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BACKGROUND: The effect of docosahexaenoic acid (DHA) on the developing fetal central nervous system (CNS) and related functional outcomes in infancy remain unexplored. Sleep and wake states of newborns provide a tool for assessing the functional integrity of the CNS. OBJECTIVE: We investigated whether CNS integrity in newborns, measured with sleep recordings, was associated with maternal concentrations of long-chain polyunsaturated fatty acids, especially DHA. DESIGN: Plasma phospholipid fatty acid concentrations were measured in 17 women at parturition. On postpartum day 1 (P1) and day 2 (P2), a pressure-sensitive pad under the infants' bedding recorded body movements and respiratory patterns to measure sleep and wake states. RESULTS: Maternal plasma phospholipid DHA ranged from 1.91% to 4.5% by wt of total fatty acids. On the basis of previously published data and the median DHA concentration, the women were divided into 2 groups: high DHA (> 3.0% by wt of total fatty acids) and low DHA (

Acute kidney injury (AKI) is a common complication in cardiac surgery patients, with a reported incidence of 20 to 30%. The development of AKI is associated with worse short- and long-term mortality, and longer hospital length of stay. The pathogenesis of cardiac surgery-associated AKI is poorly understood but likely involves an interplay between preoperative comorbidities and perioperative stressors. AKI is commonly diagnosed by using increases in serum creatinine or decreased urine output and staged using a standardized definition such as the Kidney Disease Improving Global Outcomes classification. Novel biomarkers under investigation may provide earlier detection and better prediction of AKI, enabling mitigating therapies early in the perioperative period. Recent clinical trials of cardiac surgery patients have demonstrated the benefit of goal-directed oxygen delivery, avoidance of hyperthermic perfusion and specific fluid and medication strategies. This review article highlights both advances and limitations regarding the prevention, prediction, and treatment of cardiac surgery-associated AKI., (Copyright © 2023 American Society of Anesthesiologists. All Rights Reserved.)

Introduction. Thoracic interfascial plane blocks are increasingly used for pain management after minimally invasive thoracotomy for valve repair and replacement procedures. We hypothesized that the addition of these blocks to the intercostal nerve block injected by the surgeon would further reduce pain scores and opioid utilization. Methods. In this retrospective cohort study, 400 consecutive patients who underwent minimally invasive thoracotomy for mitral or aortic valve replacement and were extubated within 2 hours of surgery were enrolled. The maximum pain score and opioid utilization on the day of surgery and other outcome variables were compared between patients who received interfascial plane blocks and those who did not. Results. 193 (48%) received at least one interfascial plane block while 207 (52%) received no interfascial plane block. Patients who received a thoracic interfascial plane block had a maximum VAS score on the day of surgery (mean 7.4 ± 2.5) after the block was administered which was significantly lower than patients in the control group who did not receive the block (mean 7.9 ± 2.2) ( P = .02). Opioid consumption in the interfascial plane block group on the day of surgery was not significantly different from the control group. Conclusion. Compared to intercostal blocks alone, the addition of thoracic interfascial plane blocks was associated with a modest reduction in maximum VAS score on the day of surgery. However, no difference in opioid consumption was noted. Patients who received interfascial plane blocks also had decreased blood transfusion requirements and a shorter hospital length of stay.

Introduction: The goal of this investigation is to assess the association between prehospital use of aspirin (ASA) and patient-centered outcomes in a large global cohort of hospitalized COVID-19 patients., Methods: This study utilizes data from the Society of Critical Care Medicine Discovery Viral Infection and Respiratory Illness Universal Study (VIRUS) Registry. Adult patients hospitalized from February 15th, 2020, to September 30th, 2021, were included. Multivariable regression analyses were utilized to assess the association between pre-hospital use of ASA and the primary outcome of overall hospital mortality., Results: 21,579 patients were included from 185 hospitals (predominantly US-based, 71.3%), with 4691 (21.7%) receiving pre-hospital ASA. Patients receiving ASA, compared to those without pre-admission ASA use, were generally older (median 70 vs. 59 years), more likely to be male (58.7 vs. 56.0%), caucasian (57.4 vs. 51.6%), and more commonly had higher rates of medical comorbidities. In multivariable analyses, patients receiving pre-hospital ASA had lower mortality (HR: 0.89, 95% CI 0.82-0.97, p=0.01) and reduced hazard for progression to severe disease or death (HR: 0.91, 95% CI 0.84-0.99, p=0.02) and more hospital free days (1.00 days, 95% CI 0.66-1.35, p=0.01) compared to those without pre-hospital ASA use. The overall direction and significance of the results remained the same in sensitivity analysis, after adjusting the multivariable model for time since pandemic., Conclusions: In this large international cohort, pre-hospital use of ASA was associated with a lower hazard for death in hospitalized patients with COVID-19. Randomized controlled trials may be warranted to assess the utility of pre-hospital use of ASA., (Copyright © 2022 SEPAR. Published by Elsevier España, S.L.U. All rights reserved.)

