Transient analysis of macromolecular blood-tissue exchange in microvascular bed

Movement of macromolecules across microvascular walls was studied in the hamster cheek pouch with intravital fluorescence microscopy. A graded series of Fluorescein Isothiocyanate labeled Dextrans(FITC) of 20,000 -70,000 molecular weight were used as representative macromolecular tracers. The time dependent extravasation of FITC-Dextrans was video taped for approximately two and a half hours. Permeation of macromolecules from individual microvessels was quantified by digital video image processing. Histograms of the light intensity distributions for selected fields at various times have been measured and used to construct integral optical density - time profiles of the extravasated fluorochromes for particular leaky sites. An integrated value of the Residence Time Distribution function of the tracer passing through the pore structure of a microvascular wall was obtained from experimental data. Linear velocities and dispersion coefficients were calculated by fitting the solution of a convection-diffusion equation with a step change in macromolecular concentration at the boundary. The Marquardt nonlinear regression algorithm was used to optimize parameters. The average linear velocities were 1.69 ± 0.54 x 10-7 cm/sec for FITC-Dx 20; 0.59 ± 0.17 x 10-7 cm/sec for FITC-Dx 40; and 0.45 ± 0.09 x 10-7 cm/sec for FITC-Dx 70. The effective dispersion coefficients decrease from 4.40 ± 1.45 x 10-12 cm2/sec for FITC-Dx 20 to 0.47 ± 0.09 x 10-12 cm-2/sec for FITC-Dx 40 and to 0.26 ± 0.07 x 10-12 cm-2/sec for FITC-Dx 70. These data suggest that convection is the predominant mode of transendothelial macromolecular transport in continuous subcutaneous microvessels and is an increasingly important mechanism as the molecular size of the molecules increases. Postcapillary pressures were measured in a series of experiments using a servo-nulling system. These results were used to calculate the linear velocities and the dispersion coefficients using two models of restricted transport. It was shown that the Fiber-Matrix theory can be applied for the quantitative discription of the macromolecular transport. In addition, the effect of UV-irradiation on the postcapillary pressure was investigated. The results indicate that pressure drops to about 25% of the control within 10 seconds of illumination. A possible mechanism for this phenomena is suggested

Re-Regulating Dietary Supplements

In 1994, Congress introduced the Dietary Supplement Health and Education Act (DSHEA) to create a regulatory framework for the dietary supplement industry. Despite the increased market size of dietary supplements, the Food and Drug Administration’s (FDA) pre-market authority to regulate the introduction of dietary supplements into the stream of commerce has remained subdued. Under DSHEA, the FDA has limited authority to review dietary supplements before entering the market. Unlike pharmaceuticals, which must be proven safe and effective prior to approval and marketing, dietary supplements can be sold to consumers without such reassurances. We call on Congress to amend DSHEA to grant the FDA the additional express statutory authority to fix these problems

Re-Regulating Dietary Supplements

In 1994, Congress introduced the Dietary Supplement Health and Education Act (DSHEA) to create a regulatory framework for the dietary supplement industry. Since the passage of DSHEA nearly thirty years ago, U.S. adults have steadily increased their annual consumption of dietary supplements. The once $4 billion industry comprising approximately 4,000 products has swelled to a$40 billion trade with anywhere from 50,000 to 80,000 dietary supplements available over-the-counter. Despite the increased market size of dietary supplements, the Food and Drug Administration’s (FDA) pre-market authority to regulate the introduction of dietary supplements into the stream of commerce has remained subdued. Under DSHEA, the FDA has limited authority to review dietary supplements before entering the market. Unlike pharmaceuticals, which must be shown to be safe and effective prior to approval and marketing, dietary supplements can be sold to consumers without such reassurances. Instead, the FDA’s authority is generally limited to post-market enforcement under DSHEA. In fact, the FDA lacks the express authority to remove dietary supplements from the market unless it can establish that the products are unsafe, adulterated, mislabeled or misbranded. Given the morbidity and mortality associated with adulterated dietary supplements and the challenges in addressing the latest fads before they cause harm, Congress must give the FDA the power it needs to be proactive. The FDA desperately needs the tools to regulate the dietary supplement industry and remove harmful dietary supplements from the market. We call on Congress to amend DSHEA to grant the FDA the express statutory authority to (1) regulate dietary supplements prior to entering the market; (2) require manufacturers to submit Supplement Labels to the FDA for pre-market review; (3) require that supplements undergo both pre-market composition testing and post-market randomized composition testing; (4) strengthen agency authority to remove adulterated dietary supplements from the market; and (5) establish an excise tax on dietary supplements

