Prophylaxis and treatment of experimental lung metastases in mice after treatment with liposome-encapsulated 6-O-stearoyl-N-acetylmuramyl-L-α-aminobutyryl-D-isoglutamine

A new lipophilic muramyl dipeptide analog, 6-O-stearoyl-N-acetylmuramyl-L--aminobutyryl-D-isoglutamine, when incorporated in liposomes, was effective in both the prevention and eradication of experimental pulmonary metastases in mice. Multilamellar vesicles composed of synthetic phospholipids (phosphatidylglycerol and phosphatidylcholine) containing saturated myristoyl or unsaturated dioleoyl acyl chains were found to potentiate the antimetastatic activity of this glycopeptide. Prophylactic and therapeutic efficacy was observed against the three murine tumors tested: FSa, an immunogenic fibrosarcoma; NFSa, a nonimmunogenic fibrosarcoma; and B16 melanoma. Neither the administration of empty liposomes or free glycopeptide, nor their coadministration, had a significant antimetastatic effect. This approach is promising for the therapy of cancer metastases in humans, particularly in the prevention of metastatic seeding and in the treatment of micrometastases.This is contribution No. 180 from the Institute of Bio-Organic Chemistry, Syntex Research.     

Role of lymphokines in immunoregulatory function of mucosal T cells in humans and nonhuman primates

The findings presented above and in other studies provide substantial evidence that lymphocytes in the intestinal lamina propria differ from lymphocyte populations in the circulation or in other tissue sites in a number of ways. First, lamina propria lymphocytes are phenotypically distinct and have evidence of activation. Lymphocytes in the intestinal lamina propria are different in their potential for expression of lymphokine gene products, since activated cells from the lamina propria have high expression of mRNA for IL-2, IL-4, IL-5 and IFN-gamma in comparison to circulating lymphocytes. Mesenteric lymph node T cells also differ from circulating lymphocytes in their high expression of IL-4 and IL-5 mRNA. A further difference between mesenteric lymph node and lamina propria T cells is that the former are capable of proliferating in response to IL-4, whereas the latter are not. These phenotypic and mRNA differences of lamina propria lymphocytes also correlate well with their high helper activity in vitro for immunoglobulin synthesis in the pokeweed mitogen system. Finally, lamina propria T cells at a site of inflammation are able to provide high helper activity in response to specific antigens. These observations are all consistent with the conclusion that T cells in the lamina propria are pleomorphic, but are highly enriched for subpopulations of activated memory cells that are geared for effector functions. These functions are likely to be critical in maintaining normal host defense in the mucosal environment.     

Differential Effects of Left versus Right Monaural Biofeedback for Heart Rate Increase

Cerebral lateralization in the voluntary increase of heart rate was investigated in a biofeedback experiment involving 20 right-handed female subjects randomly assigned to one of two groups: right or left ear input of stimulus and biofeedback information. The stimulus was a 1000 Hz tone which signalled the start and duration of 30 20-sec training trials. Feedback was a click presented every time an interbeat interval was shorter than a criterion established through a shaping schedule. A monetary bonus provided additional reinforcement at the end of each trial. Subjects given right ear feedback increased their heart rate significantly more than subjects given left ear feedback. The largest difference between the group means (7 bpm) was recorded after the first 20 training trials. The results are discussed in terms of hemispheric perceptual and functional differences.     

Virus overrides the propensity of human CD40L-activated plasmacytoid dendritic cells to produce Th2 mediators through synergistic induction of IFN-{gamma} and Th1 chemokine production