Objectives: To determine the association of prior use of renin-angiotensin-aldosterone system inhibitors (RAASIs) with mortality and outcomes in hospitalized patients with COVID-19., Design: Retrospective observational study., Setting: Multicenter, international COVID-19 registry., Subjects: Adult hospitalized COVID-19 patients on antihypertensive agents (AHAs) prior to admission, admitted from March 31, 2020, to March 10, 2021., Interventions: None., Measurements and Main Results: Data were compared between three groups: patients on RAASIs only, other AHAs only, and those on both medications. Multivariable logistic and linear regressions were performed after controlling for prehospitalization characteristics to estimate the effect of RAASIs on mortality and other outcomes during hospitalization. Of 26,652 patients, 7,975 patients were on AHAs prior to hospitalization. Of these, 1,542 patients (19.3%) were on RAASIs only, 3,765 patients (47.2%) were on other AHAs only, and 2,668 (33.5%) patients were on both medications. Compared with those taking other AHAs only, patients on RAASIs only were younger (mean age 63.3 vs 66.9 yr; p < 0.0001), more often male (58.2% vs 52.4%; p = 0.0001) and more often White (55.1% vs 47.2%; p < 0.0001). After adjusting for age, gender, race, location, and comorbidities, patients on combination of RAASIs and other AHAs had higher in-hospital mortality than those on RAASIs only (odds ratio [OR] = 1.28; 95% CI [1.19-1.38]; p < 0.0001) and higher mortality than those on other AHAs only (OR = 1.09; 95% CI [1.03-1.15]; p = 0.0017). Patients on RAASIs only had lower mortality than those on other AHAs only (OR = 0.87; 95% CI [0.81-0.94]; p = 0.0003). Patients on ACEIs only had higher mortality compared with those on ARBs only (OR = 1.37; 95% CI [1.20-1.56]; p < 0.0001)., Conclusions: Among patients hospitalized for COVID-19 who were taking AHAs, prior use of a combination of RAASIs and other AHAs was associated with higher in-hospital mortality than the use of RAASIs alone. When compared with ARBs, ACEIs were associated with significantly higher mortality in hospitalized COVID-19 patients., Competing Interests: Dr. Perkins received funding from TelmedIQ. Dr. Kaufman’s institution received funding from the Society of Critical Care Medicine, and she received funding from consulting for Mendaera. Dr. Christie’s institution received funding from Navicent Health Foundation. Ms. Boman, Drs. Kumar’s, Walkey’s, and Kashyap’s institutions received funding from the Gordon and Betty Moore Foundation. Ms. Boman, Drs. Kumar’s, and Kashyap’s institutions received funding from Janssen R & D. Dr. Aston’s institution received funding from the National Institutes of Health. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2022 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Background: The use of high-flow nasal cannula (HFNC) and noninvasive ventilation (NIV) for hypoxemic respiratory failure secondary to COVID-19 are recommended by critical-care guidelines; however, apprehension about viral particle aerosolization and patient self-inflicted lung injury may have limited use. We aimed to describe hospital variation in the use and clinical outcomes of HFNC and NIV for the management of COVID-19., Methods: This was a retrospective observational study of adults hospitalized with COVID-19 who received supplemental oxygen between February 15, 2020, and April 12, 2021, across 102 international and United States hospitals by using the COVID-19 Registry. Associations of HFNC and NIV use with clinical outcomes were evaluated by using multivariable adjusted hierarchical random-effects logistic regression models. Hospital variation was characterized by using intraclass correlation and the median odds ratio., Results: Among 13,454 adults with COVID-19 who received supplemental oxygen, 8,143 (60%) received nasal cannula/face mask only, 2,859 (21%) received HFNC, 878 (7%) received NIV, 1,574 (12%) received both HFNC and NIV, with 3,640 subjects (27%) progressing to invasive ventilation. The hospital of admission contributed to 24% of the risk-adjusted variation in HFNC and 30% of the risk-adjusted variation in NIV. The median odds ratio for hospital variation of HFNC was 2.6 (95% CI 1.4-4.9) and of NIV was 3.1 (95% CI 1.2-8.1). Among 5,311 subjects who received HFNC and/or NIV, 2,772 (52%) did not receive invasive ventilation and survived to hospital discharge. Hospital-level use of HFNC or NIV were not associated with the rates of invasive ventilation or mortality., Conclusions: Hospital variation in the use of HFNC and NIV for acute respiratory failure secondary to COVID-19 was great but was not associated with intubation or mortality. The wide variation and relatively low use of HFNC/NIV observed within our study signaled that implementation of increased HFNC/NIV use in patients with COVID-19 will require changes to current care delivery practices. (ClinicalTrials.gov registration NCT04323787.)., (Copyright © 2022 by Daedalus Enterprises.)