Re-Regulating Dietary Supplements

In 1994, Congress introduced the Dietary Supplement Health and Education Act (DSHEA) to create a regulatory framework for the dietary supplement industry. Despite the increased market size of dietary supplements, the Food and Drug Administration’s (FDA) pre-market authority to regulate the introduction of dietary supplements into the stream of commerce has remained subdued. Under DSHEA, the FDA has limited authority to review dietary supplements before entering the market. Unlike pharmaceuticals, which must be proven safe and effective prior to approval and marketing, dietary supplements can be sold to consumers without such reassurances. We call on Congress to amend DSHEA to grant the FDA the additional express statutory authority to fix these problems

Importancia de la sensibilización en el sector profesional en el área educativa sobre discapacidad.

Determinar la importancia de la sensibilización del sector profesional en el área educativa sobre Discapacidad. La Discapacidad no tiene barreras, razas o limitaciones socio-económicas, afectas tanto a la clase alta como la clase pobre, no sabe de religiones ni discrimina la inteligencia, no importa edad o género, simplemente cualquier persona puede adquirir en cualquier momento una discapacidad que lo limite su vida profesional, familiar, social o escolar. El Proyecto está enfocado a brindar información acerca del tema de la discapacidad a profesionales de la enseñanza, así como alumnos del último año de la carrera de magisterio en el Municipio de la Antigua Guatemala, Departamento de Sacatepéquez, que debido a factores extrínsecos e intrínsecos desconocen del tema. El objetivo de la investigación fue el sensibilizar al sector profesional en el área educativa sobre el tema de discapacidad, por medio de la realización de un Simposio el cual se llevó a cabo en: Centro Cultural “César Brañas”, ubicado en la 5ta. Calle Poniente No. 44, “Calle al Cementerio” en la Antigua Guatemala, en el mes de agosto con una duración de dos días, planificado para 200 alumnos del último año de la carrera de Magisterio y profesionales en el área educativa. El evento será realizado por medio de un panel foro (Simposio) donde se abordaron diferentes temas sobre discapacidad, utilizando para ello diferentes técnicas como la expositiva, experiencias vivenciales, la realización de una mesa redonda, entre otras. El propósito de este proyecto e investigación fue el llegar a ser un medio informativo que logre formar a los profesionales en la enseñanza como multiplicadores, para de esta manera identificar y ayudar a las personas con discapacidad. Y empezar el camino de la eliminación de cualquier mito que tenga carácter desvalorizante hacia las personas con discapacidad

Alternative pre-mRNA splicing of the mu opioid receptor gene, OPRM1: Insight into complex mu opioid actions

Most opioid analgesics used clinically, including morphine and fentanyl, as well as the recreational drug heroin, act primarily through the mu opioid receptor, a class A Rhodopsin-like G protein-coupled receptor (GPCR). The single-copy mu opioid receptor gene

