Modulating Toll-like Receptor 7 and 9 Responses as Therapy for Allergy and Autoimmunity

Type I allergic diseases, such as allergic rhinitis and asthma, depend on allergen-induced T-helper type 2 (Th2) cells and IgE-secreting plasma cells. Fortunately, this harmful immune response can be modified by engaging Toll-like receptor (TLR)7 and TLR9, offering hopes to allergy sufferers. While clinical trials employing synthetic ligands for TLR7 or TLR9 are under way, one can wonder whether TLR7 or TLR9 engagements may trigger inadvertent autoreactivity and/or Th1-/Th17-mediated tissue pathology. To neutralize such danger, we have pioneered the development of potent TLR9 pathway antagonists, inhibitory oligonucleotides (INH-ODNs), which work in a sequence-specific manner. Interestingly, INH-ODNs also have TLR7-inhibitory properties; however, these effects appear to be sequence independent and phosphorothioate backbone dependent. In B cells, co-engagement of the B-cell receptor for antigen and TLR7 or TLR9 may influence how INH-ODNs impose their regulatory effects. INH-ODNs block TLR9 activation by competitively antagonizing ligand binding to proteolytically cleaved C-terminal TLR9 fragment. One may envision future use of INH-ODNs in systemic autoimmune diseases, DNA-mediated sepsis, or other situations in which chronic inflammation results from abnormal TLR7- and/or TLR9-mediated immune activation.     

Backward Planning a Craniomaxillofacial Trauma Curriculum for the Surgical Workforce in Low-Resource Settings

Background

Trauma is a significant contributor to global disease, and low-income countries disproportionately shoulder this burden. Education and training are critical components in the effort to address the surgical workforce shortage. Educators can tailor training to a diverse background of health professionals in low-resource settings using competency-based curricula. We present a process for the development of a competency-based curriculum for low-resource settings in the context of craniomaxillofacial (CMF) trauma education.

Methods

CMF trauma surgeons representing 7 low-, middle-, and high-income countries conducted a standardized educational curriculum development program. Patient problems related to facial injuries were identified and ranked from highest to lowest morbidity. Higher morbidity problems were categorized into 4 modules with agreed upon competencies. Methods of delivery (lectures, case discussions, and practical exercises) were selected to optimize learning of each competency.

Results

A facial injuries educational curriculum (1.5 days event) was tailored to health professionals with diverse training backgrounds who care for CMF trauma patients in low-resource settings. A backward planned, competency-based curriculum was organized into four modules titled: acute (emergent), eye (periorbital injuries and sight preserving measures), mouth (dental injuries and fracture care), and soft tissue injury treatments. Four courses have been completed with pre- and post-course assessments completed.

Conclusions

Surgeons and educators from a diverse geographic background found the backward planning curriculum development method effective in creating a competency-based facial injuries (trauma) course for health professionals in low-resource settings, where contextual aspects of shortages of surgical capacity, equipment, and emergency transportation must be considered.

     

Sonographic detection of intrapulmonary shunting of venous gas bubbles during exercise after diving in a professional diver

We report a case of right-to-left intrapulmonary (IP) shunting of venous gas bubbles at a high level of exercise after diving. The diagnosis was made using a 4-chamber view of the heart via echocardiography during exercise. This case is the first in which we could find evidence of IP shunt recruitment during exercise after diving, and the bubble grade was the highest ever seen in our laboratory. Venous bubbles crossing over through IP shunts during exercise after diving is a very rare event.     

Selective loss of hippocampal long-term potentiation, but not depression, following fluid percussion injury

We investigated the early effects of in vivo fluid percussion injury (FPI) on hippocampal synaptic potentials and excitability. In vitro field potential recordings and immunocytochemistry were performed in the CA1 region in slices from naïve, post-FPI, or sham-operated rats. The following electrophysiological and morphological parameters were affected following FPI: (1) threshold for population spike generation was increased suggesting that post-FPI neurons were hypoexcitable; (2) long-term potentiation (LTP) could not be induced in injured hippocampi; (3) GFAP and inducible NO synthase (iNOS) immunoreactivity were enhanced post-FPI; and (4) following injury, synaptophysin immunoreactivity was enhanced in CA1 stratum radiatum. The effects of FPI on synaptic plasticity were LTP-specific, since long-term depression (LTD) could be equally induced and maintained in post-FPI, sham-operated and control slices. Sham-operated slices were characterized by synaptic excitability indistinguishable from naïve controls, but displayed decreased ability for LTP production and expressed high levels of iNOS. We conclude that FPI causes a selective loss of LTP, possibly due to a previous potentiation induced by trauma as reflected by the increased expression of synaptic proteins. Sham surgical procedures were, however, not without effects on long-term potentiation itself; the latter effects appear to be mediated by an increased production of NO. Our study demonstrates for the first time that hippocampal slices can be used to investigate the correlates of in vivo FPI. Furthermore, we describe LTP-specific deficits in post-traumatic brain injury, suggesting that FPI can selectively erase one of the two main NMDA-dependent forms of synaptic plasticity in the hippocampus.     