To describe the prevalence, associated risk factors, and outcomes of serious neurologic manifestations (encephalopathy, stroke, seizure, and meningitis/encephalitis) among patients hospitalized with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection., Design: Prospective observational study., Setting: One hundred seventy-nine hospitals in 24 countries within the Society of Critical Care Medicine Discovery Viral Infection and Respiratory Illness Universal Study COVID-19 Registry., Patients: Hospitalized adults with laboratory-confirmed SARS-CoV-2 infection., Interventions: None., Results: Of 16,225 patients enrolled in the registry with hospital discharge status available, 2,092 (12.9%) developed serious neurologic manifestations including 1,656 (10.2%) with encephalopathy at admission, 331 (2.0%) with stroke, 243 (1.5%) with seizure, and 73 (0.5%) with meningitis/encephalitis at admission or during hospitalization. Patients with serious neurologic manifestations of COVID-19 were older with median (interquartile range) age 72 years (61.0-81.0 yr) versus 61 years (48.0-72.0 yr) and had higher prevalence of chronic medical conditions, including vascular risk factors. Adjusting for age, sex, and time since the onset of the pandemic, serious neurologic manifestations were associated with more severe disease (odds ratio [OR], 1.49; p < 0.001) as defined by the World Health Organization ordinal disease severity scale for COVID-19 infection. Patients with neurologic manifestations were more likely to be admitted to the ICU (OR, 1.45; p < 0.001) and require critical care interventions (extracorporeal membrane oxygenation: OR, 1.78; p = 0.009 and renal replacement therapy: OR, 1.99; p < 0.001). Hospital, ICU, and 28-day mortality for patients with neurologic manifestations was higher (OR, 1.51, 1.37, and 1.58; p < 0.001), and patients had fewer ICU-free, hospital-free, and ventilator-free days (estimated difference in days, -0.84, -1.34, and -0.84; p < 0.001)., Conclusions: Encephalopathy at admission is common in hospitalized patients with SARS-CoV-2 infection and is associated with worse outcomes. While serious neurologic manifestations including stroke, seizure, and meningitis/encephalitis were less common, all were associated with increased ICU support utilization, more severe disease, and worse outcomes., Competing Interests: The authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2022 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Rationale: The impact of palliative care consultation on end-of-life care has not previously been evaluated in a multi-center study., Objectives: To evaluate the impact of palliative care consultation on the incidence of cardiopulmonary resuscitation (CPR) performed and comfort care received at the end-of-life in hospitalized patients with COVID-19., Methods: We used the Society of Critical Care Medicine's COVID-19 registry to extract clinical data on patients hospitalized with COVID-19 between March 31st, 2020 to March 17th, 2021 and died during their hospitalization. The proportion of patients who received palliative care consultation was assessed in patients who did and did not receive CPR (primary outcome) and comfort care (secondary outcome). Propensity matching was used to account for potential confounding variables., Measurements and Main Results: 3,227 patients were included in the analysis. There was no significant difference in the incidence of palliative care consultation between the CPR and no-CPR groups (19.9% vs. 19.4%, p = 0.8334). Patients who received comfort care at the end-of-life were significantly more likely to have received palliative care consultation (43.3% vs. 7.7%, p < 0.0001). After propensity matching for comfort care on demographic characteristics and comorbidities, this relationship was still significant (43.2% vs. 8.5%; p < 0.0001)., Conclusion: Palliative care consultation was not associated with CPR performed at the end-of-life but was associated with increased incidence of comfort care being utilized. These results suggest that utilizing palliative care consultation at