Cascade polycyclizations in natural product synthesis.

Cascade (domino) reactions have an unparalleled ability to generate molecular complexity from relatively simple starting materials; these transformations are particularly appealing when multiple rings are forged during this process. In this tutorial review, we cover recent highlights in cascade polycyclizations as applied to natural product synthesis, including pericyclic, heteroatom-mediated, cationic, metal-catalyzed, organocatalytic, and radical sequences.

Computational ligand design in enantio- and diastereoselective ynamide [5+2] cycloisomerization.

Transition metals can catalyse the stereoselective synthesis of cyclic organic molecules in a highly atom-efficient process called cycloisomerization. Many diastereoselective (substrate stereocontrol), and enantioselective (catalyst stereocontrol) cycloisomerizations have been developed. However, asymmetric cycloisomerizations where a chiral catalyst specifies the stereochemical outcome of the cyclization of a single enantiomer substrate--regardless of its inherent preference--are unknown. Here we show how a combined theoretical and experimental approach enables the design of a highly reactive rhodium catalyst for the stereoselective cycloisomerization of ynamide-vinylcyclopropanes to [5.3.0]-azabicycles. We first establish highly diastereoselective cycloisomerizations using an achiral catalyst, and then explore phosphoramidite-complexed rhodium catalysts in the enantioselective variant, where theoretical investigations uncover an unexpected reaction pathway in which the electronic structure of the phosphoramidite dramatically influences reaction rate and enantioselectivity. A marked enhancement of both is observed using the optimal theory-designed ligand, which enables double stereodifferentiating cycloisomerizations in both matched and mismatched catalyst-substrate settings.

Combining cycloisomerization with trienamine catalysis: a regiochemically flexible enantio- and diastereoselective synthesis of hexahydroindoles.

The synthesis of polysubstituted hexahydroindoles through trienamine-organocatalyzed cycloadditions of pyrrolidinyl dienals, prepared by palladium-catalyzed cycloisomerization, is reported. The cycloadditions of this novel class of dienals proceed with excellent levels of enantio- and diastereoselectivity, with the regioselectivity of cycloaddition with respect to the tethering ring readily tuned through design of the cycloisomerization substrate. This work culminates in the first examples of double-stereodifferentiating trienamine catalysis, where catalyst stereocontrol dominates facial selectivity in the cycloaddition, affording azacyclic products that are specifically functionalized at every position.

Reducing call-to-needle times: the critical role of pre-hospital thrombolysis.

BACKGROUND: Current guidelines recommend that patients with acute myocardial infarction should receive thrombolysis within 60 min of seeking professional help. AIM: To compare current rates of pre-hospital thrombolysis in Grampian with historical data, and assess the effect of pre-hospital thrombolysis on the proportion of patients achieving 'call-to-needle' times within national guidelines. DESIGN: Prospective audit. METHODS: Data were collected on all patients (n=535) admitted to the coronary care unit and thrombolysed, either in hospital or in the community from July 2000 to June 2002, using standardized forms. RESULTS: One hundred and thirty-three patients (25%) received pre-hospital thrombolysis and 402 (75%) received in-hospital thrombolysis. This compares with a 19% (195/1046) pre-hospital thrombolysis rate in the mid-1990s (p=0.005). Median 'call-to-needle' times were 45 min for pre-hospital thrombolysis and 105 min for patients who received in-hospital thrombolysis (p < 0.001). Only 24% (96/396) of patients receiving in-hospital thrombolysis were treated within the recommended guideline, vs. 79% (88/111) of pre-hospital thrombolysis patients (p <0.001). DISCUSSION: Pre-hospital thrombolysis rates in Grampian are increasing. Administration of thrombolysis in the community greatly increases the proportion of patients achieving a 'call-to-needle' time of 60 min, with a median time saving of approximately 1 h.

Mapping of a gene for severe pediatric gastroesophageal reflux to chromosome 13q14.