Depending on the activation status, plasmacytoid dendritic cells (PDC) and myeloid DC have the ability to induce CD4 T cell development toward T helper cell type 1 (Th1) or Th2 pathways. Thus, we tested whether different activation signals could also have an impact on the profile of chemokines produced by human PDC. Signals that induce human PDC to promote a type 1 response (i.e., viruses) and a type 2 response [i.e., CD40 ligand (CD40L)] also induced PDC isolated from tonsils to secrete chemokines preferentially attracting Th1 cells [such as interferon-gamma (IFN-gamma)-inducible protein (IP)-10/CXC chemokine ligand 10 (CXCL10) and macrophage inflammatory protein-1beta/CC chemokine ligand 4 (CCL4)] or Th2 cells (such as thymus and activation-regulated chemokine/CCL17 and monocyte-derived chemokine/CCL22), respectively. Activated natural killer cells were preferentially recruited by supernatants of virus-activated PDC, and supernatants of CD40L-activated PDC attracted memory CD4(+) T cells, particularly the CD4(+)CD45RO(+)CD25(+) T cells described for their regulatory activities. It is striking that CD40L and virus synergized to trigger the production of IFN-gamma by PDC, which induces another Th1-attracting chemokine monokine-induced by IFN-gamma/CXCL9 and cooperates with endogenous type I IFN for IP-10/CXCL10 production. In conclusion, our studies reveal that PDC participate in the selective recruitment of effector cells of innate and adaptive immune responses and that virus converts the CD40L-induced Th2 chemokine patterns of PDC into a potent Th1 mediator profile through an autocrine loop of IFN-gamma.     

Bolus versus continuous feeding regimens post gastrostomy tube placement in children

Background/purposeOwing to the frequency of gastrostomy tube placement in children and the numerous regimens used to start feeds after placement we attempted to see if it matters if the initial feeds after a gastrostomy tube placement are provided in a bolus or continuous manner.MethodsUsing a prospective randomized trial, children were randomized to initial bolus or continuous chimney feeding after gastrostomy tube placement. Feeding tolerance and complications related to the gastrostomy tube were collected for 4 weeks after placement.ResultsDemographics were similar in the two groups. Times to goal feeds were similar in both groups, but in the first two weeks more feeding modifications were required in the bolus group. Other than the rate of leakage during the second week after placement which occurred more in the bolus group, all other clinical outcomes were similar in the two groups.ConclusionsOther than minor, clinically insignificant differences noted above, the method of initial feeding after a gastrostomy tube placement does not affect feeding tolerance or gastrostomy tube complication in the first month after placement.Level of evidenceTherapeutic, level II.     

Use of Professional Associate Ratings to Assess the Performance of Practicing Physicians: Past, Present, Future

The American Board of Family Practice (ABFP) is developing a computer-based testing system that will create realistic clinical encounters using an adaptation of an item generation process. Simulated patients' entire lives will be stochastically produced from a knowledge base, with constraints applied to prevent implausible simulations. The constraint mechanisms include knowledge acquisition decisions about grouping closely related medical concepts and widespread use of Bayesian networks to manage dependencies between concepts. Bayesian networks and fuzzy definitions provide stochastic variability between simulations produced from the same data. Examinees will interact with these patients using a large and stable set of queries and interventions. Multiple management plans associated with patient simulations provide a framework for scoring performance. All major components, including Health States, history generating "Lead To" objects, and Plans are reusable and often substitutable. Although initial knowledge acquisition demands are enormous, the system has good potential for low cost maintenance of content areas, and economies of scale as simulations and components are reused.     

Significantly higher pathologic complete remission rate after neoadjuvant therapy with trastuzumab, paclitaxel, and epirubicin chemotherapy: results of a randomized trial in human epidermal growth factor receptor 2-positive operable breast cancer.

PURPOSE: The objective of this study was to determine whether the addition of trastuzumab to chemotherapy in the neoadjuvant setting could increase pathologic complete response (pCR) rate in patients with human epidermal growth factor receptor 2 (HER2) -positive disease. PATIENTS AND METHODS: Forty-two patients with HER2-positive disease with operable breast cancer were randomly assigned to either four cycles of paclitaxel followed by four cycles of fluorouracil, epirubicin, and cyclophosphamide or to the same chemotherapy with simultaneous weekly trastuzumab for 24 weeks. The primary objective was to demonstrate a 20% improvement in pCR (assumed 21% to 41%) with the addition of trastuzumab to chemotherapy. The planned sample size was 164 patients. RESULTS: Prognostic factors were similar in the two groups. After 34 patients had completed therapy, the trial's Data Monitoring Committee stopped the trial because of superiority of trastuzumab plus chemotherapy. pCR rates were 25% and 66.7% for chemotherapy (n = 16) and trastuzumab plus chemotherapy (n = 18), respectively (P = .02). The decision was based on the calculation that, if study continued to 164 patients, there was a 95% probability that trastuzumab plus chemotherapy would be superior. Of the 42 randomized patients, 26% in the chemotherapy arm achieved pCR compared with 65.2% in the trastuzumab plus chemotherapy arm (P = .016). The safety of this approach is not established, although no clinical congestive heart failure was observed. A more than 10% decrease in the cardiac ejection fraction was observed in five and seven patients in the chemotherapy and trastuzumab plus chemotherapy arms, respectively. CONCLUSION: Despite the small sample size, these data indicate that adding trastuzumab to chemotherapy, as used in this trial, significantly increased pCR without clinical congestive heart failure.     