the end-of-life may better align the needs and values of patients with the care they receive., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Kumar is currently funded by funding the Gordon and Betty Moore Foundation, Centers for Disease Control and Prevention Foundation through the University of Washington, and Janssen Research & Development, LLC. Dr. Kashyap receives funding from the NIH/National Heart, Lung and Blood Institute: R01HL 130881, UG3/UH3HL 141722; Gordon and Betty Moore Foundation and Janssen Research & Development, LLC; and royalties from Ambient Clinical Analytics. Inc. Dr. Gajic receives funding from the Agency of Healthcare Research and Quality R18HS 26609-2, NIH/National Heart, Lung and Blood Institute: R01HL 130881, UG3/UH3HL 141722; Department of Defense DOD W81XWH; American Heart Association Rapid Response Grant—COVID-19; and royalties from Ambient Clinical Analytics. Inc. Dr. Walkey currently receives funding from the NIH/National Heart, Lung and Blood Institute grants R01HL151607, R01HL139751, R01HL136660, Agency of Healthcare Research and Quality, R01HS026485, Boston Biomedical Innovation Center/NIH/NHLBI 5U54HL119145-07, and royalties from UpToDate., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Importance: Obesity, diabetes, and hypertension are common comorbidities in patients with severe COVID-19, yet little is known about the risk of acute respiratory distress syndrome (ARDS) or death in patients with COVID-19 and metabolic syndrome., Objective: To determine whether metabolic syndrome is associated with an increased risk of ARDS and death from COVID-19., Design, Setting, and Participants: This multicenter cohort study used data from the Society of Critical Care Medicine Discovery Viral Respiratory Illness Universal Study collected from 181 hospitals across 26 countries from February 15, 2020, to February 18, 2021. Outcomes were compared between patients with metabolic syndrome (defined as ≥3 of the following criteria: obesity, prediabetes or diabetes, hypertension, and dyslipidemia) and a control population without metabolic syndrome. Participants included adult patients hospitalized for COVID-19 during the study period who had a completed discharge status. Data were analyzed from February 22 to October 5, 2021., Exposures: Exposures were SARS-CoV-2 infection, metabolic syndrome, obesity, prediabetes or diabetes, hypertension, and/or dyslipidemia., Main Outcomes and Measures: The primary outcome was in-hospital mortality. Secondary outcomes included ARDS, intensive care unit (ICU) admission, need for invasive mechanical ventilation, and length of stay (LOS)., Results: Among 46 441 patients hospitalized with COVID-19, 29 040 patients (mean [SD] age, 61.2 [17.8] years; 13 059 [45.0%] women and 15713 [54.1%] men; 6797 Black patients [23.4%], 5325 Hispanic patients [18.3%], and 16 507 White patients [57.8%]) met inclusion criteria. A total of 5069 patients (17.5%) with metabolic syndrome were compared with 23 971 control patients (82.5%) without metabolic syndrome. In adjusted analyses, metabolic syndrome was associated with increased risk of ICU admission (adjusted odds ratio [aOR], 1.32 [95% CI, 1.14-1.53]), invasive mechanical ventilation (aOR, 1.45 [95% CI, 1.28-1.65]), ARDS (aOR, 1.36 [95% CI, 1.12-1.66]), and mortality (aOR, 1.19 [95% CI, 1.08-1.31]) and prolonged hospital LOS (median [IQR], 8.0 [4.2-15.8] days vs 6.8 [3.4-13.0] days; P < .001) and ICU LOS (median [IQR], 7.0 [2.8-15.0] days vs 6.4 [2.7-13.0] days; P < .001). Each additional metabolic syndrome criterion was associated with increased risk of ARDS in an additive fashion (1 criterion: 1147 patients with ARDS [10.4%]; P = .83; 2 criteria: 1191 patients with ARDS [15.3%]; P < .001; 3 criteria: 817 patients with ARDS [19.3%]; P < .001; 4 criteria: 203 patients with ARDS [24.3%]; P < .001)., Conclusions and Relevance: These findings suggest that metabolic syndrome was associated with increased risks of ARDS and death in patients hospitalized with COVID-19. The association with ARDS was cumulative for each metabolic syndrome criteria present.