CONTEXT: Gastroesophageal reflux (GER) has not previously been widely regarded as a hereditary disease. A few reports have suggested, however, that a genetic component may contribute to the incidence of GER, especially in its severe or chronic forms. OBJECTIVE: To identify a genetic locus that cosegregates with a severe pediatric GER phenotype in families with multiple affected members. DESIGN: A genome-wide scan of families affected by severe pediatric GER using polymorphic microsatellite markers spaced at an average of 8 centimorgans (cM), followed by haplotyping and by pairwise and multipoint linkage analyses. SETTING: General US community, with research performed in a university tertiary care hospital. SUBJECTS: Affected and unaffected family members from 5 families having multiple individuals affected by severe pediatric GER, identified through a patient support group. MAIN OUTCOME MEASURES: Determination of inheritance patterns and linkage of a genetic locus with the severe pediatric GER phenotype by logarithm-of-odds (lod) score analysis, considering a lod score of 3 or greater as evidence of linkage. RESULTS: In these families, severe pediatric GER followed an autosomal dominant hereditary pattern with high penetrance. A gene for severe pediatric GER was mapped to a 13-cM region on chromosome 13q between microsatellite markers D13S171 and D13S263. A maximum multifamily 2-point lod score of 5.58 and a maximum multifamily multipoint lod score of 7.15 were obtained for marker D13S1253 at map position 35 cM when presumptively affected persons were modeled as unknown (a maximum multipoint score of 4.88 was obtained when presumptively affected persons were modeled as unaffected). CONCLUSION: These data suggest that a gene for severe pediatric GER maps to chromosome 13q14. JAMA. 2000;284:325-334

Outcomes of a randomized community-level HIV prevention intervention for women living in 18 low-income housing developments.

OBJECTIVES: Women in impoverished inner-city neighborhoods are at high risk for contracting HIV. A randomized, multisite community-level HIV prevention trial was undertaken with women living in 18 low-income housing developments in 5 US cities. METHODS: Baseline and 12-month follow-up population risk characteristics were assessed by surveying 690 women at both time points. In the 9 intervention condition housing developments, a community-level intervention was undertaken that included HIV risk reduction workshops and community HIV prevention events implemented by women who were popular opinion leaders among their peers. RESULTS: The proportion of women in the intervention developments who had any unprotected intercourse in the past 2 months declined from 50% to 37.6%, and the percentage of women's acts of intercourse protected by condoms increased from 30.2% to 47.2%. Among women exposed to intervention activities, the mean frequency of unprotected acts of intercourse in the past 2 months tended to be lower at follow-up (mean = 4.0) than at baseline (mean = 6.0). These changes were corroborated by changes in other risk indicators. CONCLUSIONS: Community-level interventions that involve and engage women in neighborhood-based HIV prevention activities can bring about reductions in high-risk sexual behaviors.

Comparative efficacy and safety of ondansetron, droperidol, and metoclopramide for preventing postoperative nausea and vomiting: a meta-analysis.

UNLABELLED: Postoperative nausea and vomiting are important causes of morbidity after anesthesia and surgery. We performed a meta-analysis of published, randomized, controlled trials to determine the relative efficacy and safety of ondansetron, droperidol, and metoclopramide for the prevention of postoperative nausea and vomiting. We performed a literature search of English references using both the MEDLINE database and a manual search. Double-blinded, randomized, controlled trials comparing the efficiency of the prophylactic administration of ondansetron, droperidol, and/or metoclopramide therapy during general anesthesia were included. A total of 58 studies were identified, of which 4 were excluded for methodological concerns. For each comparison of drugs, a pooled odds ratio (OR) with a 95% CI was calculated using a random effects model. Ondansetron (pooled OR 0.43, 95% CI 0.31, 0.61; P < 0.001) and droperidol (pooled OR 0.68, 95% CI 0.54, 0.85; P < 0.001) were more effective than metoclopramide in preventing vomiting. Ondansetron was more effective than droperidol in preventing vomiting in children (pooled OR 0.49; P = 0.004), but they were equally effective in adults (pooled OR 0.87; P = 0.45). The overall risk of adverse effects was not different among drug combinations. We conclude that ondansetron and droperidol are more effective than metoclopramide in reducing postoperative vomiting. IMPLICATIONS: We performed a systematic review of published, randomized, controlled trials to determine the relative efficacy and safety of ondansetron, droperidol, and metoclopramide for preventing postoperative nausea and vomiting. Ondansetron and droperidol were more effective than metoclopramide in reducing postoperative vomiting. The overall risk of adverse effects did not differ.

