Medial column fusion for degenerative pesplanovalgus deformity. Report of 9 patients.

Degenerative pesplanovalgus is a progressive disabling condition; there are more than one surgical procedure used in the treatment with varied outcomes. The aim of the current study is to highlight the benefits of the medial column fusion surgery in the treatment of this condition. Nine adult patients with rigid degenerative pesplanovalgus (without significant valgus heel deformity) underwent medial column fusion between January 2015 to December 2020. The procedure was combined with subtalar fusion in four patients and lateral column lengthening in one patient. The mean follow-up period was 19.5 months (range, 15-27). Regular clinical and radiological reviews was carried out in the postoperative period. The mean Manchester Oxford foot score was good in 7 patients, and fair in two patients. The mean Meary angle was 5.8 ± 5.4° preoperatively and improved to 0.9 ± 7.7° at final follow-up, and the mean Pitch angle also improved from 12.5 ± 3.7° preoperatively to 23.2 ± 4.1° (P < .001). In a patient, and at a different stage, talo-navicular fusion was added to the medial column fusion.The outcome of this series of cases was encouraging and medial column fusion continues to be a good option in the management of rigid pesplanovalgus deformity.

Alternative approaches for the treatment of airway diseases: focus on nanoparticle medicine.

Despite the various treatment options and international guidelines currently available for the appropriate therapeutic management of asthma, a large population of patients with asthma continues to have poorly controlled disease. There is therefore a need for novel approaches to achieve better asthma control, especially for severe asthmatics. This review discusses the use of nanoparticles for the specific targeting of inflammatory pathways as a promising approach for the effective control of severe persistent asthma as well as other chronic inflammatory diseases.

Group-Related Variables in Intervention Programs for Intimate Partner Violence Perpetrators: A Systematic Review.

Intervention programs for male intimate partner violence (IPV) perpetrators mostly use the group intervention modality. Notwithstanding, the literature has neglected the study of group-related variables and their possible association with these interventions' functioning and outcomes. This systematic review aimed to analyze group-related variables, their predictors, and their relation to the functioning and outcomes of intervention programs for IPV perpetrators. The systematic review was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The following databases were searched from inception to November 2022: Web of Science, Scopus, PUBMED, and PsycINFO. Of the 5,941 identified studies, 13 were included in the review. The main predictors of group-related variables were: intervention stage, motivational strategies, and leadership (counseling approach). The group-related variables as predictors of intervention outcomes were: group management behaviors and support (facilitator behavior within the group); positive confrontation, protherapeutic behavior, active involvement, positive interaction with peers, and positive interaction with the facilitator (participant behavior within the group); and group cohesion and group climate (group dynamics). Group cohesion and participants' protherapeutic behavior stood out for their association with positive treatment outcomes (i.e., greater participation and working alliance, lower rates of violent behavior during follow-up). The findings from this review suggest that group processes are key factors in intervention programs for IPV perpetrators, and a better understanding of how these group processes are shaped, and how they can contribute to positive program outcomes, provides a new approach and insights to improve their effectiveness.

Adverse Events of the Long-Term Use of Opioids for Chronic Non-cancer Pain: A Narrative Review.

BACKGROUND: The long-term use of opioids for chronic non-cancer pain (CNCP) has drawn more attention and debate. Although opioids are frequently used to treat chronic pain, their effectiveness and safety over extended periods are still unknown. OBJECTIVES: The purpose of this review is to provide an overview of what is currently known about the adverse events of long-term use of opioids in CNCP. It also delivers patient-centered strategies designed to mitigate these risks. METHODS: We conducted a literature search in PubMed, MEDLINE, EMBASE, and Web of Science databases. Search terms included CNCP, pain pathophysiology, opioid pharmacodynamics, opioid prescribing trends, guidelines for opioid use, and opioid side effects.  Results: Our review highlights that while opioids may provide short-term relief from CNCP, their effectiveness diminishes over time due to the development of opioid tolerance. This tolerance often leads to increased dosages, which can subsequently result in opioid dependence. Additionally, long-term opioid therapy is associated with a spectrum of adverse effects, including constipation, drowsiness, respiratory depression, and potential for drug interactions. Furthermore, our review indicates that alternative pain management strategies play a crucial role in controlling CNCP. They offer significant benefits with fewer adverse events. These strategies include non-opioid medications, physical therapy, cognitive-behavioral therapy (CBT), various interventional procedures, injection therapy, and acupuncture. CONCLUSION: Using opioids to manage CNCP presents several challenges. Given these challenges, alternative treatments are being considered as viable options. Moreover, it is crucial to customize treatment plans to align with the patients' specific health requirements, existing conditions, and potential risks to ensure the best possible outcomes.

