Syringe services program staff and participant perspectives on changing drug consumption behaviors in response to xylazine adulteration.

BACKGROUND: Xylazine is an increasingly common adulterant in the North American unregulated drug supply that is associated with adverse health outcomes (e.g., skin infections, overdose). However, there are significant knowledge gaps regarding how xylazine was initially identified and how syringe services program (SSP) staff and clients (people who use drugs) responded to its emergence. METHODS: From June-July 2023, we conducted qualitative interviews with medical (e.g., clinicians) and frontline SSP staff (e.g., outreach workers) and adult clients with a history of injection drug use at a Miami-based SSP. Inductive memos identified emergent codes; thematic analysis involving team consensus established final themes. RESULTS: From interviews with SSP staff (n = 8) and clients (n = 17), xylazine emergence was identified at different times, in various ways. Initially, during summer 2022, clients identified a "tranquilizer-like substance" that worsened sedation and withdrawal and caused wounds. SSP medical staff later identified this adulterant as xylazine by treating new medical cases and through diverse information-sharing networks that included professional societies and news sources; however, frontline SSP staff and clients needed additional educational resources about xylazine and its side effects. With limited guidance on how to reduce harm from xylazine, SSP clients altered their drug consumption routes, reduced drug use, and relied on peers' experiences with the drug supply to protect themselves. Some individuals also reported preferring xylazine-adulterated opioids and increasing their drug use, including the use of stimulants to avoid over sedation. CONCLUSIONS: Xylazine's emergence characterizes the current era of unprecedented shifts in the unregulated drug supply. We found that xylazine spurred important behavioral changes among people who use drugs (e.g., transitioning from injecting to smoking). Incorporating these experiences into early drug warning surveillance systems and scaling up drug-checking services and safer smoking supply distribution could help mitigate significant health harms caused by xylazine and other emergent adulterants.

LuxHMM: DNA methylation analysis with genome segmentation via hidden Markov model.

BACKGROUND: DNA methylation plays an important role in studying the epigenetics of various biological processes including many diseases. Although differential methylation of individual cytosines can be informative, given that methylation of neighboring CpGs are typically correlated, analysis of differentially methylated regions is often of more interest. RESULTS: We have developed a probabilistic method and software, LuxHMM, that uses hidden Markov model (HMM) to segment the genome into regions and a Bayesian regression model, which allows handling of multiple covariates, to infer differential methylation of regions. Moreover, our model includes experimental parameters that describe the underlying biochemistry in bisulfite sequencing and model inference is done using either variational inference for efficient genome-scale analysis or Hamiltonian Monte Carlo (HMC). CONCLUSIONS: Analyses of real and simulated bisulfite sequencing data demonstrate the competitive performance of LuxHMM compared with other published differential methylation analysis methods.

LuxRep: a technical replicate-aware method for bisulfite sequencing data analysis.

BACKGROUND: DNA methylation is commonly measured using bisulfite sequencing (BS-seq). The quality of a BS-seq library is measured by its bisulfite conversion efficiency. Libraries with low conversion rates are typically excluded from analysis resulting in reduced coverage and increased costs. RESULTS: We have developed a probabilistic method and software, LuxRep, that implements a general linear model and simultaneously accounts for technical replicates (libraries from the same biological sample) from different bisulfite-converted DNA libraries. Using simulations and actual DNA methylation data, we show that including technical replicates with low bisulfite conversion rates generates more accurate estimates of methylation levels and differentially methylated sites. Moreover, using variational inference speeds up computation time necessary for whole genome analysis. CONCLUSIONS: In this work we show that taking into account technical replicates (i.e. libraries) of BS-seq data of varying bisulfite conversion rates, with their corresponding experimental parameters, improves methylation level estimation and differential methylation detection.

Work overload and associated factors in healthcare professionals during the COVID-19 pandemic.