Hyperglycemia without hyperinsulinemia produces both sympathetic neural activation and vasodilation in normal humans.

To explore the effects of the acute induction of hyperglycemia on sympathetic activity and vascular function we studied eight normal control subjects (28 +/- 3 years of age). Muscle sympathetic nerve activity (MSNA) and forearm vascular resistance (FVR) were measured before (5.4 +/- 0.2 mmol/L) and during systemic infusion of 20% dextrose with octreotide (250 microg/h) and low dose insulin (4 mU x m(-2) x min(-1)) with 60 min of hyperglycemia (venous plasma glucose, 12.5 +/- 0.6 mmol/L). To control for the effects of hyperosmolarity and volume infusion subjects returned for two control studies with equal volume 20% mannitol and 0.2% saline infusions instead of dextrose infusion. The increase in MSNA during hyperglycemia (178 +/- 48 units) was significantly greater than the increase during mannitol (69 +/- 46 units, p < 0.001) or during 0.2% saline (28 +/- 28 units, p < 0.001). The decreases in FVR after 60 min of hyperglycemia (20 +/- 4 units, p = 0.002) and mannitol (13 +/- 4 units, p = 0.033) were significantly greater than the decrease during saline (0.1 +/- 4 units). The changes in FVR during hyperglycemia and mannitol did not differ. Acute hyperglycemia causes sympathoexcitation and peripheral vasodilation. The vascular effect may be mediated by increased osmolar load.

Hyperinsulinemia produces cardiac vagal withdrawal and nonuniform sympathetic activation in normal subjects.

The exact mechanisms for the decrease in R-R interval (RRI) during acute physiological hyperinsulinemia with euglycemia are unknown. Power spectral analysis of RRI and microneurographic recordings of muscle sympathetic nerve activity (MSNA) in 16 normal subjects provided markers of autonomic control during 90-min hyperinsulinemic/euglycemic clamps. By infusing propranolol and insulin (n = 6 subjects), we also explored the contribution of heightened cardiac sympathetic activity to the insulin-induced decrease in RRI. Slight decreases in RRI (P < 0.001) induced by sevenfold increases in plasma insulin could not be suppressed by propranolol. Insulin increased MSNA by more than twofold (P < 0.001), decreased the high-frequency variability of RRI (P < 0.01), but did not affect the absolute low-frequency variability of RRI. These results suggest that reductions in cardiac vagal tone and modulation contribute at least in part to the reduction in RRI during hyperinsulinemia. Moreover, more than twofold increases in MSNA occurring concurrently with a slight and not purely sympathetically mediated tachycardia suggest regionally nonuniform increases in sympathetic activity during hyperinsulinemia in humans.

Sympathetic nerve activity and insulin sensitivity in normotensive offspring of hypertensive parents.

Insulin resistance and elevated sympathetic nerve activity (SNA) are observed in young borderline hypertensive humans. A positive family history of hypertension (FH) is a strong risk factor for developing hypertension. To assess whether insulin resistance and increased sympathetic tone precede the onset of hypertension, we studied 17 young adults with and 17 without a documented family history of hypertension. Subjects were matched for age (33+/-0.4 years in FH positive and 32+/-0.5 years in FH negative; mean+/-SE) and body mass index (BMI, 25+/-1 kg/m2 in both FH positive and FH negative subjects). We measured blood pressure (BP), heart rate (HR), muscle sympathetic nerve activity (MSNA, microneurography), forearm blood flow, and insulin sensitivity (total glucose uptake determined by an euglycemic/hyperinsulinemic clamp using stable isotope tracer infusion), and calculated forearm vascular resistance (FVR). Mean BP and HR were similar in both groups (86+/-3 mm Hg and 61+/-2 beats/min, and 85+/-2 mm Hg and 62 +/-2 beats/min, respectively, in FH positive and negative respectively, P = ns). Baseline MSNA (24 +/-3 bursts/min in FH positive v 20+/-3 bursts/min in FH negative, P = ns) and total glucose uptake [0.104+/-0.014 mg/(kg x min x microU insulin/mL) in FH positive v 0.095+/-0.014 mg/(kg xmin x microU insulin/mL) in FH negative, P = ns] did not differ between the groups. Sympathetic and vascular responses to insulin were also similar in both groups. The increase in MSNA was 10+/-2 bursts/ min in FH positive and 10+/-1 bursts/min in FH negative, P = ns. Thus, age- and weight-matched offspring with and without a FH of hypertension did not vary in MSNA or insulin sensitivity. These findings suggest that in the absence of obesity and high arterial pressure, a FH of hypertension may not be accompanied by decreased insulin sensitivity or increased MSNA.

