Amine-Carbamate Self-Immolative Spacers Counterintuitively Release 3° Alcohol at Much Faster Rates than 1° Alcohol Payloads.

Self-immolative (SI) spacers are degradable chemical connectors widely used in prodrugs and drug conjugates to release pharmaceutical ingredients in response to specific stimuli. Amine-carbamate SI spacers are particularly versatile, as they have been used to release different hydroxy cargos, ranging from 2° and 3° alcohols to phenols and oximes. In this work, we describe the ability of three amine-carbamate SI spacers to release three structurally similar imidazoquinoline payloads, bearing either a 1°, a 2° or a 3° alcohol as the leaving group. While the spacers showed comparable efficacy at releasing the 2° and 3° alcohols, the liberation of the 1° alcohol was much slower, unveiling a counterintuitive trend in nucleophilic acyl substitutions. The release of the 1° alcohol payload was only possible using a SI spacer bearing a pyrrolidine ring and a tertiary amine handle, which opens the way to future applications in drug delivery systems.

Ex vivo mass spectrometry-based biodistribution analysis of an antibody-Resiquimod conjugate bearing a protease-cleavable and acid-labile linker.

Immune-stimulating antibody conjugates (ISACs) equipped with imidazoquinoline (IMD) payloads can stimulate endogenous immune cells to kill cancer cells, ultimately inducing long-lasting anticancer effects. A novel ISAC was designed, featuring the IMD Resiquimod (R848), a tumor-targeting antibody specific for Carbonic Anhydrase IX (CAIX) and the protease-cleavable Val-Cit-PABC linker. In vitro stability analysis showed not only R848 release in the presence of the protease Cathepsin B but also under acidic conditions. The ex vivo mass spectrometry-based biodistribution data confirmed the low stability of the linker-drug connection while highlighting the selective accumulation of the IgG in tumors and its long circulatory half-life.

Sphingosine-1-phosphate regulation of luteinising hormone-induced steroidogenesis and proliferation of bovine theca cells in vitro.

CONTEXT: Sphingosine-1-phosphate (S1P) is synthesised by follicle granulosa cells under the influence of follicle-stimulating hormone and seems to be necessary for the biological effects of this gonadotrophin. AIMS: To determine if luteinising hormone (LH) increases S1P production and if this sphingolipid, either induced by LH or added to culture media, regulates steroidogenesis and cell viability in bovine theca cells. METHODS: We used bovine theca cell cultures treated with: S1P (0, 0.1, 1 and 10µM; Experiment 1), LH (0, 0.02, 0.2 and 2ngmL-1 ; Experiment 2) and LH (0.02ngmL-1 ) plus a sphingosine kinase inhibitor (SKI-178; 0, 5 and 10µM; Experiment 3). KEY RESULTS: Treatment with S1P did not affect (P >0.05) theca cell viability or their ability to produce progesterone and testosterone. LH (0.02ngmL-1 ) increased (P <0.05) S1P production, and stimulated the expression of phosphorylated sphingosine kinase-1 (pSPHK1). However, the inhibition of SPHK1, by a specific SPHK1 inhibitor (SKI-178), reduced (P <0.05) cell viability and progesterone secretion. Additionally, the use of SKI-178 increased theca cell testosterone production (P<0.05). CONCLUSIONS: S1P added to culture media did not affect cell viability or steroid synthesis. However, LH stimulated the production of S1P, by increasing phosphorylation of SPHK1 in theca cells. This intracellular S1P was inhibitory on testosterone production but augmented progesterone and viable cell number. IMPLICATIONS: These results suggest a novel signalling pathway for LH in theca cells and underline the importance of S1P in the regulation of steroid synthesis.

5-fluorouacil in the treatment of odontogenic keratocysts-incidence of recurrence and inferior alveolar nerve paresthesia: a systematic review.

PURPOSE: To evaluate the recurrence rate of odontogenic keratocyst (OKC) after treatment with 5-fluoracil as an adjunctive therapy and to evaluate, as well, the efficacy of this medication in reducing the incidence of inferior alveolar nerve paresthesia associated with other chemotherapeutic agents. MATERIAL AND METHODS: The research question (developed according to the patient/population, intervention, comparison, and outcomes [PICO] method) addressed was "Does the use of 5-fluorouracil as an adjunctive therapy in the treatment of OKC reduce both the recurrence rate and the incidence of inferior alveolar nerve paresthesia as compared with other chemotherapeutic agents?" A systematic review was performed by searching 4 databases: PubMed, EBSCO, Portal Evidencia, and Cochrane Reviews. Each search was conducted twice. Two independent reviewers evaluated the data. For each database, a search strategy was developed that included the following generic terms: Fluorouracil, 5-Fluorouracil, or liquid nitrogen and odontogenic cyst or odontogenic keratocyst. Three filters were applied to the searches, as well, consisting of the terms clinical trials, English papers, and Spanish papers. RESULTS: Of the 74 papers retrieved. The titles and abstracts of the selected papers were reviewed to determine whether those papers were relevant to our research question; only 3 papers were selected for this systematic review: 2 retrospective cohort studies and 1 clinical trial. Assessments risk bias and the quality of evidence were performed. CONCLUSIONS: The risk of bias and quality of evidence in this systematic review are moderate due to the study's design, although the clinical results were excellent with respect to the reduction of both OKC recurrence and paresthesia associated with this kind of cyst.

