Special Feature: Complex Systems: From Chemistry to Systems Biology Special Feature: Complexity in bacterial cell–cell communication: Quorum signal integration and subpopulation signaling in the Bacillus subtilis phosphorelay

A common form of quorum sensing in Gram-positive bacteria is mediated by peptides that act as phosphatase regulators (Phr) of receptor aspartyl phosphatases (Raps). In Bacillus subtilis, several Phr signals are integrated in sporulation phosphorelay signal transduction. We theoretically demonstrate that the phosphorelay can act as a computational machine performing a sensitive division operation of kinase-encoded signals by quorum-modulated Rap signals, indicative of cells computing a “food per cell” estimate to decide whether to enter sporulation. We predict expression from the rapA-phrA operon to bifurcate as relative environmental signals change in a developing population. We experimentally observe that the rapA-phrA operon is heterogeneously induced in sporulating microcolonies. Uninduced cells sporulate rather synchronously early on, whereas the RapA/PhrA subpopulation sporulates less synchronously throughout later stationary phase. Moreover, we show that cells sustain PhrA expression during periods of active growth. Together with the model, these findings suggest that the phosphorelay may normalize environmental signals by the size of the (sub)population actively competing for nutrients (as signaled by PhrA). Generalizing this concept, the various Phrs could facilitate subpopulation communication in dense isogenic communities to control the physiological strategies followed by differentiated subpopulations by interpreting (environmental) signals based on the spatiotemporal community structure.     

Smoking reduction does work: resulting alterations in the incidence and histological subtypes of lung cancer in New South Wales in the last 20 years

BACKGROUND: There is irrefutable evidence of the association between lung cancer and smoking. The effects of public health campaigns to reduce population-smoking rates on the incidence and the histological distribution of lung cancer were examined. METHODS: The data held in the New South Wales Cancer Registry from 1972 to 2001 was accessed. RESULTS: The data revealed a decreasing incidence of lung cancer amongst males and a rate that continued to increase amongst females. Interestingly, there was also an effect on the histological distribution of lung cancers, with falling rates of small cell lung cancer and squamous cell cancer, both of which have a high association with smoking; and an increasing incidence of adenocarcinomas. CONCLUSIONS: These trends reveal patterns seen worldwide. The increasing proportion of adenocarcinomas in particular may be related to the changing composition of cigarettes and filters.     

High rates of depressive symptoms among patients with systemic sclerosis are not explained by differential reporting of somatic symptoms

OBJECTIVE: Between 36% and 65% of patients with systemic sclerosis (SSc) report symptoms of depression above cutoff thresholds on self-report questionnaires. The objective of this study was to assess whether these high rates result from differential reporting of somatic symptoms related to the high physical burden of SSc. METHODS: Symptom profiles reported on the Center for Epidemiologic Studies Depression Scale (CES-D) were compared between a multicenter sample of 403 patients with SSc and a sample of respondents to an Internet depression survey, matched on total CES-D score, age, race/ethnicity, and sex. An exact nonparametric generalized Mantel-Haenszel procedure was used to identify differential item functioning between groups. RESULTS: Patients with SSc reported significantly higher frequencies (moderate to large effect size; P < 0.01) on 4 CES-D somatic symptom items: bothered, appetite, effort, and sleep. Internet respondents had higher item scores on 2 items that assessed interpersonal difficulties (unfriendly, large effect size; P < 0.01; disliked, large effect size; P < 0.01) and on 2 items that assessed lack of positive effect (happy, moderate effect size; P = 0.01; enjoy, large effect size; P < 0.01). Adjustment of standard CES-D cutoff criteria for potential bias due to somatic symptom reporting resulted in a reduction of only 3.6% in the number of SSc patients with significant symptoms of depression. CONCLUSION: High rates of depressive symptoms in SSc are not due to bias related to the report of somatic symptoms. The pattern of differential item functioning between the SSc and Internet groups, however, suggests some qualitative differences in depressive symptom presentation.     