INTRODUCTION: The COVID-19 pandemic changed the work routine of professionals at the family healthcare center (Núcleo de Atenção à Saúde da Família - NASF-AB), providing new conditions and work overload. OBJECTIVE: The purpose of this study was to explore factors associated with work overload in NASF-AB professionals during the COVID-19 pandemic. METHODS: A cross-sectional study was carried out with NASF-AB workers in the city of Salvador, Bahia, Brazil, from May to August 2021. Working conditions and overload were assessed using the National Program for Improving Access and the Quality of Primary Care questionnaire (Programa Nacional de Melhoria do Acesso e da Qualidade da Atenção Básica - PMAQ) and the scale measuring burden of professionals in mental health services (Escala de Avaliação da Sobrecarga de Profissionais em Serviços de Saúde Mental - IMPACTO-BR), respectively. A multivariate linear regression model was used. A total of 68 health professionals participated in the study, including 19 physiotherapists, 13 occupational therapists, 10 social workers, 10 nutritionists, 9 psychologists and 7 physical education professionals. RESULTS: There was a significant association between overall overload and being female (p=<0.005), having spaces for reflection on the work process (p=0.027), and having difficulty moving around to conduct activities in the territory (p=0.002) for increasing the chance of work overload. CONCLUSIONS: Our findings encourage workers' health policies and closer ties and negotiation with local management, as well as the return of the institutional support figure for the effectiveness and resolution of actions in primary healthcare units.

Transportation Barriers in Pediatric Orthopaedic Clinic Visits.

OBJECTIVES: To identify what transportation barriers pediatric patients face when traveling to a major metropolitan orthopaedic center, how these barriers affect care, and what changes can be made to address this issue. STUDY DESIGN: A cross-sectional transportation survey was administered to 107 caregivers of patients being seen in the orthopaedic clinic at a tertiary children's hospital in a large metropolitan area. Using logistic regression analysis, we compared socioeconomic characteristics, transportation methods, and scheduling practices among caregivers who reported missing at least one visit in the past and those who reported never missing a visit. RESULTS: 13% (14/108) of caregivers reported missing one or more past visits due to late arrival or transportation issues. Families that traveled more than 45 minutes to clinic (P = 0.04), waited more than one week to schedule a visit (P = 0.002), or reported difficulty scheduling a visit (P = 0.02) were significantly more likely to have a history of nonattendance. In addition, patients who were nonambulatory (P = 0.007), used a mobility device (P = 0.007), or were non-White (P < 0.05) were significantly more likely to have missed a visit. CONCLUSION: Travel time, difficult or delayed scheduling, and patient ambulatory status were all associated with missing orthopaedic clinic visits although other socioeconomic factors were not related. Interventions to improve orthopaedic clinic attendance should focus on promoting accessibility for patients with mobility limitations and encouraging simple and timely scheduling practices.

Leucine Suppresses α-Cell cAMP and Glucagon Secretion via a Combination of Cell-Intrinsic and Islet Paracrine Signaling.

Glucagon is critical for the maintenance of blood glucose, however nutrient regulation of pancreatic α-cells remains poorly understood. Here, we identified a role of leucine, a well-known ß-cell fuel, in the α-cell-intrinsic regulation of glucagon release. In islet perifusion assays, physiologic concentrations of leucine strongly inhibited alanine- and arginine-stimulated glucagon secretion from human and mouse islets under hypoglycemic conditions. Mechanistically, leucine dose-dependently reduced α-cell cAMP, independently of Ca2+, ATP/ADP, or fatty acid oxidation. Leucine also reduced α-cell cAMP in islets treated with somatostatin receptor 2 antagonists or diazoxide, compounds that limit paracrine signaling from ß/δ-cells. Studies in dispersed mouse islets confirmed an α-cell-intrinsic effect. The inhibitory effect of leucine on cAMP was mimicked by glucose, α-ketoisocaproate, succinate, and the glutamate dehydrogenase activator BCH and blocked by cyanide, indicating a mechanism dependent on mitochondrial metabolism. Glucose dose-dependently reduced the impact of leucine on α-cell cAMP, indicating an overlap in function; however, leucine was still effective at suppressing glucagon secretion in the presence of elevated glucose, amino acids, and the incretin GIP. Taken together, these findings show that leucine plays an intrinsic role in limiting the α-cell secretory tone across the physiologic range of glucose levels, complementing the inhibitory paracrine actions of ß/δ-cells.