Attitudes Toward Intimate Partner Violence Against Women in Latin America: A Systematic Review.

Attitudes toward intimate partner violence against women (IPVAW) are being increasingly recognized as a central issue for comprehensively understanding this complex phenomenon. While IPVAW remains widespread in Latin America, knowledge about it and research on attitudes toward IPVAW are limited. This systematic review synthesized quantitative peer-reviewed studies that address attitudes toward IPVAW in Latin America. The review was conducted between April 2020 and July 2022 in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses recommendations using the Web of Science, Scopus, and PsycINFO databases. In total, 52 of the 149 eligible articles were selected based on the inclusion criteria. Four sets of attitudes toward IPVAW were identified: legitimacy, acceptability, attitudes toward the intervention, and perceived severity. Attitude correlates were the most common research topic in more than half of the studies but were generally focused on a single country. Among the few multi-country studies, the sample of Latin American countries was small. The remaining studies were divided into three research themes: attitude as a predictor, interventions for attitude change, and scale validation. Our study aims to motivate future research on the identified knowledge gaps and may be useful for the implementation of appropriate prevention policies and intervention programs to counter IPVAW on a regional scale.

Participants in Court-mandated Intervention Programs for Intimate Partner Violence Perpetrators with Substance Use Problems: A Systematic Review of Specific Risk Factors.

Men with alcohol and/or other drug use problems (ADUPs) court-mandated to attend intervention programs for intimate partner violence (IPV) perpetrators have been identified as a high-risk, highly resistant group of IPV perpetrators, as they present lower treatment adherence and higher dropout and recidivism rates. Previous research suggests that IPV perpetrators with ADUPs may require tailored interventions to address their specific risk factors. The present systematic review was conducted using PRISMA guidelines to identify the specific risk factors in men with and without ADUPs on entry to court-mandated perpetrator programs. The following databases were searched from inception to November 2021: Web of Science, PsycINFO, and Scopus. There was a screening of 3,995 records, and 29 quantitative studies were included in the review. Risk factors present in males court-mandated to perpetrator programs were grouped into four categories: sociodemographic risk factors, personality disorders and psychological adjustment, social-relational risk factors, and risk factors related to attitudes towards women. Results indicated that the main risk factors in IPV perpetrators with ADUPs, compared to those without, were higher clinical symptomatology (e.g., anger and impulsivity), personality disorders, poorer executive functions, having experienced more stressful life events, higher exposure to childhood trauma, lower intimate social support, and higher responsibility attributed to the offenders' personal context. These results contribute to a deeper understanding of the complex phenomenon of IPV and ADUPs, and could help to inform key targets for perpetrator programs that may improve the well-being of their (ex)partners and increase the effectiveness of intervention programs for IPV perpetrators.

Los hombres que presentan consumo problemático de alcohol y otras drogas (CPAD) y que acuden por mandato judicial a programas de intervención para agresores de pareja constituyen un grupo de agresores resistentes a la intervención y de alto riesgo, ya que presentan una menor adherencia al tratamiento y una mayor frecuencia de abandono y reincidencia. La investigación previa indica que los participantes con CPAD pueden necesitar intervenciones adaptadas en las que se traten los factores de riesgo específicos. La presente revisión sistemática se ha llevado a cabo siguiendo las directrices PRISMA con el fin de conocer los factores de riesgo específicos en participantes con y sin CPAD al inicio de la intervención. La búsqueda bibliográfica se realizó en las siguientes bases de datos hasta noviembre del 2021: Web of Science, PsycINFO y Scopus. Se examinaron 3,995 estudios, incluyéndose 29 estudios cuantitativos en la revisión. Los factores de riesgo de los hombres que acudieron por mandato judicial a intervenciones con agresores de pareja se agrupan en cuatro categorías: sociodemográficos, trastornos de la personalidad y ajuste psicológico, sociorrelacionales y relativos a las actitudes hacia la mujer. Los resultados indican que los principales factores de riesgo en agresores de pareja con CPAD, comparados con aquellos que no tienen este problema, se caracterizan por una mayor sintomatología clínica (e.g., ira e impulsividad), trastornos de la personalidad, deficiencias en las funciones ejecutivas, mayor exposición a hechos vitales estresantes, trauma en la infancia, menor apoyo social íntimo y mayor tendencia a atribuir la responsabilidad de la conducta violenta a su contexto personal. Estos resultados contribuyen a una comprensión más profunda de la compleja relación entre la violencia de pareja y el CPAD y de los objetivos clave de los programas para agresores, con el fin de aumentar el bienestar de la (ex)pareja y la eficacia de dichos programas.

