Expert Opinion by Clinicians on the Use of Insulin Therapy in People with Hepatic Impairment

People with type 2 diabetes mellitus (T2DM) have a higher risk of developing chronic liver disease (CLD) and its complications. T2DM, obesity, and insulin resistance are all strongly associated with nonalcoholic fatty liver disease (NAFLD). Conversely, people suffering from cirrhosis have reduced glucose tolerance in approximately 60% of cases, diabetes in 20% of cases, and insulin-mediated glucose clearance is lowered by 50% as compared with those who do not have cirrhosis. An exploratory review was conducted using existing published evidence from clinical studies on dosing and titrations of individual insulin formulations in people with CLD to optimize insulin dosage titration for minimizing hypoglycemia risk. This article discusses current hyperglycemia treatment techniques for patients with CLD as well as the consensus recommendations on insulin use in special populations with T2DM and hepatic impairment. Based on available evidence and expert diabetologists’ recommendations, careful insulin dose titration, customized glycemic targets, and frequent glucose screening are recommended for optimal glycemic management without hypoglycemia in CLD. Long-acting insulin should be avoided or used when short-acting insulin fails to provide adequate glycemic control with raised fasting blood sugar levels. While the patient’s glucose profile is being evaluated, the prandial insulin dose can be lowered by 25% initially. The dose can be titrated based on the patient’s postprandial glycemic expression and whether their food intake meets the Child–Pugh scores A and B categories. Titrating premixed insulins is difficult for patients in class C since their appetite and overall health are constantly compromised and in flux.

Endoscopic Ultrasound-Guided Vascular Procedures: A Review

Since the 1980s, endoscopic ultrasound has advanced from being purely diagnostic to an interventional modality. The gastrointestinal tract offers an exceptional window for assessing the vascular structures in the mediastinum and in the abdomen. This has led to a rapidly growing interest in endoscopic ultrasound-controlled vascular interventions as a minimally invasive alternative to surgical and radiological procedures.

Elucidation of the pathophysiology of intradialytic muscle cramps: pharmacokinetics applied to translational research

In the conventional concept of translational research, investigations flow from the laboratory bench to the bedside. However, clinical research can also serve as the starting point for subsequent laboratory investigations that then lead back to the bedside. This article chronicles the evolution of a series of studies in which a detailed analysis of pharmacokinetics in hemodialysis patients revealed new physiological insight that, through a systems approach incorporating kinetic, physicochemical, physiologic, and clinical trial results, led to an elucidation of the pathophysiology of intradialytic skeletal muscle cramps. Based on this understanding, a therapeutic path forward is proposed.

Augmented renal clearance

Adding to the complexity of caring for critically ill patients is the fact that many of them have a creatinine clearance that exceeds 130 mL/min/1.73 m². This phenomenon, termed augmented renal clearance (ARC), has only recently been widely recognized and its pathogenesis remains incompletely understood. However, ARC has been shown to result in increased dose requirements for drugs that are primarily eliminated by renal excretion, including many antimicrobial agents and enoxaparin. Recognition of ARC is hampered by the fact that the standard creatinine-based equations used to estimate renal function are not accurate in this clinical setting and the diagnosis is best established using both serum and urine creatinine measurements to calculate clearance. So a high index of clinical suspicion and awareness is usually required before this step is taken to confirm the diagnosis of ARC.

Intracerebroventricular drug administration

Among the various routes of drug administration, perhaps the least studied is intracerebroventricular (ICV) administration. This route has been shown to be particularly useful in administering to the central nervous system (CNS) drugs that do not cross the blood-brain barrier readily. As such, the ICV route is a valuable option for providing therapeutic CNS drug concentrations to treat patients with CNS infectious and neoplastic diseases. This route of drug administration also has the advantage of minimizing systemic toxicity.

The stable isotope method for determining absolute bioavailability

The bioavailability of a drug is usually assessed in healthy subjects. However, it is reasonable to expect that significant alterations in bioavailability may occur in actual patients with different diseases or in individuals belonging to special populations. Relatively few studies have been conducted to examine this possibility. The stable isotope method is well suited to compare absolute bioavailability in patients and healthy subjects. Studies in which this method was used indicate that significant changes in the bioavailability of some drugs are particularly likely in patients with advanced liver disease and in those whose splanchnic blood flow is reduced. The expectation is that bioavailability in neonates, children, and pregnant women may also differ from that in non-pregnant adults.