Tuberculosis in a South African prison - a transmission modelling analysis

Background. Prisons are recognised internationally as institutions with very high tuberculosis (TB) burdens where transmission is predominantly determined by contact between infectious and susceptible prisoners. A recent South African court case described the conditions under which prisoners awaiting trial were kept. With the use of these data, a mathematical model was developed to explore the interactions between incarceration conditions and TB control measures. Methods. Cell dimensions, cell occupancy, lock-up time, TB incidence and treatment delays were derived from court evidence and judicial reports. Using the Wells-Riley equation and probability analyses of contact between prisoners, we estimated the current TB transmission probability within prison cells, and estimated transmission probabilities of improved levels of case finding in combination with implementation of national and international minimum standards for incarceration. Results. Levels of overcrowding (230%) in communal cells and poor TB case finding result in annual TB transmission risks of 90% per annum. Implementing current national or international cell occupancy recommendations would reduce TB transmission probabilities by 30% and 50%, respectively. Improved passive case finding, modest ventilation increase or decreased lock-up time would minimally impact on transmission if introduced individually. However, active case finding together with implementation of minimum national and international standards of incarceration could reduce transmission by 50% and 94%, respectively. Conclusions. Current conditions of detention for awaiting-trial prisoners are highly conducive for spread of drug-sensitive and drug-resistant TB. Combinations of simple well-established scientific control measures should be implemented urgently

Nicotine Regulates Activity Of Lateral Habenula Neurons Via Presynaptic And Postsynaptic Mechanisms

There is much interest in brain regions that drive nicotine intake in smokers. Interestingly, both the rewarding and aversive effects of nicotine are probably critical for sustaining nicotine addiction. The medial and lateral habenular (LHb) nuclei play important roles in processing aversion, and recent work has focused on the critical involvement of the LHb in encoding and responding to aversive stimuli. Several neurotransmitter systems are implicated in nicotine\u27s actions, but very little is known about how nicotinic acetylcholine receptors (nAChRs) regulate LHb activity. Here we report in brain slices that activation of nAChRs depolarizes LHb cells and robustly increases firing, and also potentiates glutamate release in LHb. These effects were blocked by selective antagonists of α6-containing (α6∗) nAChRs, and were absent in α6∗-nAChR knockout mice. In addition, nicotine activates GABAergic inputs to LHb via α4β2-nAChRs, at lower concentrations but with more rapid desensitization relative to α6∗-nAChRs. These results demonstrate the existence of diverse functional nAChR subtypes at presynaptic and postsynaptic sites in LHb, through which nicotine could facilitate or inhibit LHb neuronal activity and thus contribute to nicotine aversion or reward

Myofibrillar myopathy hallmarks associated with ZAK deficiency

The ZAK gene encodes two functionally distinct kinases, ZAKα and ZAKβ. Homozygous loss of function mutations affecting both isoforms causes a congenital muscle disease. ZAKβ is the only isoform expressed in skeletal muscle and is activated by muscle contraction and cellular compression. The ZAKβ substrates in skeletal muscle or the mechanism whereby ZAKβ senses mechanical stress remains to be determined. To gain insights into the pathogenic mechanism, we exploited ZAK-deficient cell lines, zebrafish, mice and a human biopsy. ZAK-deficient mice and zebrafish show a mild phenotype. In mice, comparative histopathology data from regeneration, overloading, ageing and sex conditions indicate that while age and activity are drivers of the pathology, ZAKβ appears to have a marginal role in myoblast fusion in vitro or muscle regeneration in vivo. The presence of SYNPO2, BAG3 and Filamin C (FLNC) in a phosphoproteomics assay and extended analyses suggested a role for ZAKβ in the turnover of FLNC. Immunofluorescence analysis of muscle sections from mice and a human biopsy showed evidence of FLNC and BAG3 accumulations as well as other myofibrillar myopathy markers. Moreover, endogenous overloading of skeletal muscle exacerbated the presence of fibres with FLNC accumulations in mice, indicating that ZAKβ signalling is necessary for an adaptive turnover of FLNC that allows for the normal physiological response to sustained mechanical stress. We suggest that accumulation of mislocalized FLNC and BAG3 in highly immunoreactive fibres contributes to the pathogenic mechanism of ZAK deficiency