Self-Determined Goals of Male Participants Attending an Intervention Program for Intimate Partner Violence Perpetrators: A Thematic Analysis.

Treatment adherence and motivation to change are among the main challenges in intervention programs for Intimate Partner Violence (IPV) perpetrators. Motivational strategies have shown promising results in increasing the effectiveness of intervention programs for IPV perpetrators. One of these motivational strategies is goal setting. The aim of this study was to analyze and categorize the self-determined goals (n = 204) of 227 male participants attending an intervention program for IPV perpetrators. Findings of the thematic analysis suggested three levels of analysis: 4 core categories, 12 categories, and 35 codes. The four core categories were "interpersonal relationships" (39.7%), "personal resources for daily life" (29.3%), "coping strategies" (27.8%), and "motivation to change" (3.2%). Identifying the main categories of self-determined goals of IPV perpetrators could guide professionals to tailor the intervention to participants' specific needs and implement evidence-based strategies to strengthen goal attainment and improve treatment outcomes.

6-Paradol Alleviates Testosterone-Induced Benign Prostatic Hyperplasia in Rats by Inhibiting AKT/mTOR Axis.

INTRODUCTION: Benign prostatic hyperplasia (BPH) is a common disease among elderly men. Its pharmacological treatment is still unsatisfactory. 6-Paradol (6-PD) is an active metabolite found in many members of the Zingiberaceae family. It was reported to possess anti-proliferative, antioxidant, and anti-inflammatory activities. The present study aimed at exploring the potential of 6-PD to inhibit testosterone-induced BPH in rats as well as the probable underlying mechanism. METHODS: Male Wistar rats were divided into 6 groups and treated as follows: Group 1 (control group) received vehicles only, Group 2 testosterone only, Groups 3 and 4 received 6-PD (2.5 and 5.0 mg/kg; respectively) and testosterone, and Group 6 received finasteride and testosterone. RESULTS: Daily treatment of animals with 6-PD at the two dose levels of 2.5 and 5 mg/kg significantly ameliorated a testosterone-induced rise in prostate index and weight. This was confirmed by histological examinations of prostatic tissues that indicated a reduction in the pathological changes as well as inhibition of the rise in glandular epithelial height in 6-PD treated rats. Immunohistochemical investigations showed that 6-PD prevented the up-regulation of cyclin D1 induced by testosterone injections. Further, 6-PD significantly modulated mRNA expression of both Bcl2 and Bax in prostate tissues of testosterone-treated rats in favor of anti-proliferation. It also showed antioxidant activities as evidenced by inhibition of accumulation of malondialdehyde (MDA) and exhaustion of catalase (CAT) activity. In addition, 6-PD displayed significant anti-inflammatory activities as it prevented up-regulation of interleukin-6 (IL-6) and nuclear factor kappa B (NF-κB). Immunoblotting analysis revealed that 6-PD significantly inhibited testosterone-induced activation of AKT and mTOR in prostate tissues. CONCLUSIONS: 6-PD protects against testosterone-induced BPH in rats. This can be attributed, at least partly, to its antiproliferative, antioxidant, and anti-inflammatory properties as well as its ability to inhibit activation of the AKT/mTOR axis.

Fractal Model for Predicting Elemental Sulfur Saturation in the Presence of Natural Fracture.