Limited acceptance of buprenorphine in recovery residences in South Florida: A secret shopper survey.

BACKGROUND: Buprenorphine is a first-line treatment for opioid use disorder (OUD), essential for reducing opioid overdose mortality and improving treatment retention. Despite federal policies that mandate the acceptance of buprenorphine in recovery residences, individuals in South Florida taking this medication often face significant barriers to admission. This study uses a secret shopper survey to examine whether federal policies regarding prescribed buprenorphine use are being violated in South Florida recovery residences. METHODS: We selected recovery residences in South Florida due to the region's high opioid overdose death rate and its prominence as a recovery hub. From a list of 141 Florida Association of Recovery Residences (FARR)-certified residences in Palm Beach, Broward, and Miami-Dade, we randomly surveyed 100 programs across all treatment levels (I-IV) using a standardized script. The primary outcome was whether residences accepted individuals taking buprenorphine, classified into three categories: (1) unconditional acceptance, where any person taking buprenorphine was accepted; (2) denial, where admission was refused for all individuals taking buprenorphine; and (3) conditional acceptance, where admission was granted under specific conditions. Secondary outcomes included requirements for conditional acceptance, such as dose limits or tapering policies. RESULTS: The distribution of the 100 surveyed recovery residences was comparable to the 141 FARR-certified facilities: 67 % were in Palm Beach, 31 % in Broward, and 2 % in Miami-Dade. Most residences (55 %) were level II certified, followed by 26 % level IV, 14 % level I, and 5 % level III. Sixteen percent of residences permitted admission of individuals taking any buprenorphine dose, 31 % had conditional policies, and 53 % prohibited buprenorphine. The maximum acceptance across all counties and levels was 20 %. No significant differences were observed by county (p = 0.61) or facility level (p = 0.29). Of 31 residences with conditional policies, 25.8 % (n = 8) required a mandatory taper, 38.7 % (n = 12) allowed a maximum 8 mg daily dosage, 12.9 % (n = 4) had a maximum 12 mg daily dosage, 6.5 % (n = 2) had a maximum 16 mg daily dosage, 6.5 % (n = 2) required a provider letter, and 9.7 % (n = 3) did not provide further information. CONCLUSIONS: Access to FARR-certified recovery residences is severely limited for individuals in South Florida taking buprenorphine. Urgent action is needed to improve access to evidence-based OUD treatments, address complexities influencing recovery residence policy and practice, and ensure appropriate allocation of public funds like State Opioid Response dollars.

Investigating the Determinants of Nonaccidental Trauma Evaluation in Pediatric Femur Fractures.

BACKGROUND: Femoral fractures in children have the highest probability for abuse after skull fractures and humeral shaft fractures. However, the reported proportion of pediatric femur fractures that result from nonaccidental trauma (NAT) varies in the literature from 2% to 60%. The purpose of this study was to determine the patient characteristics associated with a physician's decision to conduct a NAT workup and challenge universal clinical practice guidelines stating that all children younger than 3 years with a diaphyseal femur fracture be evaluated for NAT. METHODS: A retrospective review was conducted on patients aged 0 to 36 months diagnosed with a femur fracture between January 1, 2004, and April 9, 2019, at our institution. NAT was defined as a diagnosis of trauma that was nonaccidental in the medical chart after a positive workup by skeletal survey, ophthalmological examination, or other appropriate referral made by the institution's child abuse and neglect team. Patients with incomplete medical records were excluded. RESULTS: A total of 299 patients were identified, and 22 were excluded. 71% (197/277) were screened for NAT. Patients younger than 1 year were significantly more likely to undergo a NAT workup (P = 0.009; Odds Ratio [OR], 2.3; 95% CI, 1.2 to 4.4) and receive a positive result from the NAT workup (P < 0.0005; OR, 11.3; 95% CI, 4.6 to 27.4). Additional injuries were also a significant predictor of a positive NAT workup (P < 0.001; OR, 5.3; 95% CI, 2.4 to 11.9). Patient race/ethnicity, sex, and fracture type were not markedly associated with the physician's decision to conduct a NAT workup. CONCLUSIONS: Infants younger than 1 year with a femur fracture and children younger than 3 years presenting with a femur fracture and another injury are at increased risk of possible NAT. While clinical practice guidelines may minimize racial bias in NAT evaluation, this study demonstrates that universal NAT workups for walking-age children in the absence of other evidence of abuse may be unnecessary. LEVEL OF EVIDENCE: This is a Level III retrospective cohort study.