The dynamic impact of renewable energy sources on environmental economic growth: evidence from selected Asian economies.

The linkage between renewable energy resources and environmental influences on economic growth among selected Asian economies play a vital role in sustainable economic development. This study encompasses the panel data sets for eight selected Asian countries, and the period starts from 1990 to 2018. This research relies on the panel vector error correction model (PVECM) for data estimation. The overall findings indicate that biomass, geothermal, and wind power sources of energy have a positive and significant impact on the economic advancement of Asian economies. Besides that, as opposed to the other two renewable energy sources, windpower has a greater impact on economic development. Furthermore, the empirical findings of current research have significant implications towards selected Asian countries' energy policy related to both private and public sector enterprises as it helps in identifying the industrial sectors which have greater contribution towards the economy and their energy requirements in long term.

Does globalization affect the green economy and environment? The relationship between energy consumption, carbon dioxide emissions, and economic growth.

This study analyzes the relationship between globalization, energy consumption, and economic growth among selected South Asian countries to promote the green economy and environment. This study also finds causal association between energy growth and nexus of CO2 emissions and employed the premises of the EKC framework. The study used annual time series analysis, starting from 1985 to 2019. The data set has been collected from the World Development Indicator (WDI). The result of a fully modified ordinary least square (FMOLS) method describes a significantly worse quality environment in the South Asian region. The individual country as Bangladesh shows a positively significant impact on the CO2 emissions and destroys the level of environment regarding non-renewable energy and globalization index. However, negative and positive growth levels (GDP) and square of GDP confirm the EKC hypothesis in this region. This study has identified the causality between GDP growth and carbon emission and found bidirectional causality between economic growth and energy use.

Prevalence of Malocclusion and Distribution of Occlusal Characteristics in 13- to 18-year-old Adolescents Attending Selected High Schools in the Municipality of San Juan, PR (2012-2013).

OBJECTIVE: A cross-sectional study was conducted (2012-2013) to evaluate the prevalence of 1) malocclusion and 2) occlusal characteristics in 13- to 18-yearold adolescents in San Juan, Puerto Rico (PR) from selected high schools in the municipality of San Juan. METHODS: The study sample consisted of 155 adolescents. The University of Puerto Rico's IRB approved the study and consent and assent were completed for or by each participant, as applicable. A calibrated dentist performed a single-visit dental evaluation at each school. Occlusal characteristics were measured and recorded according to the criteria reported in the US National Health and Nutrition Examination Survey (NHANES III) and included overjet, overbite, anterior and posterior crossbites, incisor irregularity, maxillary midline diastema and Angle's classification. Descriptive and inferential statistical analyses were performed using SAS statistical software. RESULTS: The mean age of the study subjects was 16 (±1.2) years; all subjects (100%) presented at least 1 abnormal occlusal trait. The most frequent anomaly noted was maxillary malalignment (83%), followed by lower incisor irregularity and excessive overbite (79%) and excessive overjet (63%); the least common occlusal trait was open bite (1.9%). Compared by gender, no statistically significant difference was observed for any variable (p = 0.05). Seventy-three percent (73%) of the subjects presented with Class I malocclusion, 7.1% with Class II malocclusion and 19.4% with Class III malocclusion. CONCLUSION: A high prevalence of malocclusion was observed in this group of adolescents, highlighting the need to implement preventive measures to improve oral health in this population.

Cross-sectional associations of impaired glucose metabolism measures with bleeding on probing and periodontitis.