Frequency response characteristics of sympathetically mediated vasomotor waves in humans.

In a recent study, we demonstrated that transmission from peripheral sympathetic nerves to vascular smooth muscles is strongest in the frequency band from 0.2 to 0.5 Hz in conscious rats. In contrast, sympathetic modulation of vasomotor tone in humans is suggested to be reflected in the power spectrum of arterial blood pressure in a frequency range centered around approximately 0.1 Hz. Therefore, we addressed whether frequency response characteristics of sympathetic transmission from peripheral sympathetic nerves to vascular smooth muscles in humans differ from those in rats. In 12 male subjects, skin-sympathetic fibers of the left median nerve were electrically stimulated via microneurography needles with stimulation frequencies ranging from 0.01 to 0.5 Hz. Simultaneously, blood flow in the innervated skin area at the palm of the ipsilateral hand was recorded by a laser-Doppler device. The skin blood flow in the same area of the contralateral hand was recorded as a control. Median nerve stimulation produced transient decreases in skin blood flow in the ipsilateral hand. At frequencies ranging from 0.025 to 0.10 Hz, median nerve stimulation evoked high-power peaks at the same frequencies in the skin blood flow power spectra of the ipsilateral but not of the contralateral hand. The greatest responses were found in the frequency range from 0.075 to 0.10 Hz. Therefore, these data indicate that the transmission from peripheral sympathetic nerves to cutaneous vascular smooth muscles in humans is slower than in rats. In addition, the frequency range believed to be most important in sympathetic modulation of vasomotor activity in humans corresponds to the frequency band of the greatest response of cutaneous vascular smooth muscle contraction to sympathetic nerve stimulation.

Pulmonary blood flow redistribution with low levels of positive end-expiratory pressure.

BACKGROUND: Recent studies have questioned the importance of the gravitational model of pulmonary perfusion. Because low levels of positive end-expiratory pressure (PEEP) are commonly used during anesthesia, the authors studied the distribution of pulmonary blood flow with low levels of PEEP using a high spatial resolution technique. They hypothesized that if hydrostatic factors were important in the distribution of pulmonary blood flow, PEEP would redistribute flow to more dependent lung regions. METHODS: The effects of zero cm H2O PEEP and 5 cm H2O PEEP on pulmonary gas exchange were studied using the multiple inert gas elimination technique; the distribution of pulmonary blood flow, using fluorescent-labeled microspheres, was also investigated in mechanically ventilated, pentobarbital-anesthetized dogs. The lungs were removed, cleared of blood, dried at total lung capacity, and then cubed to obtain approximately 1,000 small pieces of lung (approximately 1.7 cm3). RESULTS: Positive end-expiratory pressure increased the partial pressure of oxygen by 6 +/- 2 mmHg (P < 0.05) and reduced all measures of ventilation and perfusion heterogeneity (P < 0.05). By reducing flow to nondependent ventral lung regions and increasing flow to dependent dorsal lung regions, PEEP increased (P < 0.05) the dorsal-to-ventral gradient. Redistribution of blood flow with PEEP accounted for 7 +/- 3%, whereas structural factors accounted for 93 +/- 3% of the total variance in blood flow. CONCLUSIONS: The increase in dependent-to-nondependent gradient with PEEP is partially consistent with the gravitationally based lung zone model. However, the results emphasize the greater importance of anatomic factors in determining the distribution of pulmonary blood flow.