Protective or potentially harmful? Altering drug consumption behaviors in response to xylazine adulteration.

Background: Xylazine is an increasingly common adulterant in the North American unregulated drug supply that is associated with adverse health outcomes (e.g., skin infections, overdose). However, there are significant knowledge gaps regarding how xylazine was initially identified and how syringe services program (SSP) staff and clients (people who use drugs) responded to its emergence. Methods: From June-July 2023, we conducted qualitative interviews with medical (e.g., clinicians) and frontline SSP staff (e.g., outreach workers) and adult clients with a history of injection drug use at a Miami-based SSP. Inductive memos identified emergent codes; thematic analysis involving team consensus established final themes. Results: From interviews with SSP staff (n = 8) and clients (n = 17), xylazine emergence was identified at different times, in various ways. Initially, during summer 2022, clients identified a "tranquilizer-like substance" that worsened sedation and withdrawal and caused wounds. SSP medical staff later identified this adulterant as xylazine by treating new medical cases and through diverse information-sharing networks that included professional societies and news sources; however, frontline SSP staff and clients needed additional educational resources about xylazine and its side effects. With limited guidance on how to reduce harm from xylazine, SSP clients altered their drug consumption routes, reduced drug use, and relied on peers' experiences with the drug supply to protect themselves. Some individuals also reported preferring xylazine-adulterated opioids and increasing their drug use, including the use of stimulants to avoid over sedation. Conclusions: Xylazine's emergence characterizes the current era of unprecedented shifts in the unregulated drug supply. We found that xylazine spurred important behavioral changes among people who use drugs (e.g., transitioning from injecting to smoking). Incorporating these experiences into early drug warning surveillance systems and scaling up drug-checking services and safer smoking supply distribution could help mitigate significant health harms caused by xylazine and other emergent adulterants.

Prevalence of xylazine among people who inject drugs seeking medical care at a syringe services program clinic: Miami, Florida, 2023.

Background: We aimed to report the preliminary xylazine prevalence among people who inject drugs (PWID) treated at a student-run free clinic in Miami, FL, USA and to identify characteristics associated with screening positive for xylazine. Methods: A retrospective chart review of 59 patients presenting to a syringe services program (SSP) clinic in was conducted between April 27th and August 17th, 2023. We measured presence of xylazine with rapid visual immunoassay strips on patient urine samples. Results: Xylazine was present in 55.9 % (33/59) of urine samples including 2 without detected opioids. Xylazine presence was significantly associated with unsheltered homelessness (p = 0.018), presence of wound(s) (p = 0.008), and testing positive for hepatitis C antibody (p = 0.014), fentanyl (p = 0.005) and MDMA (p = 0.002). Conclusions: A high prevalence of xylazine in the Southeastern United States furthers evidence of the geographical spread of xylazine and rapidly evolving illicit drug supply. Widespread xylazine screening is urgently needed to inform people who inject drugs and to studyinterventions to minimize harms associated with xylazine.

Fracture Resistance and Failure Mode of Custom-made Post-and-cores of Polyetheretherketone and Nano-ceramic Composite.