AIM: This study assessed the associations of pre-diabetes and insulin resistance with bleeding on probing (BOP) and periodontitis among adults. MATERIALS AND METHODS: We included 1191 Hispanic adults aged 40-65 years, free of diabetes, enrolled in San Juan Overweight Adults Longitudinal Study. Pre-diabetes was defined as impaired fasting glucose (IFG), impaired glucose tolerance (IGT), or impaired glycated haemoglobin. Impaired one-hour plasma glucose (1hPG) was defined as levels >155 mg/dl. Insulin resistance was defined using the study population-specific 75th percentile (HOMA-IR ≥ 3.13). High BOP was defined as percentage of teeth with bleeding ≥30%. Periodontitis was defined according to the CDC/AAP definition. RESULTS: After multivariable adjustment for age, gender, education, smoking status, alcohol consumption, physical activity, obesity, HDL-C, and plaque index, pre-diabetes with and without 1hPG, IFG, impaired 1hPG, IGT, and HOMA-IR were significantly associated with high BOP; pre-diabetes, IFG, and impaired 1hPG were significantly associated with severe periodontitis. Most of these associations remained significant when the analyses were restricted to non-smokers. CONCLUSIONS: This study suggests associations between pre-diabetes and insulin resistance with BOP and periodontitis. Given the high prevalence of impaired glucose metabolism and periodontitis, the assessment of the temporal sequence of these associations is of utmost importance.

Sinus Augmentation and Simultaneous Implant Placement Success: Pilot Study (2008-2011).

OBJECTIVE: 1) To describe implant success in the posterior maxillary when a sinus augmentation procedure was performed simultaneously with implant placement and then compare differences in success when sinus augmentation was delayed in patients attending the maxillofacial surgery clinic of the University of Puerto Rico, 2008 through 2011. 2) To determine sociodemographic characteristics, ASA classification, graft material, and final restoration and, using a questionnaire, determine as well patient satisfaction. METHODS: A retrospective cohort study was conducted (approved by IRB) with 172 patients, using medical records. A total of 102 implants were placed in grafted maxillary areas, 55 placed simultaneously and 47 delayed. Patients were contacted, invited to participate, and, upon agreement, instructed to sign an informed consent. RESULTS: A total of 45 implants were evaluated clinically (22 immediate and 23 delayed), all with 100% success (according to Buser and Weber criteria). In the sample group, 72.5% of the participants were women and 26.8% were men; their ages ranged from 42 to 87 years, with a mean age of 57 years. Patient participation was low (44%). The categories of appearance and esthetics and function were both rated at 86.2%; cost of restoration came in at 86.1%, and maintenance was rated at 71.2%. CONCLUSION: Implant placement with simultaneous sinus augmentation was successful, and no differences were found between implants that were placed immediately and those that were delayed, which is similar to what has been found by previous studies. Patients reported being satisfied with the final cost of the implant restoration.

Caries Experience and Periodontal Status during Pregnancy in a Group of Pregnant Women with HIV+ Infections from Puerto Rico.

OBJECTIVES: The aim of this study was to determine the caries rate and periodontal status in a sample of pregnant women with HIV+ infections from Puerto Rico. METHODS: A pilot study was conducted on a cross sectional convenience sample of 25 pregnant women with HIV+ infections from Puerto Rico who visit the CEMI clinic (Centro de Estudios Materno Infantil) at the University of Puerto Rico. The women subjects were evaluated for caries, DMFT (D: Decay tooth; M: Missing tooth due to caries; F: Filled tooth) index, oral lesions associated with HIV+/AIDS and periodontal disease parameters, with a Florida probe by a calibrated dentist on periodontal indexes such as as bleeding on probing, CEJ (cemento-enamel junction) and pocket depth. Periodontal disease was classified as having 4 sites with pocket depth greater than 4 mm and caries were identified following the Radike criteria. Data was statistically analyzed using the SSPS Program (Statistical Software Program for Social Sciences) and descriptive statistics were calculated. RESULTS: Mean DT (decayed teeth), MT (missing teeth due to caries), FT (filled teeth) and DMFT (decay, missing and filled teeth) were 4.8, 1.86, 5.3 and 12, respectively; mean sites of bleeding on probing=12.06; mean sites with pocket depth>4 mm=6.95 and mean sites with loss of attachment greater than 4 mm=7.66. [Almost 50% of the patients had generalized chronic periodontitis. A 72% prevalence of periodontal disease was found. No oral lesions related to HIV+/AIDS were reported. CD4 and viral load was statistically associated with bleeding on probing and severe signs of periodontal disease. CONCLUSIONS: High levels of dental disease were found in pregnant women with HIV+/AIDS infections from Puerto Rico, and these women were in need of substantial dental services.

Colonization of mutans streptococci in Costa Rican children from a high-risk population.

