant difference among the groups in CD4 count, length of HIV seropositivity, presence of diarrhea, or severity of malnutrition. Patients with zinc deficiency (LSZ) had a significantly higher incidence of bacterial infection than did patients with normal zinc. Patients with borderline zinc levels had an intermediate incidence of bacterial infection. There were no significant differences among the three groups in the incidence of PCP, viral, or fungal infections. Severe zinc deficiency was noted in 29% and borderline levels in an additional 21% of hospitalized AIDS patients. A low zinc level was not associated with the length of HIV seropositivity, CD4 count, or degree of malnutrition. Hypozincemia was associated with an increased incidence of concomitant systemic bacterial infections.

Using the patient's history to estimate the probability of coronary artery disease: a comparison of primary care and referral practices.

PURPOSE: According to probability theory, the interpretation of new information should depend on the prior probability of disease. We asked if this principle applies to interpreting the history in patients with chest pain. We compared the prevalence of coronary artery disease (CAD) in patients who had similar histories but who came from populations with different disease prevalence. PATIENTS AND METHODS: We studied two high-disease-prevalence populations (patients referred for coronary arteriography) and two low-disease-prevalence populations (patients from primary care practices). We used clinical characteristics of one arteriography population to develop a logistic rule for estimating the probability of coronary artery narrowing. The number of clinical findings determined the logistic score, which was proportional to the prevalence of CAD. RESULTS: The prevalence of CAD was much lower in the primary care population than in the arteriography population, even when patients with similar logistic scores, and thus similar clinical histories, were compared. CONCLUSION: A clinician must take account of the overall prevalence of disease in the clinical setting when using the patient's history to estimate the probability of disease. Failure to observe this caution may lead to errors in test selection and interpretation.

Diuresis in the ascitic patient: a randomized controlled trial of three regimens.

To compare the efficacy of three commonly used diuretic regimens in the treatment of ascites, we randomized 90 patients to three treatment groups: Sequential Spironolactone (spironolactone followed by furosemide if necessary), Combination (spironolactone and furosemide in combination), and Furosemide (furosemide given alone). Diuretics were begun at a low dose by mouth and the dosage increased until a 0.4-0.8 kg daily diuresis was achieved. The clinical and laboratory findings were comparable for the three experimental groups on admission to the study. All three regimens achieved a comparable rate of diuresis. To do so was far more difficult with furosemide alone, which required repetitious upward adjustments in dosage and massive KCl supplements. The incidence of encephalopathy, hepatorenal syndrome, and marked electrolyte abnormalities was similar for the three treatment groups except that severe hyperkalemia was more frequent on combination therapy. We conclude that diuresis should be initiated with one of the two spironolactone regimens and not with furosemide as the sole agent.

Enhanced bioavailability and decreased clearance of analgesics in patients with cirrhosis.

The effect of moderate cirrhosis on the bioavailability and systemic clearance of three model analgesic compounds (pethidine, pentazocine, and salicylamide) with substantial first-pass metabolism was examined in 8 cirrhotic subjects and 4 agematched healthy controls. There was a 46% decrease in the clearance of pentazocine and a 278% increase in bioavailability. The corresponding figures for pethidine were 36% and 81%. The area under the plasma curve after oral salicylamide was increased by 551% in cirrhotic subjects compared with controls. This study demonstrated that drugs with the highest hepatic clearance will have the largest relative increases in bioavailability in cirrhotic patients due to portosystemic shunting. The decrease in clearance and increase in bioavailability will have multiplicative, rather than simply additive, effects on total area under the curve and, if related, pharmacologic response.