CLINICAL RELEVANCE: Custom-made post-and-cores of polyetheretherketone (PEEK) and nano-ceramic composite showed good fracture resistance and failure mode. Clinicians should be aware that these materials might be an efficient alternative for post-and-cores, because they promote esthetics while reducing the risk of root fractures. SUMMARY: Purpose: The purpose of this study was to evaluate the fracture resistance and failure mode of custom-made post-and-cores manufactured with different esthetic materials.Methods and Materials: A total of 48 mandibular premolar extracted teeth were selected, endodontically treated, and prepared to receive the posts. Specimens were randomly divided into four groups (n=12/group): group 1, polyetheretherketone (PEEK, Degos; G1); group 2, nano-ceramic composite (Lava Ultimate, 3M ESPE; G2); group 3, cast metal post (NiCr alloy, control; G3); group 4, fiberglass post (Whitepost, FGM, control; G4) customized with a nano-hybrid resin composite (Z250, 3M ESPE). Experimental post-and-cores (G1 and G2) were manufactured with a computer-aided design/computer-aided manufacturing system. All posts were cemented with self-adhesive resin cement (Rely X U200, 3M ESPE), and specimens were stored in distilled water at 37°C for 60 days. A universal testing machine was used to measure the fracture resistance (0.5 mm/min at an angle of 45° to the long axis of the tooth). Fractures were classified as repairable or catastrophic. One-way analysis of variance with Tukey post hoc and χ2 tests for independence and Bonferroni adjustments were applied (α=0.05).Results: The fracture resistance values (mean ± SD, in newtons) were 379.4 ± 119.8 (G1), 506.4 ± 138 (G2), 939.6 ± 146.5 (G3), and 449.6 ± 66.5 (G4). Only G3 exhibited a significant difference (p<0.05). The χ2 test showed an association between failure mode and post-and-core material [χ2(3) = 23.65; p<0.001]. After Bonferroni adjustment, only G3 presented a higher than expected incidence of catastrophic failures (p<0.001). In the remaining groups, most failures were repairable and related to debonding.Conclusions: Customized post-and-cores of PEEK and nano-ceramic composites exhibited good mechanical performance. Their fracture resistance was comparable to that observed for fiberglass customized posts, yet lower than that for cast metal posts. For PEEK post-and-cores, in particular, additional studies are needed to improve adhesiveness and reduce the risk of debonding.

Effect of Surface Sealants and Polishing Time on Composite Surface Roughness and Microhardness.

The objective of this study was to evaluate the effect of surface sealants and polishing delay time on a nanohybrid resin composite roughness and microhardness. Eighty disc specimens were made with a nanohybrid resin (Esthet-X HD, Dentsply). The specimens were divided into two groups (n=40) according to polishing time: immediate, after 10 minutes; delayed, after 48 hours. Each group was subdivided into four groups (n=10), according to the surface treatment: CG, control-rubber points (Jiffy Polishers, Ultradent); PP, rubber points + surface sealant (PermaSeal, Ultradent); PF, rubber points + surface sealant (Fortify, Bisco); PB, rubber points + surface sealant (BisCover, Bisco). Surface roughness (Ra) and microhardness (50 g/15 seconds) were measured. Surface morphology was analyzed by scanning electron microscopy and atomic force microscopy. The data were analyzed statistically using one-way analysis of variance and the Games-Howell post hoc test (α=0.05). PermaSeal roughness (G2) in the delayed polishing group was significantly higher ( p=0.00) than that of the other groups. No difference was observed among the groups between immediate and delayed polishing ( p=1.00), except for PermaSeal ( p=0.00). Moreover, PermaSeal showed the lowest microhardness values ( p=0.00) for immediate polishing. Microhardness was higher at delayed polishing for all the surface treatments ( p=0.00) except Fortify ( p=0.73). Surface smoothness similar to polishing with rubber points was achieved when surface sealants were used, except for PermaSeal surface sealant, which resulted in a less smooth resin composite surface. However, surface sealant application did not significantly improve composite resin microhardness.

Color Match Between Composite Resin and Tooth Remnant in Class IV Restorations: A Case Series.