Lung transplantation is considered the gold standard for patients with chronic end-stage pulmonary disease. However, due to the complexity of management and relatively lower median survival as compared to other solid organs, many programs across the world have been slow to adopt the same. In our institution, we started lung transplantation in September 1990. And since then, we performed close to 900 lung transplantations. Here, we describe in detail the operative steps adopted in our institution for a successful lung transplantation. There have been very few variations over the years. We believe that having a standardized technique is one of the important features for success of a lung transplant program., Competing Interests: Conflict of interestThe authors declare no competing interests., (© The Author(s) 2021.)

Early childhood caries is a condition that impacts oral health-related quality of life of children's development and well being and also affects parents' work hours and poses a financial burden on them. Our objective was to study and compare the impact of early childhood caries on the quality of life of preschool children aged 22-70 months and their caregivers in an urban and rural population using the early childhood oral health impact scale. The study was conducted on children of the Rangareddy district, Telangana state, aged between 22 -70 months affected by early childhood caries and their parents/guardians. The subjects were given a questionnaire to measure the early childhood oral health impact scale, and the filled questionnaires were analyzed and tabulated. The mean early childhood oral health impact scale and domain scores for the rural population were significantly higher than that of the urban population signifying a more mediocre quality of life. There was a weak positive and insignificant relationship between early childhood caries and the early childhood oral health impact scale in the rural population, whereas there was a moderately strong, significant positive relationship between the two in the urban population. Oral health-related quality of life of young children enables parents and caregivers to implement positive dental care practices., (©Carol Davila University Press.)

Aim: The aim of this study is to investigate whether the Dental Discomfort Questionnaire (DDQ) could help to identify toothaches in children with autism spectrum disorder (ASD)., Materials and Methods: This study involved sixty children between the age groups of 6-16 years, attending the day-care schools diagnosed with ASD. Five different groups of children were identified based on the presence of a toothache and/or carious teeth. The DDQ-8 was completed by parents and evaluated by a single examiner. Data were analyzed using descriptive statistics (SPSS version 17), and a correlation was observed between the total DDQ score and the decayed, missing, and filled teeth (dmft-DMFT) score., Results: Analysis of the data showed that DDQ-8 had a significant correlation with that of DMFT score in a group "with carious teeth but no toothache" ( r = 0.497, P = 0.019) and group "with carious teeth and a toothache" ( r = 0.682 P = 0.043). A group "without carious teeth where the parents were not sure whether or not the child had a toothache" had higher mean compared to other groups with DDQ-8 scores., Conclusion: There was a significant difference in the total mean DDQ scores when they were compared with that of the control group. Children with high DDQ-8 often had a high DMFT/dmft score. A significant correlation was found when the total DDQ-8 scores were compared with that of the DMFT score., Competing Interests: There are no conflicts of interest., (Copyright: © 2020 Contemporary Clinical Dentistry.)