Pitfalls in the calculation of hemodialysis clearance and in the assessment of dialysis efficacy

The therapeutic technique of hemodialysis and the concept of clearance have both followed a long but instructive course of development. In addition, it recently has been shown that physiological changes occurring during hemodialysis have important clinical consequences both in the treatment of drug toxicity and in the selection of appropriate replacement doses of therapeutic drugs. Two major approaches for calculating hemodialysis clearance are currently used. The first approach, termed the recovery method is the “gold standard” that is recommended for use in the current US FDA draft guidance on the conduct of pharmacokinetic studies in patients with impaired renal function. The second approach, termed the A-V difference method, is used more commonly. Unfortunately, this method results in erroneous plasma clearance estimates when improper values for dialyzer flow are chosen. This constitutes a major pitfall that should be avoided in future studies.

Physiological spaces and multicompartmental pharmacokinetic models

The idea of body compartments has its origins in physiology and antedates their use in both physiologically-based predictive pharmacokinetic models and in the simpler compartmental models used to analyze pharmacokinetic data. Whereas physiologically-based pharmacokinetics has evolved to use increasingly sophisticated organ-based models, most compartmental models for data analysis are used without regard for their underlying physiological basis. However, detailed analysis of inulin and urea kinetics has offered some understanding of the physiological basis underlying some three-compartment pharmacokinetic models. In addition, these simple models have yielded new insight into physiological phenomena.

Individualization of drug therapy: an historical perspective

No abstract available.

Cohort Study of Risk Factors for Breast Cancer in Post Menopausal Women / 한국역학회지

OBJECTIVES: The present study assessed more than 800 potential risk factors to identify new predictors of breast cancer and compare the independence and relative importance of established risk factors. METHODS: Data were collected by the Women's Health Initiative and included 147,202 women ages 50 to 79 who were enrolled from 1993 to 1998 and followed for 8 years. Analyses performed in 2011 and 2012 used the Cox proportional hazard regression to test the association between more than 800 baseline risk factors and incident breast cancer. RESULTS: Baseline factors independently associated with subsequent breast cancer at the p<0.001 level (in decreasing order of statistical significance) were breast aspiration, family history, age, weight, history of breast biopsies, estrogen and progestin use, fewer live births, greater age at menopause, history of thyroid cancer, breast tenderness, digitalis use, alcohol intake, white race, not restless, no vaginal dryness, relative with prostate cancer, colon polyps, smoking, no breast augmentation, and no osteoporosis. Risk factors previously reported that were not independently associated with breast cancer in the present study included socioeconomic status, months of breast feeding, age at first birth, adiposity measures, adult weight gain, timing of initiation of hormone therapy, and several dietary, psychological, and exercise variables. Family history was not found to alter the risk associated with other factors. CONCLUSIONS: These results suggest that some risk factors not commonly studied may be important for breast cancer and some frequently cited risk factors may be relatively unimportant or secondary.

Visioneros o soñadores? la historia de la salud oral del infante / Visionaries or Dreamers? The Story of Infant Oral Health

Objetivo: revisar la historia inicial de la promoción de la salud oral para los bebés y niños peque-ños, el impacto de la directiva de la AAPD sobre los cuidados al niño, la salud oral y las formas de maximizar los resultados de salud. Métodos: revisión de literatura. Resultados: conceptos sobre la prevención primaria y la intervención temprana fueron reportados ya en el siglo XIX. Los avances para impactar positivamente en la salud oral de los niños se han realizado. Sin embargo, el consejo de los primeros entendidos y médicos que la atención bucodental y la prevención debe comenzar tempranamente con los cuidadores y la aparición del primer diente del bebé no han sido plenamente aceptado por la profesión. Conclusiones: Se presenta una perspectiva histórica sobre el cuidado de la salud oral para los bebés y niños pequeños. Existe la necesidad de alejarse de la vía de abordaje de las enfermedades bucodentales e incorporar los conceptos de atención primaria a partir del período perinatal, y de manera más amplia sobre los factores determinantes sociales de la salud.

Purpose: To review the early history of the promotion of oral health for infants and toddlers, the impact of the AAPD guideline on infant oral health care and ways to maximize health outcomes. Methods: Review of the literature. Results: Concepts on primary prevention and early intervention were reported as early as the 19th century. Progress to positively impact the oral health of children has been made. Nevertheless, the advice of early scholars and clinicians that oral care and prevention must begin early with the caregivers and the emergence of the infantÆs first tooth have not been fully embraced by the profession. Conclusions: A historical perspective on oral health care for infants and toddlers has been presented. There is a need to move away from the surgical approach of managing oral disease and embrace the concepts of primary care beginning perinatally while more broadly addressing social determinants of health.

novel insight to the functional role of stathmin 1 in IgE-mediated activation of RBL-2H3 cells