Rehydration of the tooth remnant and complete polymerization of the composite resin are aspects that should be considered in shade selection of composite resin. This article presents a case series of Class IV restorations performed to evaluate the color match between the composite resin and the tooth remnant. Thirteen Class IV restorations were performed in maxillary central incisors and evaluated according to the period following the restorative procedure: 10 minutes (baseline), 48 hours before and after finishing and polishing, and seven, 14, and 28 days. The color match of the restorations was evaluated by the ΔE values of the tooth remnant (TR) and the composite resin (CR) in each evaluation period using a spectrophotometer. The translucency, luminosity, and saturation were analyzed qualitatively in digital photographs of the restorations. The CR ΔE was statistically similar to the TR ΔE at 14 and 28 days ( p>0.05). The saturation and luminosity of most of the restorations remained unchanged, but there was a greater change in the translucency. The color match of the composite resin in Class IV restorations was observed after 14 days of clinical assessment in this case series.

Quality of life in mucopolysaccharidoses: construction of a specific measure using the focus group technique.

OBJECTIVE: To describe the perceptions of patients, their caregivers, and their healthcare providers to the development of a new specific instrument for assessment of the quality of life (QoL) in patients with mucopolysaccharidoses (MPS) using a qualitative focus group (FG) design. FGs were held in two Brazilian states (Rio Grande do Sul and Rio de Janeiro). RESULTS: Three versions of the new instrument were developed, each for a different age group: children (age 8-12 years), adolescents (age 13-17), and adults (age ≥ 18). The FGs mostly confirmed the relevance of items. All FGs unanimously agreed on the facets: School, Happiness, Life Prospects, Religiosity, Pain, Continuity of Treatment, Trust in Treatment, Relationship with Family, Relationship with Healthcare Providers, Acceptance, and Meaning of Life. The overall concept of QoL (as proposed by the WHO-World Health Organization) and its facets apply to this patient population. However, other specific facets-particularly concerning clinical manifestations and the reality of the disease-were suggested, confirming the need for the development of a specific QoL instrument for MPS.

Quality of life and adherence to treatment in early-treated Brazilian phenylketonuria pediatric patients.

Early dietary treatment of phenylketonuria (PKU), an inborn error of phenylalanine (Phe) metabolism, results in normal cognitive development. Although health-related quality of life (HRQoL) of PKU patients has been reported as unaffected in high-income countries, there are scarce data concerning HRQoL and adherence to treatment of PKU children and adolescents from Brazil. The present study compared HRQoL scores in core dimensions of Brazilian early-treated PKU pediatric patients with those of a reference population, and explored possible relationships between adherence to treatment and HRQoL. Early-treated PKU pediatric patient HRQoL was evaluated by self- and parent-proxy reports of the Pediatric Quality of Life Inventory (PedsQL) core scales. Adherence to treatment was evaluated by median Phe levels and percentage of results within the therapeutic target range in two periods. Means for total and core scales scores of PedsQL self- and parent proxy-reports of PKU patients were significantly lower than their respective means for controls. Adequacy of median Phe concentrations and the mean percentage of values in the target range fell substantially from the first year of life to the last year of this study. There was no significant difference in mean total and core scale scores for self- and parent proxy-reports between patients with adequate and those with inadequate median Phe concentrations. The harmful consequences for intellectual capacity caused by poor adherence to dietary treatment could explain the observed decrease in all HRQoL scales, especially in school functioning. Healthcare system and financial difficulties may also have influenced negatively all HRQoL dimensions.

Influence of Adhesive Core Buildup Designs on the Resistance of Endodontically Treated Molars Restored With Lithium Disilicate CAD/CAM Crowns.