Aim: This study aimed to investigate the oral and nasal prevalence of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) in 4 to 13-year-old rural schoolchildren., Materials and Methods: A total of 100 children aged 4 to 13 years were randomly selected and divided into ten groups based on their age (Group 1 = 4-year-old children to Group 10 = 13-year-old children). From each participating child, sampling was done from the anterior nares and dorsum of the tongue. All samples were inoculated into Baird-Parker agar medium and HiCrome™ MeReSa agar medium for the isolation of SA and MRSA. Both the culture plates were checked for the presence of SA and MRSA and overall SA and MRSA carriage. The distribution of SA and MRSA was evaluated. Descriptive statistics were performed using SPSS software (version 17.0)., Results: Overall SA in 4-13 years' age group was 47%, while CA-MRSA was 35%. On the tongue, 16 children had concomitant MRSA and SA, while only 23.8% ( n = 20) of the children comprised the presence of SA when MRSA was absent ( P < 0.001). In the nasal cavity, 30 children had concomitant MRSA and SA, while only 21.4% ( n = 15) of the children had the presence of SA when MRSA was absent ( P < 0.001). When tongue and nose were assessed, 11 children encompassed concomitant MRSA and SA, while only 16.9% ( n = 13) of the children had the presence of SA when MRSA was absent in both sites ( P < 0.001)., Conclusion: A significant relation was found between nasal SA and CA-MRSA carriage, with oral SA and CA-MRSA carriage. The study concludes that oral cavity is possibly as important as the nasal area as a zone of SA and MRSA. Dentists dealing with pediatric population should take proper precautions to prevent cross contamination of SA and MRSA in the dental clinic., Competing Interests: There are no conflicts of interest., (Copyright: © 2019 Contemporary Clinical Dentistry.)

Morbid obesity is associated with impairment of cardiovascular, pulmonary, gastrointestinal, and renal physiology with significant perioperative consequences and has been linked with higher morbidity and mortality after cardiac surgery. Cardiac surgery patients have a higher incidence of difficult airway and difficult laryngoscopy than general surgery patients do, and obesity is associated with difficult mask ventilation and direct laryngoscopy. Positioning injuries occur more frequently because obese patients are at greater risk of pressure injury, such as rhabdomyolysis and compartment syndrome. Despite the association between obesity and several chronic disease states, the effects of obesity on perioperative outcomes are conflicting. Studies examining outcomes of overweight and obese patients in cardiac surgery have reported varying results. An "obesity paradox" has been described, in which the mortality for overweight and obese patients is lower compared with patients of normal weight. This review describes the physiologic abnormalities and clinical implications of obesity in cardiac surgery and summarizes recommendations for anesthesiologists to optimize perioperative care of the obese cardiac surgical patient., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The dental arch perimeter and transpalatal width are the most significant arch dimensions in the developing individuals. Its management during the primary, mixed and early permanent dentition are greatly important for the normal development of the dental arches and significantly improve the occlusion in adulthood. Malocclusion is a constant source of threat to the facial appearance. Severe anterior crowding and narrow maxillary arches adversely affect the smile, facial profile and consequently patient becomes handicapped socially as well as psychologically. Maxillary expansion has been used in resolving the problems of crowding, constricted arches and allow for forward growth of the mandible in growing children. This case report describes the use of a customized modified Haas appliance in intercepting the maxillary anterior crowding and gain the transpalatal width and arch perimeter of the maxilla, enhance the smile and facial profile and to allow the forward mandibular growth without any anterior occlusal interferences.

Early loss of permanent anterior teeth in growing children has a psychological impact on the child. Anterior teeth are important both aesthetically and functionally. When a permanent tooth is lost, the teeth adjacent to the created space tend to migrate into the space resulting in the space loss. Management of regaining space with the removable appliance always depends on child cooperation for using the appliance as well as for the recall visits. The advantages of fixed appliances over the removable appliances are minimal discomfort, reduced need for patient cooperation and increased control of tooth movements in all three directions of space. Thus, a short course of fixed appliance like the modified 2 by 3 fixed appliance followed by fixed functional space maintainer could be an ideal treatment option for such cases.

Optimization of a benzofuranyl S1P1 agonist lead compound (3) led to the discovery of 1-(3-fluoro-4-(5-(2-fluorobenzyl)benzo[d]thiazol-2-yl)benzyl)azetidine-3-carboxylic acid (14), a potent S1P1 agonist with minimal activity at S1P3. Dosed orally at 0.3 mg/kg, 14 significantly reduced blood lymphocyte counts 24 h postdose and attenuated a delayed type hypersensitivity (DTH) response to antigen challenge.