Sour gas reservoirs are an important part of unconventional gas reservoirs, which are widely distributed in the world. However, elemental sulfur deposition, channel plugging, and productivity reduction consequentially occur in the development of high sour gas fields as pressure drops. The accurate prediction of sulfur deposition is a very important work for sour gas reservoirs. In this paper, a fractal model is presented for predicting elemental sulfur saturation in the presence of natural fracture. The model takes into consideration the effects of non-Darcy flow. In addition, the influence parameters such as fractal dimension, fractal index, and non-Darcy flow are studied. The results showed the following: (1) sulfur deposition was overestimated by Hu's model, and this paper model is more accurate for prediction of sulfur deposition; (2) elemental sulfur deposition decreases with the increase of the fractal dimension, while elemental sulfur deposition increases with the decrease of the fractal index; and (3) non-Darcy flow should be considered because it causes a faster rate of sulfur deposition. This research will provide a basis and reference for predicting elemental sulfur saturation in the presence of natural fracture for sour gas reservoirs.

Evaluation of the hepatoprotective, anti-inflammatory, antinociceptive and antiepileptic activities of Chrysanthemum trifurcatum.

Chrysanthemum trifurcatum is common to Mediterranean countries and widely-used in traditional medicine. Due to the scarcity of data about the pharmacological properties of C. trifurcatum, this present study was designed to determine the effects of C. trifurcatumethanolic extract (CEE) for its anti-nociceptive, anti-epileptic, anti-inflammatory, and hepatoprotective activities in mice and rat models. We demonstrate that CEE contains alkaloids, carbohydrates, and flavonoids, and in a dose-dependent (300 and 500 mg/kg) manner exhibited significant reductions in paracetamol (PCM; 500 mg/kg)-induced increased serum AST, ALT and ALP levels, similar to as seen by silymarin (25 mg/kg). Additionally, CEE (300 mg/kg) elicited inhibition in acetic acid-induced abdominal writhes, delayed latency time to paw's licking in hot plate tests, exerted an anti-convulsant effect by prolonging the onset of clonic and tonic convulsions, and reduced pentylenetetrazole (PTZ; 80 mg/kg)-induced mortality. Moreover, CEE (500 mg/kg) exhibited a prominent reduction in carrageenan-induced paw edema. These studies indicate that CEE possesses profound central and peripheral analgesic, anti-convulsant, anti-inflammatory, and hepatoprotective activities.

Validation of the Working Alliance Inventory-Observer Short Version with male intimate partner violence offenders.

The working alliance is a key element to increase intimate partner violence (IPV) offenders' motivation, adherence to treatment, and active participation in batterer intervention programs (BIPs). The objective of the present study is to assess the psychometric properties and factor structure of the Working Alliance Inventory-Observer Short Version (WAI-O-S) with a sample of IPV offenders. The sample was 140 men convicted for IPV and court-mandated to a community-based BIP. Inter-rater agreement and reliability were evaluated by computing the intraclass correlation coefficient. To test the latent structure a Bayesian confirmatory factor analysis approach was used. To test criterion-related validity, the WAI-O-S factorial scores were correlated to protherapeutic behavior, stage of change and motivation to change. The WAI-O-S showed an adequate reliability. Results from Bayesian confirmatory factor analyses showed two first-order factors (Bond and Agreement), and a second-order factor (General working alliance) explaining the relationship between the first-order factors. Results also support the validity of this instrument. The availability of reliable and valid observational measure of the working alliance provides a useful tool to overcome self-report measurement limitations such as social desirability, deception, and denial among IPV offenders.

ANTECEDENTES/OBJETIVO: La alianza terapéutica es clave para incrementar la motivación, adherencia al tratamiento y participación en los programas de intervención con maltratadores. El objetivo del presente estudio es evaluar las propiedades psicométricas y estructura factorial del Working Alliance Inventory-Observer Short Version (WAI-O-S) con una muestra de hombres maltratadores. MÉTODO: Se utilizó una muestra de 140 hombres condenados por violencia de género y derivados a un programa de intervención con maltratadores. El acuerdo inter-jueces y la fiabilidad se evaluaron mediante el coeficiente de correlación intraclase. La estructura latente se obtuvo con un análisis factorial confirmatorio Bayesiano. Las puntuaciones del WAI-O-S se correlacionaron con la conducta proterapéutica, estadio y motivación para el cambio para analizar la validez. RESULTADOS: El WAI-O-S mostró una fiabilidad adecuada. El análisis factorial confirmatorio dio lugar a dos factores de primer orden (Vínculo y Acuerdo), y un factor de segundo orden (Alianza terapéutica general). Los resultados obtenidos también avalan la validez del instrumento. CONCLUSIONES: Una medida observacional fiable y válida de la alianza terapéutica, proporciona una herramienta útil para superar las limitaciones de las medidas basadas en auto-informes que se utilizan con población de hombres maltratadores, tales como la deseabilidad social, la negación y el engaño.