Microneurographically determined muscle sympathetic nerve activity levels are reproducible in insulin-dependent diabetes mellitus.

Our objective was to determine whether microneurographically determined muscle sympathetic nerve activity (MSNA) levels are equally reproducible in control and insulin-dependent diabetes mellitus (IDDM) subjects. We used a retrospective review of MSNA levels in 14 IDDM and 16 control subjects who had at least two microneurographic studies in the last 8 years in our laboratory. Results showed mean MSNA levels were lower in IDDM (9.2+/-1.2 bursts/min) than in control subjects (16.8+/-1.7 bursts/min) (p<0.002) but mean within individual MSNA coefficients (IDDM: 47+/-8%; controls 30+/-5%) and ranges of variation (IDDM: 6.6+/-1.9; controls: 7.5+/-1.9 bursts/min) did not differ between IDDM and control subjects. Thus, microneurographically determined MSNA levels are equally reproducible in IDDM and controls subjects. These results confirm and substantiate our previous findings of diminished MSNA in IDDM subjects.

Heart rate variability before and after treatment with electroconvulsive therapy.

It has been suggested that depression may be associated with decreased parasympathetic activity. Based on this work, we tested the hypothesis that treatment of depression with electroconvulsive therapy (ECT) would result in a relative increase in cardiac vagal (parasympathetic) activity. Changes in respiratory sinus arrhythmia, a marker of cardiac parasympathetic activity, were examined in nine patients with depressive episodes before and after ECT using spectral analysis. Hamilton Depression Rating Scale scores decreased significantly. In terms of the heart rate measures, RR interval tended to decrease and the amplitude of respiratory sinus arrhythmia decreased significantly following the course of ECT. This reduction in respiratory sinus arrhythmia contributed to the overall decrease in RR interval variability. Additionally, the magnitude of symptom improvement as measured by the Hamilton Scale correlated with the decrease in amplitude of the respiratory sinus arrhythmia. We report that treatment of depression with ECT was associated with a relative decrease in parasympathetic activity, in contrast to our initial hypothesis of a relative increase. This finding may not be related to the ECT per se but rather to the resolution of depression, as there was a significant correlation between the decrease in Hamilton Depression Rating Scale scores and decrease in parasympathetic activity. Further work is necessary to better understand the autonomic changes associated with depressive illness and the clinical risks and benefits associated with various treatment modalities.

Contrasting autonomic and hemodynamic effects of insulin in healthy elderly versus young subjects.

Acute increases in plasma insulin produce both sympathoexcitation and vasodilation in normal young adults. Aging is associated with insulin resistance and may alter the sympathetic or the vascular responses to insulin. Therefore, we assessed sympathetic and vascular responses to acute physiological increases in plasma insulin levels in 10 healthy, normotensive elderly (65+/-2 years) and 12 normal young (27+/-1 years) subjects matched for body mass index (25+/-1 kg/m2 in both groups). We measured muscle sympathetic nerve activity (microneurography), FBF (plethysmography), heart rate, and blood pressure and calculated forearm vascular resistance and insulin sensitivity (M value) during a 90-minute hyperinsulinemic/euglycemic clamp. M values were 4.3+/-0.4 mg x kg(-1) x min(-1) in the elderly and 8.4+/-1.4 mg x kg(-1) x min(-1) in the young subjects (P<.05). Baseline muscle sympathetic nerve activity was higher in the elderly subjects (33+/-3 versus 15+/-2 bursts per minute, P<.05); however, the absolute and percent increases in muscle sympathetic nerve activity were smaller in the elderly than in the young subjects (+10+/-1 versus +15+/-1 bursts per minute, or +37+/-11% versus +110+/-16%, P<.05). Forearm vascular resistance decreased with insulin from 46+/-2 to 31+/-3 units in the young but increased with insulin in the elderly subjects from 37+/-3 to 47+/-7 units (P<.05). Heart rate increased in young but not in elderly subjects. Insulin did not change blood pressure in either group. In conclusion, as opposed to vasodilation in young adults, insulin caused vasoconstriction in healthy elderly individuals. The failure of the vasodilator action of insulin in the elderly may permit even modest insulin-induced sympathoexcitation to elicit vasoconstriction. We speculate that the vasoconstrictor response to insulin may further potentiate insulin resistance in the elderly.