Cells acquire cholesterol either by de novo synthesis in the endoplasmic reticulum or by internalization of cholesterol-containing lipoproteins, particularly low density lipoprotein (LDL), via receptor-mediated endocytosis. The inherited disorder Niemann-Pick type C (NPC), in which abnormal LDL-cholesterol trafficking from the endo/lysosomal compartment leads to substantial cholesterol and glycolipid accumulation in lysosomes, is caused by defects in either of two genes that encode for proteins designated as NPC1 and NPC2. NPC2 is a small intralysosomal protein that has been characterized biochemically as a cholesterol binding protein. We determined the rate and mechanism by which NPC2 delivers cholesterol to model phospholipid membranes. A fluorescence dequenching assay was used to monitor the kinetics of cholesterol transfer from the protein to membranes. The endogenous tryptophan fluorescence of the NPC2 was quenched upon binding of cholesterol, and the subsequent addition of acceptor vesicles resulted in dequenching of the tryptophan signal, enabling the monitoring of cholesterol transfer to membranes. The rates of cholesterol transfer were evaluated as a function of acceptor vesicle concentration, acceptor vesicle phospholipid headgroup composition, and aqueous phase properties. The results suggest that NPC2 rapidly transports cholesterol to phospholipid vesicles via a collisional mechanism which involves a direct interaction with the acceptor membrane. Transfer of cholesterol to membranes is faster in an acidic environment and is greatly enhanced by the presence of the unique lysosomal/late endosomal phospholipid lyso-bisphosphatidic acid (LBPA) (also known as bismonoacylglycerol phosphate). Finally, we found that the rate of transfer of cholesterol from vesicles to NPC2 was dramatically increased by the presence of lyso-bisphosphatidic acid in the donor vesicles. These results support a role for the NPC2 protein in the egress of LDL derived cholesterol out of the endosomal/lysosomal compartment.

Based on the structures of several lipophilic trioxolane antimalarial prototypes, we set out to determine which functional groups were associated with good antimalarial profiles and identify more polar (lower LogP/LogD) lead compounds with good physicochemical properties. More lipophilic trioxolanes tended to have better oral activities than their more polar counterparts. Trioxolanes with a wide range of neutral and basic, but not acidic, functional groups had good antimalarial profiles.

Unlike diprotic chloroquine (CQ), its two 4-aminoquinoline carbon isosteres (1, 2) are monoprotic at physiological pH. Compared to CQ, hematin binding affinity of 1 decreased 6.4-fold, and there was no measurable binding for 2. Although 1 was a weak inhibitor of hemozoin formation, neither isostere inhibited P. falciparum in vitro. Evidently, the CQ-hematin interaction is largely a function of its pyridine substructure, but inhibition of hemozoin formation and parasite growth depends on its 4-aminopyridine substructure.

This paper describes the synthesis of a nicotine hapten (Nic) that possesses a carboxyl sidearm functional group allowing for conjugation to a peptide via amide bond formation. Nic was attached to the N-terminal amino group of a 19-residue peptide composed of a conformationally biased agonist of human C5a (YSFKPMPLaR), which is used as a molecular adjuvant and a B cell epitope of human MUC1 glycoprotein (YKQGGFLGL) to yield a peptide-based nicotine vaccine, NicYKQGGFLGLYSFKPMPLaR. Rats immunized with this vaccine were significantly less sensitive to behavioral effects (a Pavlovian discrimination task) induced by their exposure to high concentrations of nicotine (0.4 mg/kg) relative to their non-vaccinated counterparts. The attenuation of these nicotine-induced behavioral effects emanated from the presence of nicotine-specific antibodies (Abs) that were present in the sera of vaccinated rats even after their repeated exposure to high concentrations of nicotine during the time required to perform the behavioral assays. These results suggest that immunization with NicYKQGGFLGLYSFKPMPLaR in the absence of adjuvant is an effective means of inducing a nicotine-specific Ab response, which is capable of attenuating nicotine-induced behavioral/psychoactive effects., (Copyright 2002 Elsevier Science B.V.)