The Willingness to Intervene in Cases of Intimate Partner Violence Against Women (WI-IPVAW) Scale: Development and Validation of the Long and Short Versions.

Willingness to intervene when one becomes aware of a case of intimate partner violence against women (IPVAW) reflects the level of tolerance and acceptance of this type of violence in society. Increasing the likelihood of intervention to help victims of IPVAW is also a target for prevention strategies aiming to increase informal social control of IPVAW. In this study, we present the development and validation of the Willingness to Intervene in Cases of Intimate Partner Violence (WI-IPVAW) scale. We report data for both the long and short versions of the scale. We analyzed the latent structure, the reliability and validity of the WI-IPVAW across four samples (N = 1648). Factor analyses supported a bifactor model with a general non-specific factor expressing willingness to intervene in cases of IPVAW, and three specific factors reflecting different intervention preferences: a preference for setting the law enforcement process in motion ("calling the cops" factor), a preference for personal intervention ("personal involvement" factor), and a preference for non-intervention ("not my business" factor). Configural, metric, and partial scalar invariance across genders were supported. Two short versions of the scale, with nine and six items, respectively, were constructed on the base of quantitative and qualitative criteria. The long and short versions of the WI-IPVAW demonstrated both high reliability and construct validity, as they were strongly related to the acceptability of IPVAW, victim-blaming attitudes, perceived severity of IPVAW, and hostile sexism. These results confirm that both the long and short versions of the WI-IPVAW scale are psychometrically sound instruments to analyze willingness to intervene in cases of IPVAW in different settings and with different research needs (e.g., long versions for clinical and research settings, and short versions for large population surveys). The WI-IPVAW is also useful for assessing prevention policies and public education campaigns design to promote a more responsive social environment in cases of IPVAW, thus contributing to deter and reduce this major social and public health problem.

The genus Artemisia L. in the northern region of Saudi Arabia: essential oil variability and antibacterial activities.

Four species of the genus Artemisia L. (Artemisia monosperma, Artemisia scoparia, Artemisia judaica and Artemisia sieberi) growing in the northern region of Saudi Arabia were investigated with respect to their volatile oil contents. The yield of oil varied between 0.30 and 0.41%, % (w/w). A. monosperma showed the highest number of compounds with 30 components representing 93.78% of oil composition. However, A. judaica showed the lowest number of compounds with only 16 components representing 87.47% of essential oil. A. scoparia and A. sieberi are both composed of 17 components, representing 97.14 and 94.2% of total oil composition. A. sieberi and A. judaica were dominated by spathulenol (30.42 and 28.41%, respectively). For A. monosperma, butanoic acid (17.87%) was a major component. However, A. scoparia was a chemotype of acenaphthene. (83.23%). Essential oil of studied species showed high antibacterial activities against common human pathogens.

Fortification of alcoholic beverages (12% v/v) with tea (Camellia sinensis) reduces harmful effects of alcohol ingestion and metabolism in mouse model.