Incomplete response to endoscopic sphincterotomy in patients with sphincter of Oddi dysfunction: evidence for a chronic pain disorder

OBJECTIVES: The efficacy of endoscopic treatment of sphincter of Oddi dysfunction (SOD) with endoscopic sphincterotomy (ES) remains controversial. Although some studies have shown a positive impact on patient symptoms after treatment, these reports have been largely qualitative and evaluated on short-term response. The aim of our study was to quantitatively measure the long-term outcomes of endoscopic therapy in patients with SOD. METHODS: Thirty-three patients with suspected SOD underwent selective sphincter of Oddi manometry (SOM) of the biliary and/or pancreatic sphincter. Each patient completed a telephone-based survey measuring symptomatic pain before and after SOM +/- ES. The questioner was blinded to the results of SOM. The patients with normal SOM or SOD but who did not undergo ES served as controls. RESULTS: Of these 33 patients (27 women, mean age 48.7 yr, range 13-74), 19 (57.5%) were found to have SOD (12 biliary, six pancreatic, one both). The average follow-up was 18.1 months (range 7-34). Of the patients with SOD, 17 (89%) underwent ES. At follow-up of the 19 patients undergoing ES, five were taking narcotics for persistent pain, two were taking antidepressants, and 15 identified the endoscopic therapy as the reason for their relief. Of the 14 controls, seven were taking narcotics, seven were taking antidepressants, and two identified the endoscopy as the reason for their relief; some patients were taking both antidepressants and narcotics. CONCLUSIONS: Patients found to have SOD who undergo ES are more likely to be improved on long-term follow-up when compared with patients with suspected SOD but normal manometry without ES. However, almost uniformly, despite ES, patients continue to have pain, which is consistent with most chronic pain disorders and which suggests a multifactorial cause for the pain.     

Right ventricular function in adults with pulmonary hypertension with and without atrial septal defect

Using equilibrium (gated) radionuclide ventriculography, right ventricular (RV) function was studied in 22 adults with pulmonary hypertension and in 16 patients without evidence of cardiac disease. To assess the effect of volume overload on RV performance in pulmonary hypertension, RV ejection fractions were compared in patients with and without left-to-right shunts due to atrial septal defect (ASD). In addition, the effect of ASD repair on RV function was examined. In 14 patients with pulmonary hypertension without RV volume overload (group I), the RV ejection fraction (0.35 ± 0.11, mean ± standard deviation [SD]) was significantly lower than in the normal group (0.47 ± 0.11, p < 0.01). In 8 patients with left-to-right shunts due to ASD (group II) and with RV systolic pressures similar to those in group I, the mean RV ejection fraction (0.53 ± 0.15) was normal and was significantly higher than in group I (p < 0.01). Right ventricular end-diastolic volumes, estimated from combined radionuclide and hemodynamic data, were higher (p < 0.01) in group II patients (171 ± 70 ml/m²) than in group I patients (70 ± 13 ml/m²). In 5 patients who underwent isolated shunt repair, mean RV ejection fraction decreased postoperatively from 0.57 ± 0.17 to 0.40 ± 0.12 (p < 0.05). It is concluded that (1) pulmonary hypertension frequently causes a decrease in RV systolic function due to abnormal afterload; (2) in patients with RV volume overload due to left-to-right shunt, systolic function, as measured by the ejection fraction, remains normal despite pulmonary hypertension, possibly through the Starling mechanism; and (3) RV systolic function often decreases after repair of an ASD.     

The Potential Application of Mitochondrial Medicine in Toxicologic Poisoning

The advancement of biomolecular techniques has continued to advance in the area of mitochondrial medicine. This has allowed clinicians and researchers to more effectively study the bioenergetics of the mitochondria in various disease states. One potential technique in mitochondrial medicine is the generation of cytoplasmic hybrids. A cytoplasmic hybrid or cybrid are created by introducing mitochondrial DNA (mtDNA) of interest into cells depleted of mtDNA. A cybrid is therefore a hybrid cell that mixes the nuclear genome from one cell with the mitochondrial genes from another cell. Cybrids are currently utilized in mitochondrial research to demonstrate mitochondrial involvement in a wide range of diseases that include diabetes, Parkinson’s disease and inherited diseases. At this time the use of cybrids to study toxicologic poisoning is limited and offers a potential avenue of research in this area.     

Rare and Well Done: Endoscopic Control of Colonic Hemorrhage in Severe Ulcerative Colitis

Digestive Diseases and Sciences -