IgE-mediated cell signaling, induced by cross-linking of high affinity receptor for IgE [FepsilonRI] in the presence of antigen [Ag], is a well known mechanism described for mast cell activation in allergy and hypersensitivity reactions, which induces a spectrum of cellular responses such as secretion and up-regulation of cell surface FepsilonRL Although for several years IgE binding to FepsilonRI was considered to be a passive sensitization process, the outcomes of several recent studies have revealed a variety of different cellular responses to IgE binding compared to IgE plus Antigen binding. The present study applied a functional proteomics-based approach to investigate mast cell signaling events and provided new insights to FcsRI-mediated cell signaling in RBL-2H3.1 cells, and may point to the activation of alternative signaling pathways in response to IgE or IgE plus Ag. Comparative analysis by 2-D PAGE of RBL cells activated with IgE plus Ag for three and four hours compared to non-activated cells was followed by mass spectrometric protein identification and provided evidence for the induction of Stathmin 1 [STMN1] gene expression in response to IgE plus Ag activation. Complementary SDS-PAGE analysis showed a distinct up-regulation of STMN1 induction in response to challenge with IgE plus Ag compared to sensitization with IgE only. Phosphoproteomics analysis gave evidence for significant increase at phosphorylation of STMN1 on ser16 after 1min, though a slight rise at 5 min, and on ser38 after 1 and 5min sensitization with IgE and a similar result was observed for 1min IgE plus Ag-activation. IgE plus Ag-activation was also found to induce the phosphorylation of ser38 to a greater extent than sensitization with IgE. In contrast, IgE alone was more effective than IgE plus Ag at inducing phosphorylation of ser 16. Collectively this study provides further insights into the role of Stathmin 1 in FepsilonRI-mediated activation of cells of mast cell lineage and might shed light on the diverse response of these cells to IgE or IgE plus Ag

Prevalence of intestinal microsporidiosis in Human Immunodeficiency Virus-infected patients with diarrhea in major United States cities

To determine the prevalence of intestinal microsporidiosis in HIV-infected patients, we performed a prospective study of HIV-infected patients with diarrheal illnesses in three US hospitals and examined an observational database of HIV-infected patients in 10 US cities. Among 737 specimens from the three hospitals, results were positive for 11 (prevalence 1.5 percent); seven (64 percent) acquired HIV through male-to-male sexual contact, two (18 percent) through male-to-male sexual contact and injection drug use, and one (9 percent) through heterosexual contact; one (9 percent) had an undetermined mode of transmission. Median CD4 count within six months of diagnosis of microsporidiosis was 33 cells/µL (range 3 to 319 cells/µL). For the national observational database (n = 24,098), the overall prevalence of microsporidiosis was 0.16 percent. Prevalence of microsporidiosis among HIV-infected patients with diarrheal disease is low, and microsporidiosis is most often diagnosed in patients with very low CD4+ cell counts. Testing for microsporidia appears to be indicated, especially for patients with very low CD4+ cell counts.

Para determinar a prevalência de microsporidiose intestinal em pacientes infectados pelo HIV foi realizado um estudo prospectivo em três hospitais dos Estados Unidos da América do Norte (EUA) e analizada uma base de dados nacional composta de dados coletados de pacientes infectados pelo HIV em 10 cidades dos EUA. De um total de 737 amostras de fezes de pacientes infectados pelo HIV que apresentavam diarréia, amostras de 11 pacientes (prevalência de 1,5 por cento) foram positivas para microsporídios. Todos os positivos eram do sexo masculino e, entre eles, sete (64 por cento) pacientes adquiriram a infecção pelo HIV através de relação homossexual, dois (18 por cento) através de relação sexual e drogas injetáveis e um (9 por cento) através de contato heterosexual, enquanto que em um paciente o modo de transmissão do HIV não foi determinado. A contagem média de linfócitos CD4 realizada até seis meses do diagnóstico de microsporidiose foi de 33 células/microlitro (3 a 319 células/microlitro). A análise da base de dados nacional (n = 24.098) mostrou uma prevalência de microsporidiose de 0,16 por cento. A prevalência de microsporidiose em pacientes HIV-positivos com diarréia é baixa. Entretando, como a microsporidiose é mais frequentemente diagnosticada em pacientes com contagens de CD4 muito baixas, a indicação de pesquisa de microsporídios é justificada, especialmente para estes pacientes.

Analysis of restriction fragment length polymorphism in the kappa-casein gene related to weight expected progeny difference in Nellore cattle

Restriction fragment length polymorphism (RFLP) has been detected at the bovine kappa-casein locus. The polymorphism has been analyzed for its effects in cattle production, mostly for milk traits and even for maternal effect on pre-weaning weights. We used polymerase chain reaction - restriction fragment length polymorphism (PCR-RFLP) to genotype 408 Nellore animals for the non-silent mutation (Thr/Ile136 and Asp/Ala148) that characterizes the A and B variants of the polymorphism and compared expected progeny difference (EPD) for a maternal effect on 120 and 210 days weights and direct EPD for 120, 210, 450 and 550 day weight between AA and AB animals. The EPD values were obtained from the University of São Paulo (Brazil) Nellore Cattle Breeding Program, which evaluated 266,272 animals in 2001. Analysis of Variance was used to compare weight expected progeny differences (EPDs) between animals genotyped as AA and AB. The A allele frequency was 0.911. Although the AA animals had higher weight EPDs than AB animals the differences were not statistically significant (p > 0.05).

