Spontaneous dialytic ultrafiltration with intraperitoneal reinfusion of the concentrate in 15 cirrhotic patients with intractable ascites.

The clinical efficacy and tolerance of dialytic ultrafiltration of ascites through a hemofilter (DUF) with peritoneal reinfusion of the concentrate was evaluated in 15 cirrhotic patients with intractable ascites. All together, 51 DUF procedures were carried out. An average of 8.6 was ultrafiltered during 12 h with no significant change in blood pressure, hemoglobin, coagulation parameters or plasma creatinine. A significant increase in ascitic protein concentration was observed immediately after the procedure and a slight but significant increase in 24 h urinary output. A controlled evaluation of DUF compared to large paracenteses seems to be justified by these preliminary results.     

Modelling of experimentally created partial-thickness human skin burns and subsequent therapeutic cooling: A new measure for cooling effectiveness

Rapid post-injury cooling of a skin burn has been shown to have both symptomatic and therapeutic benefits. However, the latter cannot be explained by temperature reduction alone, and must thus be secondary to an altered biological response. In this study, we construct a computational model to calculate the heat transfer and damage accumulation in human skin during and after a burn. This enables us to assess the effectiveness of various cooling protocols (involving both free and forced convection to air and water respectively) in terms of their reduction in Arrhenius tissue damage. In this process, we propose an extension of the Arrhenius damage model in the form of a new measure ξ, which estimates the relevance of post-burn accrued damage. It was found that the reduction in Arrhenius damage integrals near the skin surface was too small to be physiologically relevant. Hence our results confirm that while the reduction in tissue temperatures is indeed quicker, the therapeutic benefit of cooling cannot be explained by thermal arguments (i.e. based on Arrhenius damage models) alone. We plan to validate this hypothesis by conducting future microarray analyses of differential gene expression in cooled and non-cooled burn lesions. Our computational model will support such experiments by calculating the necessary conditions to produce a burn of specified severity for a given experimental setup.     

Development of a quantitative, cell-line based assay to measure ADCC activity mediated by therapeutic antibodies

Antibody-dependent cellular cytotoxicity (ADCC) contributes to clinical efficacy of a broad range of antibody therapeutics. However, reproducible quantitation of ADCC activity on a cellular level remains highly challenging, as ADCC assays rely on primary effector cells associated with laborious cell purification procedures, resulting in highly donor-dependent results. Here, we report the development of an in vitro ADCC method based on an engineered human natural killer cell line as effectors. While eliminating the limitations of primary cells, this assay exhibits all the hallmarks of traditional ADCC assay systems. We have used this assay to measure the ADCC activity of a humanized IgG1 antibody directed against the human CD20 antigen. Our data show that this assay is capable to measure small changes in ADCC and can therefore be used to test therapeutic antibodies against cell-surface targets for their depleting activity.     

Genetic diversity and new therapeutic concepts

The differences in medicinal drug responses among individuals had been known for quite some time. Some patients exhibit a life-threatening adverse reaction while others fail to show an expected therapeutic effect. Intermediate responses between the above two extreme cases are also known. In fact, it has been recently reported that approximately 100,000 deaths and more than 2 million hospitalizations annually in the United States are due to properly prescribed medications. This interindividual variability could be due in part to genetically determined characteristics of target genes or drug metabolizing enzymes. This has now been substantiated by a variety of studies. We know that one size fits all is not correct. Therefore, the application of pharmacogenetic concepts to clinical practice is an excellent goal in the postgenomic era. The successful completion of the human genome project provided necessary molecular tools, such as high-throughput SNP genotyping, HapMap, and microarray, that can be applied to develop proper therapeutic options for individuals. Recently, there have been considerable scientific, corporate, and policy interest in pharmacotherapy. However, identification of causal variations in a target gene is only a starting point, and the progress in this rapidly developing field is slower than expected. One major drawback could be due to the multigene determinant of drug response that requires a genome-wide screening. Additionally, application of pharmacogenetic knowledge into clinical practice requires a high level of accuracy, precision (risk/benefit ratio), and strict regulations. This is because the pharmacogenetic approach raises several ethical, moral, and legal questions. It is also necessary that both health professionals and the general public must be urgently educated. Despite these limitations, translation of pharmacogenomic data into clinical practice would certainly provide better opportunities to increase the safety and efficacy of medicine in the future.     