Hypoglycemic symptom variation is related to epinephrine and not peripheral muscle sympathetic nerve response.

Hypoglycemic unawareness may be due to diminished adrenal and/or peripheral sympathochromaffin responses to hypoglycemia. To determine whether hypoglycemic symptom awareness is more closely related to adrenal or nonadrenal sympathetic activity, we studied the relationship between symptoms and the epinephrine, norepinephrine, and muscle sympathetic nerve activity (MSNA) responses to hypoglycemia in ten IDDM and ten control subjects. MSNA was measured continuously using microneurography during hyperinsulinemic (720 pmol m-2 min-1), glucose clamp with 60 min of euglycemia, 30 min of hypoglycemia, and 30 min of recovery. Subjects were asked to rate a series of symptoms every 10 min during the last 30 min of each period and were unaware of their plasma glucose concentration. MSNA increased significantly in both groups during insulin clamp (p < 0.05) and further increased during hypoglycemia (p < 0.01). Both epinephrine and norepinephrine levels significantly increased during hypoglycemia (p < 0.02). The increase in adrenergic symptom responses during hypoglycemia positively correlated with epinephrine (r = 0.75, p < 0.01), but not with MSNA in the control subjects. A similar near significant relationship for epinephrine was seen in IDDM subjects (r = 0.65, p = 0.056). No significant predictors were found for neuroglycopenic or cholinergic symptoms. Thus, the variation in hypoglycemic symptoms is not related to the MSNA response to hypoglycemia. Adrenergic symptom variation is due to differences in adrenal epinephrine secretion.

African-American homeless and low-income housed mothers: comparison of parenting practices.

The child-rearing practices of homeless and low-income housed mothers of preschool children in Head Start were compared. Overall, homeless mothers provided less learning and academic stimulation, less variety in social and cultural experiences, less warmth and affection, and a less positive physical environment for their children than did housed mothers. Mothers in both living arrangements provided more language stimulation to daughters than to sons. Implications of the findings for working with homeless families are discussed.

Tonic chemoreflex activation does not contribute to elevated muscle sympathetic nerve activity in heart failure.

BACKGROUND: Sympathetic activation in heart failure may be due to an increase in sympathetic excitatory influences or to a decrease in inhibitory signals to the brain stem. Chemoreflex sensitivity may be increased in patients with heart failure. The present study tested the hypothesis that tonic activation of excitatory chemoreceptor afferents contributes to the elevated sympathetic activity in heart failure. METHODS AND RESULTS: We recorded sympathetic nerve activity to muscle circulation from the peroneal nerve of 12 chronic heart failure patients while the patients were breathing room air and during deactivation of the chemoreceptors while the patients were breathing a 100% O2 gas mixture. All patients except 2 were in class III of the New York Heart Association functional classification. Left ventricular ejection fraction defined by radionuclide ventriculography was 24 +/- 2% (mean +/- SE). We also obtained measurements of resting sympathetic nerve activity in 9 healthy control subjects to document that sympathetic nerve activity was elevated in heart failure subjects. Resting sympathetic nerve activity was 59 +/- 5 bursts/min in heart failure patients versus 36 +/- 4 bursts/min in control subjects (P < .01). In heart failure patients, oxygen administration increased oxygen saturation from 94 +/- 0.9% to 99 +/- 0.3% (P < .0001). This increase in oxygen saturation did not affect resting muscle sympathetic nerve activity (798 +/- 122 U/min while patients breathed room air and 824 +/- 35 U/min during 100% O2 breathing) or blood pressure. CONCLUSIONS: Increased efferent sympathetic activity to muscle circulation in patients with heart failure is not explained by tonic activation of excitatory chemoreflex afferents.