Effects of tissue preincubation and hypoxia on CA3 hippocampal neurons in the in vitro slice preparation

Using the in vitro hippocampal slice preparation, we studied the electrophysiological properties of pyramidal cells in tissue that was 'preincubated' (2-6 h in a large, static volume of oxygenated bathing medium) before being placed in an interface chamber for study. Striking differences were found in 'preincubated' vs 'non-preincubated' CA3 cells. The preincubated cells had more negative resting potentials, higher input resistance, lower threshold for stimulus-evoked burst discharge and larger hyperpolarizing afterpotentials. Cells in the preincubated CA3 region were also more likely to show spontaneous synchronized burst discharge, but were relatively resistant to hypoxia-induced spreading depression. CA1 cells were less dramatically affected by preincubation, showing little difference from their non-preincubated counterparts. Possible mechanisms involved in the CA3 preincubation effect, including glial buffering alterations and changes in Na+, K+-ATPase activity, are discussed.     

Attitudes of Roma toward smoking: qualitative study in Slovenia

Aim

To understand the reasons for widespread smoking behavior among Roma in Slovenia for the purpose of developing successful smoking cessation interventions.

Method

A qualitative focus group approach using a combination of pre-structured and open-ended questions was applied to collect the data from the representative members of the Roma community in southern Slovenia. The discussions were audiotaped and transcribed, and the collected data analyzed according to qualitative content analysis theory.

Results

The content analysis revealed that smoking was a strong part of the cultural, ethnic, and individual identity of the Roma. Even children smoked. Doctor’s advice to quit smoking was usually not followed and the attempts to quit were usually unsuccessful. Difficult financial situation was never mentioned as a possible motive to quit. Roma held a tenacious belief that the harmful effects of smoking were in the hands of destiny and did not associate the smoking-related illness with the habit.

Conclusions

Traditional strategies for smoking cessation are largely ineffective among the Roma because of their different attitudes toward smoking. Therefore, innovative and culturally acceptable methods need to be developed.According to the 2002 Census, 0.2% of inhabitants in Slovenia are Roma. However, on the basis of reports of social centers and schools, their real number could be up to four times higher than this (1). The socio-economic status, education level, and employment rate among Roma are considerably worse than among other Slovenian population, which places many of them into the category of poor people and thereby, at increased health risk.From the cultural point of view, the Roma are a highly specific ethnic minority. These once nomadic people now mostly live in poor accommodation and have difficult housing situation. The health culture of the Roma and their use of health care are low despite the fact that most of them can obtain full state-provided medical insurance irrespective of their employment status (2). Due to low hygienic and microclimatic conditions, low health education, and excessive smoking, diseases of the respiratory system seem to be among their most important health problems (3-5). Although epidemiologic data hardly exist, the Roma are known to be heavy smokers. The Roma trust in traditional folk medicine and do not believe smoking is a health-threatening habit (2). The percentage of smokers among the Roma in Slovenia is unknown. Studies from other countries show that, similar to other cardiovascular risk factors, smoking is by far more frequent in Roma than in other populations (5,6).Countries with a Roma population, whose health status is usually poor and socioeconomic position the lowest in the country (7-10), realized that research into the health status of the Roma people is needed for the planning of health intervention strategies, such as antismoking campaign (11,12). From everyday practice we know that the Roma never stop smoking and that they smoke heavily. We performed a qualitative study to understand the reasons for widespread and heavy smoking among the Roma in Slovenia for the purpose of developing more successful public health actions against smoking in their community.     

Gender and Academic Medicine: A Good Pipeline of Women Graduates Is Not Advancing

Background: Women are underrepresented in the higher levels of appointment in academic medicine, despite the so-called feminization of medicine. Purpose: A 27-year (1979–2006) retrospective study was conducted regarding the success and advancement of women and men at the University of Split School of Medicine in Croatia. Methods: Data were collected from the school's archive, including number of women and men among applicants, enrollees, graduates, teachers, department chairs and the school management: high school grade averages and admission tests scores by applicant gender and gender-based graduation grade averages. The number and gender patterns of all employed and unemployed physicians in the Split-Dalmatia county were also collected. Results: Men represent the minority among applicants, enrollees, and graduates, whereas women were in the minority among faculty, department chairs, and the school management across all 27 years. Graduation grades from high school and medical school showed that women were statistically better students, although the difference was slight. In the same geographic area, women are more often unemployed and less likely to specialize. Conclusions: More women are applying, enrolling and graduating from the University of Split School of Medicine. Women also perform statistically better on entrance exam and have better graduation grades, yet they remain a minority in faculty and leadership positions. A review of county-wise employment statistics revealed that women were more frequently unemployed and less likely to specialize in this study.