OBJECTIVE: To assess the influence of adhesive core buildup designs (4-mm buildup, 2-mm buildup, and no buildup/endocrown) on the fatigue resistance and failure mode of endodontically treated molar teeth restored with lithium disilicate computer-aided design/computer-aided manufacturing (CAD/CAM) complete crowns placed with self-adhesive cement. METHODS AND MATERIALS: Forty-five extracted molars were decoronated at the level of the cementoenamel junction and endodontically treated. Specimens received different Filtek Z100 adhesive core buildups (4-mm buildup; 2-mm buildup; and no buildup endocrown preparation) and were restored with Cerec 3 CAD/CAM lithium disilicate crowns (IPS e.max CAD). The intaglio surfaces of restorations (n=15) were conditioned by hydrofluoric acid etching and silane, and prepared teeth were treated with airborne-particle abrasion, followed by cementation with RelyX Unicem 2 Automix. Specimens were then subjected to cyclic isometric loading at 10 Hz, beginning with a load of 200 N (×5000 cycles), followed by stages of 400, 600, 800, 1000, 1200, and 1400 N at a maximum of 30,000 cycles each. Specimens were loaded until failure or to a maximum of 185,000 cycles. The chewing cycle was simulated by an isometric contraction (load control) applied through a 10-mm in diameter composite resin sphere (Filtek Z100). Surviving specimens were axially loaded until failure or to a maximum load of 4500 N (crosshead speed 0.5 mm/min). The failure mode was assessed, and fractures were designated as catastrophic (tooth/root fracture that would require tooth extraction) or reparable (cohesive or cohesive/adhesive fracture of restoration only). Groups were compared using the life table survival analysis (log-rank test at p=0.05). Surviving specimens were loaded to failure and compared with one-way analysis of variance. RESULTS: The survival rates after the fatigue test were 100%, 93%, and 100% for 4-mm, 2-mm, and no buildup (endocrown), respectively and were not statistically different (only one specimen failed with a 2-mm buildup under a crown that cohesively fractured at 1,400 N). Postfatigue load to failure averaged 3181 N for 4-mm buildups (15 specimens), 3759 N for 2-mm buildups (12 specimens), and 3265 N for endocrowns (14 specimens). The 2-mm buildups were associated with higher loads to failure than endocrowns and 4-mm buildups, but no differences were found between 4-mm buildups and endocrowns (p<0.05.) One endocrown and 2 restorations with a 2-mm buildup survived the load-to-failure test (at 4500 N). Only catastrophic fractures occurred after the load-to-failure test. CONCLUSIONS: The buildup design influenced the performance of endodontically treated molars restored with lithium disilicate CAD/CAM complete crowns placed with self-adhesive resin cement. The 2-mm buildups were associated with higher loads to failure than the endocrown and the 4-mm buildup, but all restoration designs survived far beyond the normal range of masticatory forces.

Differences in backbone structure between angiotensin II agonists and type I antagonists.

Type I angiotensin II antagonists with O-methyl-L-homoserine [HSer(gamma-OMe)] and delta-methoxy-L-norvaline [Nva(delta-OMe)] at position 8 have been prepared by the solid-phase method, purified by reverse-phase HPLC, and bioassayed in the rat uterus, and their backbone conformational properties were investigated by nuclear Overhauser effect (NOE) spectroscopy. [Sar1,HSer-(gamma-OMe)8]ANGII, [HSer(gamma-OMe)8]ANGII, [Des1,HSer(gamma-OMe)8]ANGII, [Sar1,Nva(delta-OMe)8]-ANGII, and [Des1,Nva(delta-OMe)8]ANGII had, respectively, the following antagonist activities, pA2: 7.6, 7.5, < 6.0, 7.1, and 6.9. Analogs of [Sar1]ANGII with delta-hydroxy-L-norvaline [Nva(delta-OH)], delta-methoxy-L-norvaline [Nva(delta-OMe)], 4'-carboxyphenylalanine [Phe(4'-COOH)], and 4'-(trifluoromethyl)phenylalanine [Phe(4'-CF3)] at position 4 were also prepared by solid phase and bioassayed in the rat uterus. [Sar1,Nva(delta-OH)4]ANGII, [Aib1,Nva(delta-OMe)4]ANGII, [Sar1,DL-Phe(4'-COOH)4]ANGII, and [Sar1,DL-Phe(4'-CF3)4]ANGII had, respectively, agonist activities as follows: 4%, 1.5%, 3%, < 0.1%, and < 0.1%. These data emphasize that replacement of Ile8 in Sarilesin with the higher homologs HSer(gamma-OMe) and Nva(delta-OMe) does not greatly alter the structural requirements necessary for expression of type I antagonist activity, while replacement of the tyrosine hydroxyl in [Sar1]ANGII by the carboxylate or the trifluoromethyl group abolishes activity, suggesting that the tyrosinate pharmacophore cannot be replaced by any negatively charged or electronegative group. Conformational investigation of the ANGII type I antagonists [HSer(gamma-OMe)8]ANGII and [Sar1Nva(delta-OMe)8]ANGII in DMSO by 1D-NOE spectroscopy revealed that the Tyr-Ile-His bend, a conformational property found in ANGII and [Sar1]ANGII (J. Biol. Chem. 1994, 269, 5303) is not present in type I antagonists, providing for the first time an important conformational difference between angiotensin II agonists and type I antagonists.