PURPOSE: The aim of the study was to determine the colonization of mutans streptococci (MS) in dental biofilm and saliva of children from a high-risk population with low socioeconomic status from San José, Costa Rica. METHODS: A total of 68 healthy babies from 8 to 20 months of age (mean age=13 months), with caries-free status and cariogenic feeding habits (eg, nursing bottle- or breast-feeding on demand) were examined. Children divided in two groups (<13 months and 14-20 months). Samples from dental biofilm and saliva from each subject were processed and plated in blood agar (BA) and Mitis-Salivarius-Bacitracin agar (MSB) to determine MS percentage. Statistical analysis included the analysis of variance test, and stratification by age of MS levels. RESULTS: Detectable MS levels in dental biofilm and saliva were found in 75% and 72% of children, respectively. Counts higher than 20000 colony forming units (CFU) per ml were found in 4% of saliva and in 35% of biofilm samples. The two groups showed significant differences in MS levels for dental biofilm (P=.036) and saliva (P=.009). Children older than 17 months presented higher MS levels (P<.05). Analysis by MS levels (<0.1%; 0.1-1.0%;>1.0% of MS) The two groups showed an insignificant association with increasing mean age. MS density was associated with mean number of erupted primary molars. CONCLUSIONS: Mutans streptococci colonization of dental biofilm and saliva from high caries risk infants is associated with age and dental development.

Topical antimicrobial therapy in the prevention of early childhood caries: a follow-up report.

PURPOSE: The purpose of this study was to assess the efficacy of antimicrobial therapy in the prevention of early childhood caries (ECC). METHODS: The study population consisted of 83 subjects (age: 12 to 19 months (x= 15.6); gender: 40 females and 43 males). Inclusion criteria included: (1) unremarkable medical history; (2) presence of 4 maxillary primary incisors (MPI) with no visible defects; (3) clinically caries free; (4) use of a nursing bottle at naptime and/or bedtime which contained a cariogenic substrate; (5) 2 consecutive ms positive cultures from pooled MPI plaque. The subjects were randomized into 2 groups. The 39 subjects in the experimental group and the 44 subjects in the control group were evaluated every 2 months during the study period. At each evaluation, the subjects had 10% povidone iodine (experimental group) or placebo (control group) applied to their dentition. Treatment failure was defined as the appearance of a white spot lesion(s) on any of the MPI during the study period. RESULTS: Using the Kaplan-Meier procedure, the estimated percents (+/- SES) of participants to experience 12 months of disease-free survival were 91 +/- 5% for those receiving treatment and 54 +/- 9% for those in the control group. Via the log-rank test, the hazard of treatment failure is statistically significantly higher in the placebo group (log-rank statistic 10.28, two-sided P=0.0013). CONCLUSIONS: These observations indicate that topical antimicrobial therapy increases disease-free survival in children at high risk for ECC.

El trabajo independiente en los cursos regulares para trabajadores de nivel universitario / Independent work in regular courses for workers at university level

Se señalan entre los logros de las tesis y resoluciones del Primer Congreso del Partido sobre Política Educacional, la incorporación de las grandes masas de trbajadores a la educación de adultos y a los estudios superiores, sobre la base de que su preparación se lleve a cabo desde usu puestos de trabajo y sus estudios de superación técnica y profesional estén relacionados con la actividad laboral que realicen. El trabajo recoge la proyección de los componentes personales y no personales del proceso docente educativo hacia el logro de los fines y objetivos de la educación de estos especialistas. Se exponen aspectos de índole metodológica, destacándose entre éstos el uso de las guías de estudio que sirven de orientación en la autopreparación del estudiante y la acertada dirección del docente a través de las formas de organización de la enseñanza. Como objetivo fundamental pretende resaltar la importancia del trabajo independiente del estudiante, pilar fundamental en la formación de estos especialistas. Por último, expone la modesta experiencia lograda en la orientación del trabajo independiente de la asignatura Enfermería General, del primer año de la Especialidad de Licenciatura en Enfermeria

El trabajo independiente en los cursos regulares para trabajadores de nivel universitario / Independent work in regular courses for workers at university level

Se señalan entre los logros de las tesis y resoluciones del Primer Congreso del Partido sobre Política Educacional, la incorporación de las grandes masas de trbajadores a la educación de adultos y a los estudios superiores, sobre la base de que su preparación se lleve a cabo desde usu puestos de trabajo y sus estudios de superación técnica y profesional estén relacionados con la actividad laboral que realicen. El trabajo recoge la proyección de los componentes personales y no personales del proceso docente educativo hacia el logro de los fines y objetivos de la educación de estos especialistas. Se exponen aspectos de índole metodológica, destacándose entre éstos el uso de las guías de estudio que sirven de orientación en la autopreparación del estudiante y la acertada dirección del docente a través de las formas de organización de la enseñanza. Como objetivo fundamental pretende resaltar la importancia del trabajo independiente del estudiante, pilar fundamental en la formación de estos especialistas. Por último, expone la modesta experiencia lograda en la orientación del trabajo independiente de la asignatura Enfermería General, del primer año de la Especialidad de Licenciatura en Enfermeria