BACKGROUND: An animal model was used to study the health benefits inherent in tea fortified alcoholic beverages fed to laboratory mice. OBJECTIVES: An investigation of the effects of tea fortified alcoholic beverages 12% alcohol (v/v) on antioxidant capacity and liver dysfunction indicators in white Swiss mice including packed cell volume (PCV), albumin, total protein, alkaline phosphatase (ALP) and glutathione (GSH) was carried out. METHODS: Plain, black, green and purple tea fortified alcohols were developed with varying tea concentrations of 1, 2 and 4 g/250 mL in 12% v/v. Control alcoholic beverages without teas were also developed. A permit (number IRC/13/12) was obtained for the animal research from the National Museums of Kenya, Institute of Primate Research prior to the start of the study. Alcoholic beverages were orally administered every 2 days for 4 weeks at 1 mL per mouse, and thereafter animals were euthanised and liver and blood samples harvested for analyses. Assays on body weight (bwt), packed cell volume (PCV) albumin, total protein, ALP and GSH were performed. Results were statistically analysed using GraphPad statistical package and significant differences of means of various treatments determined. RESULTS: Consumption of tea fortified alcohols significantly decreased (p=0.0001) bwt at 0.32-9.58% and PCV at 5.56-22.75% for all teas. Total protein in serum and liver of mice fed on different tea fortified alcohols ranged between 6.26 and 9.24 g/dL and 2.14 and 4.02 g/dL, respectively. Albumin, ALP and GSH range was 0.92-2.88 µg/L, 314.98-473.80 µg/L and 17.88-28.62 µM, respectively. Fortification of alcoholic beverages lowered liver ALP, replenished antioxidants and increased liver albumin, improving the nutritional status of the mice. CONCLUSIONS: The findings demonstrate tea's hepatoprotective mechanisms against alcohol-induced injury through promotion of endogenous antioxidants. The beneficial effects of tea in the fortified alcoholic beverages could be used to develop safer alcoholic beverages.

Novel 3'-C/N-substituted 2',3'-beta-D-dideoxynucleosides as potential chemotherapeutic agents. 1. Thymidine derivatives: synthesis, structure, and broad spectrum antiviral properties.

A synthetic scheme for the 3'-oxime derivatives 3E, 5E, 5Z, 7E and 7Z of 1-(2,3-dideoxy-beta-D-glycero-pentofuranosyl)thymine and for 1-(2,3-dideoxy-3-nitro-beta-D-erythro-pentofuranosyl)-thymine (10) has been developed starting from appropriately 5'-protected 3'-ketothymidine. X-ray analysis showed that 3'-N-hydroxyimino 3E and 3'-N-methoxyimino 5Z derivatives have close molecular conformations: anti about the N1-C1' bond, and gauche+ about the C4'-C5' exocyclic bond. Their sugar conformations are C1'-exo-O4'-endo and C1'-exo-C2'-endo, respectively. The antiviral assays in cell cultures demonstrated that 3'-N-hydroxyimino 3E and 3'-N-acetoxyimino 7E + 7Z derivatives are endowed with significant activity against human immunodeficiency virus (HIV) with EC50 values ranging between 0.02 and 0.40 microgram/mL for both HIV-1 and HIV-2. The other compounds 5E + 5Z and 10 were at least 2 orders of magnitude less active. The 3'-N-hydroxyimino derivative 3E also shows promising activity against hepatitis B virus (HBV) (EC50 = 0.25 microgram/mL) and against herpes simplex virus type 1 (HSV-1) and HSV-2.

Inhibition of mammalian DNA polymerase-associated 3' to 5' exonuclease activity by 5'-monophosphates of 3'-azido-3'-deoxythymidine and 3'-amino-3'-deoxythymidine.

3'-Azido-3'-deoxythymidine 5'-monophosphate (AZT-MP) has been hypothesized by us to possibly affect 3'-azido-3'-deoxythymidine (AZT) excision from host cell DNA. In the present study, AZT-MP inhibited 3' to 5' exonuclease activity of calf thymus DNA polymerase delta at pharmacological relevant intracellular concentrations. Other 2',3'-dideoxynucleoside-5'-monophosphate (ddN-MP) analogs, including 3'-amino-3'-deoxythymidine-5'-monophosphate (AMT-MP), were also assayed as potential inhibitors of 3' to 5' exonuclease activity. The monophosphate derivative of 3'-amino-3'-deoxythymidine (AMT), an in vivo toxic catabolite of AZT, was the most potent of the ddN-MP analogs tested, inhibiting this activity by more than 50% at 100 microM. These results suggest that inhibition of 3' to 5' exonuclease activities by AZT-MP and AMT-MP may increase steady-state levels of AZT in host DNA, accounting in part for the cell toxicity associated with this drug. The present study also raises the question of whether AZT-MP inhibition of this activity may lead to potential mutagenic effects due to inhibition of 3' to 5' exonuclease-mediated proofreading functions involved in DNA replication.

Effect of stereoisomerism on the cellular pharmacology of beta-enantiomers of cytidine analogs in Hep-G2 cells.