Enhancing reductive cleavage of aromatic carboxamides.

[reaction: see text] A set of aromatic and especially heteroaromatic N-benzyl carboxamides, derived from naphthalene, pyridine, pyrazine, and quinoline, and the corresponding tert-butyl acylcarbamates have been synthesized and studied by cyclic voltammetry with respect to facilitated reduction. The latter undergo regiospecific cleavage of their C(O)-N bonds under very mild reductive conditions with formation of Boc-protected (benzyl)amine in most cases in nearly quantitative yields. Examples of preparative cleavage by controlled potential electrolysis, activated aluminum, and NaBH(4) are given.

The contractile response of the human uterus, fallopian tubes, and ovary to prostaglandins in vivo.

PIP: In vivo studies were carried out in 8 women to ascertain the effects of prostaglandins (PGs) E2 and F2alpha on the human fallopian tubes and ovaries. Recording devices were surgically implanted into the tubal lumen through catheters. 100 mcg. of either PGE2 or PGF2alpha or a mixture of equal amounts of the 2 totaling 100 mcg. were administered intravenously and the effects recorded. Graphs of the effects are presented. The 2 pure substances and the mixture all had a stimulatory effect on the uterus at all phases of the menstrual cycle. There were, however, qualitative and potency differences between PGE2 and PGF2alpha. On a weight basis, PGE2 had more powerful effects on the myometrium. The 2 PGs had opposing effects on the fallopian tubes, with PGF2alpha stimulating while PGE2 inhibited tubal motility. A contractile response of the ovary following intravenous administration of PGF2alpha was noted; no change in intraovarian pressure was recorded following injection of up to 100 mcg. PGE2. The compound was mildly stimulatory. The ability of PGE2 to induce relaxation of the tubes while stimulating uterine activity provides a clue as to why it is more effective in inducing abortion than PGF2alpha. It is suggested that relaxation of the tubal isthmus induced by seminal PGE2 facilitates sperm penetration into the tube.^ieng

The inhibitory effect of Ritodrine on human tubal activity in vivo.

PIP: The effect of Ritodrine (4-hydroxy alpha-1-2-4-hydroxyphenyl ethylamino acetylbenzyl alcohol hydrochloride) on fallopian tubal activity was studied in 26 women of reproductive age who underwent abdominal surgery for tuboplasty (8 women), tubal ligation (6 women), or ovarian or uterine pathology (12 women). Tubal mobility was recorded by the intratubal microballoon method. Ritodrine was given intravenously at infusion rates of 50-600 mcg/minute or orally. At infusion rates of 200-300 mcg/minute, Ritodrine suppressed the spontaneous outbursts of increased activity, but tubal quiescence was achieved only at infusion rates of 400 mcg/minute or higher. Oral administration of 5-10 mg of Ritodrine was insufficient to depress motility, however 15-20 mg achieved quiescence lasting longer than 1 hour. It was suggested that it is conceivable that the administration of a beta-adrenergic activator such as Ritodrine at appropriate times of the menstrual cycle would interfere with conception through inhibition of the ovum retention mechanism in the tube.^ieng