Targeting mTOR signaling by polyphenols: A new therapeutic target for ageing

Current ageing research is aimed not only at the promotion of longevity, but also at improving ‎health span‎ through the‎ discovery and development‎ of new therapeutic strategies‎‏‎ by investigating ‎molecular and ‎cellular ‎pathways involved in cellular senescence.‎ Understanding the mechanism of action ‎of ‎polyphenolic compounds targeting mTOR (mechanistic target of rapamycin) and related pathways opens up new directions ‎‎to revolutionize ways to slow down the ‎onset and development of age-dependent degeneration. Herein, we will ‎discuss the mechanisms by which polyphenols can delay the‎ molecular ‎pathogenesis of ageing via manipulation or more specifically inhibition of mTOR-signaling pathways. We will also discuss the implications of polyphenols in targeting mTOR and its related ‎pathways‎‎ on ‎health life span extension and longevity.‎     

Consensus in patient-therapist interactions. A measure of the therapeutic relationship related to outcome

This paper discusses consensus between patient and therapist as a measure of the quality of the psychotherapeutic relationship. Consensus is defined by two interpersonal concepts, agreement and understanding, and two intrapersonal concepts, congruency and experienced consensus. 162 patients and their therapists in a Dutch Center for Comprehensive Mental Health Care were rated on the degree of consensus. Two patient self-report outcome measures and one reported by the therapist were related to consensus. The three consensus measures that predicted outcome after 6 months were understanding by the therapist as well as agreement and experienced consensus by the patient. This result suggests that a complementary patient-therapist relationship favors a good psychotherapy result. The instruments in this paper provide a means to measure consensus during the process of psychotherapy. This is a feasible way to both monitor progress and improve the chances of a successful outcome.     

A new measure of cortical inhibition by mechanomyography and paired-pulse transcranial magnetic stimulation in unanesthetized rats

Paired-pulse transcranial magnetic stimulation (ppTMS) is a safe and noninvasive tool for measuring cortical inhibition in humans, particularly in patients with disorders of cortical inhibition such as epilepsy. However, ppTMS protocols in rodent disease models, where mechanistic insight into the ppTMS physiology and into disease processes may be obtained, have been limited due to the requirement for anesthesia and needle electromyography. To eliminate the confounding factor of anesthesia and to approximate human ppTMS protocols in awake rats, we adapted the mechanomyogram (MMG) method to investigate the ppTMS inhibitory phenomenon in awake rats and then applied differential pharmacology to test the hypothesis that long-interval cortical inhibition is mediated by the GABA(A) receptor. Bilateral hindlimb-evoked MMGs were elicited in awake rats by long-interval ppTMS protocols with 50-, 100-, and 200-ms interstimulus intervals. Acute changes in ppTMS-MMG were measured before and after intraperitoneal injections of saline, the GABA(A) agonist pentobarbital (PB), and GABA(A) antagonist pentylenetetrazole (PTZ). An evoked MMG was obtained in 100% of animals by single-pulse stimulation, and ppTMS resulted in predictable inhibition of the test-evoked MMG. With increasing TMS intensity, MMG amplitudes increased in proportion to machine output to produce reliable input-output curves. Simultaneous recordings of electromyography and MMG showed a predictable latency discrepancy between the motor-evoked potential and the evoked MMG (7.55 ± 0.08 and 9.16 ± 0.14 ms, respectively). With pharmacological testing, time course observations showed that ppTMS-MMG inhibition was acutely reduced following PTZ (P < 0.05), acutely enhanced after PB (P < 0.01) injection, and then recovered to pretreatment baseline after 1 h. Our data support the application of the ppTMS-MMG technique for measuring the cortical excitability in awake rats and provide the evidence that GABA(A) receptor contributes to long-interval paired-pulse cortical inhibition. Thus ppTMS-MMG appears a well-tolerated biomarker for measuring GABA(A)-mediated cortical inhibition in rats.     

Quantification of human Alu sequences by real-time PCR--an improved method to measure therapeutic efficacy of anti-metastatic drugs in human xenotransplants

For measuring the efficacy of new anti-metastatic drugs in preclinical models, macroscopical analysis or classical histology of secondary organs are established methods. However, macroscopical evaluation does not take into consideration intra-organ metastasis. Histological analysis is often performed in few sections of the relevant organs, and this may be misleading, since equal distribution of tumor cells within an organ is unlikely. In addition, recent studies have demonstrated that anti-tumorigenic drugs are able to promote metastasis and to change the metastatic pattern. Therefore, extensive analysis of metastasis is mandatory for the evaluation of new compounds. A feasibility study was conducted to find out if the quantification of human Alu sequences could be applied as a surrogate marker for metastasis in xenografts. Alu PCR was performed by using the LightCycler system, which allows PCR reaction and subsequent quantification of the PCR products in less than 30 min. We found that i) the equivalent of one human tumor cell in 1 x 10(6) murine cells could be detected; ii) in tumor-carrying mice, Alu signal increased over time in secondary organs; iii) this increase was more prominent using highly metastatic tumor cells; iv) Alu signal intensity in DNA extracted from tissue slides correlated with the expression of histological tumor markers; v) in three different tumor models (colon, breast and lung), treatment with Taxol or 5-fluorouracil reduced the amount of Alu in different organs. In contrast, reduction of Alu by the matrix metalloproteinase inhibitor RO 28-2653 was not significant. Taken together, quantification of Alu sequences is a fast and accurate method to evaluate the therapeutic efficacy of anti-metastatic drugs in xenografts.     