Pleiotrophic actions of erythropoietin

Erythropoietin is the prime regulator of red blood cell production. However, recent evidence suggests that the hormone has multiple effects outside the hematopoietic system. Functional receptors have been identified on a wide variety of normal and malignant cell types, and numerous biologic effects of the hormone on these cells have been observed both in vitro and in vivo. These findings are causing a reassessment of the understanding of erythropoietin physiology. Moreover, there are important implications for the use of recombinant erythropoietin in the clinical setting.

Algunos aspectos antropológicos del encuentro médico-paciente con tuberculosis pulmonar en el occidente de México / Various anthropologic features of the physician-patient encounter with pulmonary tuberculosis in Western Mexico

The present work has as its purpose a description of the information exchanged during doctor-patient encounters immediately following diagnosis of pulmonary tuberculosis. To accomplish this nine such encounters were audiotape at two public health clinics in Guadalajara, Mexico. Communication of information and affect was evaluated by adapting the Roter interactional process analysis. Results show that the physician instructed the patient to behave in ways to prevent disease transmission while assuring patient recovery. Virtually lacking from these recordings is evidence of physician concern with the struggle patients experience to incorporate this regimen of directly observed therapy in to their daily lives. Because these sessions are managed by clinicians to encourage a unidirectional flow of information from physician to patient, the former fail to attain either patient cultural understanding of his/her disease process or comprehensive understanding of how he is affected she by the illness.

Pleiotrophic Actions of Erythropoietin

Erythropoietin is the prime regulator of red blood cell production. However, recent evidence suggests that the hormone has multiple effects outside the hematopoietic system. Functional receptors have been identified on a wide variety of normal and malignant cell types, and numerous biologic effects of the hormone on these cells have been observed both in vitro and in vivo. These findings are causing a reassessment of the understanding of erythropoietin physiology. Moreover, there are important implications for the use of recombinant erythropoietin in the clinical setting.

Válvula cardíaca de carbono de duplo folheto Biplus: projeto e desenvolvimento / Biplus bileaflet carbon cardiac valve: project and development

Introduçao: Após o desenvolvimento de válvula de disco em carbono revestida com material biológico, com bons resultados após dois anos de uso clínico, os autores desenvolveram a primeira válvula brasileira de duplo folheto em carbono. A finalidade foi conseguir uma válvula com baixo nível de ruído, com revestimento de material biológico para facilitar a cicatrizaçao no anel valvar e reduzir ao máximo a superfície sintética exposta ao sangue, para se obterem menores índices de reoperaçao, trombose, tromboembolismo e usar menor dose de anticoagulante a fim de evitar acidentes hemorrágicos. Material e Métodos: A válvula é de duplo folheto com fechamento horizontal e articulado na face interna do corpo, fabricado com Carbolite. É feita em três modelos: toda em carbono semelhante a outras válvulas em uso; revestida com material biológico, ou com batente de elastômero de silicone com revestimento de material biológico. O batente de silicone tem aspecto denteado, para evitar dano ao material biológico e torna a válvula bastante silenciosa. Cada válvula é testada individualmente em acelerador de pulso (1.OOO pulsaçoes por minuto, durante cinco dias) Entao, sao feitos esterilizaçao, revestimento com pericárdio heterólogo processado em glicerina, montagem e esterilizaçao final em gás ETO, sendo conservada em glicerina. Existem 2 pacientes aórticos operados, com dois e três meses de evoluçao, em uso de anticoagulante oral, tendo sido colocadas válvulas apenas com revestimento de material biológico. Resultados Iniciais:Sao poucos casos com pequeno tempo de observaçao, destacando-se boa evoluçao clínica, ausência de percepçao do ruído da válvula e presença do sopro sistólico suave comum em todas as próteses cardíacas aórticas. O modelo com batente de silicone acha-se em teste, nao mostrando desgaste ou dano perceptível, após 30 dias de teste contínuo acelerado já equivalente a 1,4 anos de uso clínico. Conclusoes: A válvula de dois folhetos Biplus apresentou-se com desenho adequado para receber o material biológico e, também, para funcionar com batente de silicone, deixando a válvula bastante silenciosa, para melhor conforto do paciente.