Communication with our teens: associations between confidential service and parent-teen communication

PURPOSE: Many recent attempts have been made to eliminate health services minors can receive without parental consent or notification. One argument is that these "confidential" services undermine the parent-teen relationship. The objective of this study was to evaluate whether confidential services impact adolescent's communication with parents about their health. METHODS: This cross-sectional study included 59 adolescents (ages 12-21) seeking health services at an urban teen clinic in Minneapolis, MN. Participants were divided based on reasons for presenting at the clinic; confidential or non-confidential services. The main outcome variables were the following: discussion of clinic visit with parent, discussion of reason for clinic visit with parent, and communication with parent if diagnosed with a potentially serious health condition. RESULTS: The two groups were equally divided; 42.4% came for non-confidential services and 57.6% came for confidential services. Of the 59 participants, 69.5% told their parents they were coming to clinic. However, only 43.1% reported they would not tell their parent if they had a serious health problem; there was an equal split between the confidential services and non-confidential services groups. A statistical difference was not found between the confidential services and non-confidential services groups for any of the outcome variables. CONCLUSIONS: Obtaining confidential services was not a barrier to discussion with parents about clinic visit, reasons for coming to clinic, or telling their parent if they had a serious health care problem. Clinicians should continue to advocate for confidential services while encouraging open communication between adolescents and their parents.     

Considerations on the EU definition of a nanomaterial: Science to support policy making

In recent years, an increasing number of applications and products containing or using nanomaterials have become available. This has raised concerns that some of these materials may introduce new risks for humans or the environment. A clear definition to discriminate nanomaterials from other materials is prerequisite to include provisions for nanomaterials in legislation. In October 2011 the European Commission published the ‘Recommendation on the definition of a nanomaterial’, primarily intended to provide unambiguous criteria to identify materials for which special regulatory provisions might apply, but also to promote consistency on the interpretation of the term ‘nanomaterial’. In this paper, the current status of various regulatory frameworks of the European Union with regard to nanomaterials is described, and major issues relevant for regulation of nanomaterials are discussed. This will contribute to better understanding the implications of the choices policy makers have to make in further regulation of nanomaterials. Potential issues that need to be addressed and areas of research in which science can contribute are indicated. These issues include awareness on situations in which nano-related risks may occur for materials that fall outside the definition, guidance and further development of measurement techniques, and dealing with changes during the life cycle.     

Female Sexuality in Thai Discourses about Maechii (‘lay nuns’)

By examining competing discourses about women who are maechii (or ‘lay nuns’) in Buddhist Thai society, this paper demonstrates that, although maechii vow to be celibate, social constructions of their role are grounded in sexuality. The discourses examined are those of the Buddhist canon and Sangha (Order of Monkhood), the Thai Maechii Institute, the mass media, and the government. The analysis is supplemented with field observations and interviews with monks, maechii, and lay persons. Findings suggest that maechii comprise an ambiguous category linguistically, Buddhistically, and in terms of their sexuality. Case studies of the founders of nunneries conducted in ChiangMai indicate that maechii leaders have been resisting the prevalent views that most maechii are social misfits, yet also are capable of undermining monks' celibacy and, by extension, the larger social order. The analysis contributes to the understanding of the interconnectedness of gender and sexuality in contemporary Thai society.