The beta-L enantiomers of 2',3'-dideoxycytidine (beta-L-ddC) and its 5-fuoro derivative, 2',3'-dideoxy-5-fluorocytidine (beta-L-FddC), were demonstrated to be active against human immunodeficiency virus (HIV) and hepatitis B virus (HBV) replication in vitro. In the present study, we investigated the cellular pharmacology of beta-L-ddC and beta-L-FddC and compared it with that of beta-D-2',3'-dideoxy-5-fluorocytidine (beta-D-FddC). Beta-L-FddC (10 microM) was found to be phosphorylated rapidly in Hep-G2 cells to its 5'-mono-, di-, and triphosphate derivatives with intracellular triphosphate levels achieving 26.6 +/- 10.9 pmol/10(6) cells after 72 hr. In contrast, the active 5'-phosphorylated derivative of beta-D-FddC achieved lower levels with triphosphate levels of only 2.3 +/- 0.5 pmol/ (10(6) cells under the same conditions. Beta-L-ddC was also phosphorylated rapidly. A 5'-diphosphocholine (18 +/- 5.8 pmol/10(6) cells) and a 5'-diphosphoethanolamine (13.6 +/- 0.9 pmol/10(6) cells) derivative were detected in beta-D-FddC-treated cells after 72 hr, whereas in beta-L-FddC- and beta-L-ddC-treated cells, only the 5'-diphosphocholine derivative (10.9 +/- 2.8 and 60.4 +/- 5.7 pmol/10(6) cells, respectively) was detected. Beta-L-FddC-5'-triphosphate (beta-L-FddCTP), beta-D-FddC-5'-triphosphate (beta-D-FddCTP), and beta-L-ddC-5'-triphosphate (beta-L-ddCTP) followed a single phase elimination process with an intracellular half-life (T1/2) of 10.5, 5.7, and 12.3 hr, respectively. Furth ermore, beta-L-FddCTP, beta-D-FddCTP, and beta-L-ddCTP levels of 6.7 +/- 2.3, 0.3 +/- 0.1, and 12.0 pmol/10(6) cells, respectively, were still detectable 24 hr following drug removal. The higher intracellular 5'-triphosphate levels of beta-L-FddC and the extended T1/2 of its 5'-triphosphate are consistent with the more potent in vitro antiviral activity of beta-L-FddC in Hep-G2 cells when compared with its beta-D enantiomer, beta-D-FddC.

Remnant kidney pathology after five-sixth nephrectomy in rat. II. Electron microscopy study.

In Wistar male rats, hypertension was induced by 5/6 nephrectomy (5/6N). Electron microscopy revealed an increase in the number of epithelial cells on the Bowman's capsule during the early stages (4 weeks). After 8 and 12 weeks, frequent adhesion was observed between the glomerular tuft and Bowman's capsule. The abnormal podocytes showed nuclear irregularities and distortions. Characteristic foot process fusion formed cytoplasmic plates. There was a considerable increase in mesangial matrix and cells. No immune deposits or breaks in the glomerular basement membrane were observed. In the endothelial cells, the fenestration disappeared in sclerosed glomeruli. Some capillary loops were obliterated by fibrin, macrophages and foam cells. These findings combined with our previous light microscopy and immunofluorescent observations suggest a non-immunogenic glomerular sclerosis.

Remnant kidney pathology after five-sixth nephrectomy in rat. I. A biochemical and morphological study.

In Wistar male rats, hypertension was induced by 5/6 nephrectomy (5/6N). Body weight, blood pressure measurements, morphological and biochemical changes were followed (at four weekly intervals) for 12 weeks after 5/6N. Renal function was assessed by daily total urinary protein (TUP), plasma creatinine concentration [(Cr)p] and creatinine clearance rate. Plasma renin concentration (PRC), aldosterone concentration and erythrocyte content of sodium [Na]E and potassium [K]E were also investigated. Significant increases in systolic blood pressure (SBP), TUP, [(Cr)p] and [Na]E occurred after 4, 8, and 12 weeks of 5/6N. Progressive glomerulosclerosis (GSC), tubular atrophy and interstitial fibrosis were observed. Positive correlations were found between GSC and SBP and TUP. Positive correlations were also found between SBP and [Na]E and [(Cr)P]. PRC was not increased and showed no correlation with SBP. It is concluded that 5/6N produced hypertension associated with a series of morphological and biochemical alterations in kidney structure and function. In this model, mechanisms other than the renin-angiotensin system may be involved.