妊高征剖宫产术后并发大量腹水临床分析及预防措施

目的 探讨妊高征剖宫产术后并发大量腹水临床特点及预防.方法 回顾分析5例妊高征剖宫产术后大量腹水（腹水组）和21例妊高征剖宫术后无腹水病例（对照组）.结果 腹水组总蛋白、白蛋白、血色素水平明显低于对照组（P＜0.05）术前腹水明显多于对照组（P＜0.01）.术后白细胞及中性粒细胞明显高于对照组（P＜0.05）.结论 妊高征剖宫产术后大量腹水与患者术前病情（术前大量腹水、低蛋白血症、贫血）、潜在感染及术中清除大量腹水加重低蛋白血症有关.因此,补充白蛋白、控制感染、孕期纠正贫血十分重要.     

Gene prediction by spectral rotation measure: a new method for identifying protein-coding regions

A new measure for gene prediction in eukaryotes is presented. The measure is based on the Discrete Fourier Transform (DFT) phase at a frequency of 1/3, computed for the four binary sequences for A, T, C, and G. Analysis of all the experimental genes of S. cerevisiae revealed distribution of the phase in a bell-like curve around a central value, in all four nucleotides, whereas the distribution of the phase in the noncoding regions was found to be close to uniform. Similar findings were obtained for other organisms. Several measures based on the phase property are proposed. The measures are computed by clockwise rotation of the vectors, obtained by DFT for each analysis frame, by an angle equal to the corresponding central value. In protein coding regions, this rotation is assumed to closely align all vectors in the complex plane, thereby amplifying the magnitude of the vector sum. In noncoding regions, this operation does not significantly change this magnitude. Computing the measures with one chromosome and applying them on sequences of others reveals improved performance compared with other algorithms that use the 1/3 frequency feature, especially in short exons. The phase property is also used to find the reading frame of the sequence.     

Biologic therapies in psoriasis: a new therapeutic approach

Chronic plaque psoriasis is an immune-mediated, inflammatory skin disease with a heavy burden on quality of life of patients. The disease has a chronic relapsing course and may be life long. Comorbid disorders include psoriatic arthritis, obesity, dyslipidemia, hypertension and an increased rate of cardiovascular disease. Conventional systemic treatments include methotrexate, cyclosporine and acitretin, which are associated with end organ toxicity that precludes long term therapy. Biological drugs are designed to selectively interfere with the immune mechanisms that induce psoriasis. Efalizumab is effective for skin psoriasis but not psoriatic arthritis. Anti-TNF-alpha agents (etanercept, infliximab and adalimumab) are active on both psoriasis and psoriatic arthritis. Infliximab is the most effective and rapid agent, but its safety profile may be less favourable. Moreover, efficacy can reduce over time. Etanercept is moderately active but has a better safety profile, and can be discontinued and re-used without loss of efficacy. The long term safety of all these agents has not been established.     

Spontaneous dialytic ultrafiltration with intraperitoneal reinfusion of the concentrate versus large paracentesis in cirrhotic patients with intractable ascites: a randomized study.

Dialytic ultrafiltration of ascites through a hemofilter associated with peritoneal reinfusion (DUF) of the concentrate has been proposed for the treatment of refractory ascites. In five cirrhotic patients, 18 ascites evacuation procedures were randomized either to DUF (n = 8) or to large paracenteses (LP) (n = 10). The effects of these two methods on hemodynamic and renal function were assessed. After DUF, the protein concentration in ascites increased transiently from 28 +/- 7 g/l to 64.8 +/- 8 g/l (p less than 0.04); urinary output increased from day 1 to day 4 (1000 +/- 100) VS 1430 +/- 140 ml/24h; p less than 0.02). After LP, ascitic protein concentration and urinary output were unchanged. No side effects were observed with the two methods. The mean amount of albumin infused was 20 +/- 15 g after DUF and 15 +/- 5 after LP (ns).