Effects of pregabalin on central sensitization in patients with chronic pancreatitis in a randomized, controlled trial

Background

Intense abdominal pain is the dominant feature of chronic pancreatitis. During the disease changes in central pain processing, e.g. central sensitization manifest as spreading hyperalgesia, can result from ongoing nociceptive input. The aim of the present study is to evaluate the effect of pregabalin on pain processing in chronic pancreatitis as assessed by quantitative sensory testing (QST).

Methods

This randomized, double-blind, placebo-controlled trial evaluated effects of pregabalin on pain processing. QST was used to quantify pain processing by measuring thresholds to painful electrical and pressure stimulation in six body dermatomes. Descending endogenous pain modulation was quantified using the conditioned pain modulation (CPM) paradigm to elicit a DNIC (diffuse noxious inhibitory controls) response. The main effect parameter was the change in the sum of all body pain threshold values after three weeks of study treatment versus baseline values between both treatment groups.

Results

64 patients were analyzed. No differences in change in sum of pain thresholds were present for pregabalin vs. placebo after three weeks of treatment. For individual dermatomes, change vs. baseline pain thresholds was significantly greater in pregabalin vs. placebo patients for electric pain detection threshold in C5 (P = 0.005), electric pain tolerance threshold in C5 (P = 0.04) and L1 (P = 0.05), and pressure pain tolerance threshold in T4 (P = 0.004). No differences were observed between pregabalin and placebo regarding conditioned pain modulation.

Conclusion

Our study provides first evidence that pregabalin has moderate inhibitory effects on central sensitization manifest as spreading hyperalgesia in chronic pancreatitis patients. These findings suggest that QST can be of clinical use for monitoring pain treatments in the context of chronic pain.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00755573","term_id":"NCT00755573"}}NCT00755573     

Early diagnosis of neuropathy in leprosy--comparing diagnostic tests in a large prospective study (the INFIR cohort study)

Background

Leprosy is the most frequent treatable neuromuscular disease. Yet, every year, thousands of patients develop permanent peripheral nerve damage as a result of leprosy. Since early detection and treatment of neuropathy in leprosy has strong preventive potential, we conducted a cohort study to determine which test detects this neuropathy earliest.

Methods and Findings

One hundred and eighty-eight multibacillary (MB) leprosy patients were selected from a cohort of 303 and followed for 2 years after diagnosis. Nerve function was evaluated at each visit using nerve conduction (NC), quantitative thermal sensory testing and vibrometry, dynamometry, monofilament testing (MFT), and voluntary muscle testing (VMT). Study outcomes were sensory and motor impairment detected by MFT or VMT. Seventy-four of 188 patients (39%) had a reaction, neuritis, or new nerve function impairment (NFI) event during a 2-year follow-up. Sub-clinical neuropathy was extensive (20%–50%), even in patients who did not develop an outcome event. Sensory nerve action potential (SNAP) amplitudes, compound motor action potential (CMAP) velocities, and warm detection thresholds (WDT) were most frequently affected, with SNAP impairment frequencies ranging from 30% (median) to 69% (sural). Velocity was impaired in up to 43% of motor nerves. WDTs were more frequently affected than cold detection thresholds (29% versus 13%, ulnar nerve). Impairment of SNC and warm perception often preceded deterioration in MF or VMT scores by 12 weeks or more.

Conclusions

A large proportion of leprosy patients have subclinical neuropathy that was not evident when only MFT and VMT were used. SNC was the most frequently and earliest affected test, closely followed by WDT. They are promising tests for improving early detection of neuropathy, as they often became abnormal 12 weeks or more before an abnormal monofilament test. Changes in MFT and VMT score mirrored changes in neurophysiology, confirming their validity as screening tests.     

Degree of Skin Denervation and Its Correlation to Objective Thermal Sensory Test in Leprosy Patients

Background

Leprosy is an infectious disease affecting skin and peripheral nerves resulting in increased morbidity and physical deformities. Early diagnosis provides opportune treatment and reduces its complications, relying fundamentally on the demonstration of impaired sensation in suggestive cutaneous lesions. The loss of tactile sensitivity in the lesions is preceded by the loss of thermal sensitivity, stressing the importance of the thermal test in the suspicious lesions approach. The gold-standard method for the assessment of thermal sensitivity is the quantitative sensory test (QST). Morphological study may be an alternative approach to access the thin nerve fibers responsible for thermal sensitivity transduction. The few studies reported in leprosy patients pointed out a rarefaction of thin dermo-epidermal fibers in lesions, but used semi-quantitative evaluation methods.

Methodology/Principal Findings

This work aimed to study the correlation between the degree of thermal sensitivity impairment measured by QST and the degree of denervation in leprosy skin lesions, evaluated by immunohistochemistry anti-PGP 9.5 and morphometry. Twenty-two patients were included. There were significant differences in skin thermal thresholds among lesions and contralateral skin (cold, warm, cold induced pain and heat induced pain). The mean reduction in the density of intraepidermal and subepidermal fibers in lesions was 79.5% (SD = 19.6) and 80.8% (SD = 24.9), respectively.

Conclusions/Significance

We observed a good correlation between intraepidermal and subepidermal fibers deficit, but no correlation between these variables and those accounting for the degree of impairment in thermal thresholds, since the thin fibers rarefaction was homogeneously intense in all patients, regardless of the degree of sensory deficit. We believe that the homogeneously intense denervation in leprosy lesions should be objective of further investigations focused on its diagnostic applicability, particularly in selected cases with only discrete sensory impairment, patients unable to perform the sensory test and especially those with nonspecific histopathological finds.     

A Novel and Selective Poly (ADP-Ribose) Polymerase Inhibitor Ameliorates Chemotherapy-Induced Painful Neuropathy

Background

Chemotherapy-induced neuropathy is the principle dose limiting factor requiring discontinuation of many chemotherapeutic agents, including cisplatin and oxaliplatin. About 30 to 40% of patients receiving chemotherapy develop pain and sensory changes. Given that poly (ADP-ribose) polymerase (PARP) inhibition has been shown to provide neuroprotection, the current study was developed to test whether the novel PARP inhibitor compound 4a (analog of ABT-888) would attenuate pain in cisplatin and oxaliplatin-induced neuropathy in mice.

Results

An established chemotherapy-induced painful neuropathy model of two weekly cycles of 10 intraperitoneal (i.p.) injections separated by 5 days rest was used to examine the therapeutic potential of the PARP inhibitor compound 4a. Behavioral testing using von Frey, paw radiant heat, cold plate, and exploratory behaviors were taken at baseline, and followed by testing at 3, 6, and 8 weeks from the beginning of drug treatment.

Conclusion

Cisplatin-treated mice developed heat hyperalgesia and mechanical allodynia while oxaliplatin-treated mice exhibited cold hyperalgesia and mechanical allodynia. Co-administration of 50 mg/kg or 25 mg/kg compound 4a with platinum regimen, attenuated cisplatin-induced heat hyperalgesia and mechanical allodynia in a dose dependent manner. Similarly, co-administration of 50 mg/kg compound 4a attenuated oxaliplatin-induced cold hyperalgesia and mechanical allodynia. These data indicate that administration of a novel PARP inhibitor may have important applications as a therapeutic agent for human chemotherapy-induced painful neuropathy.     

Lagged Effect of Diurnal Temperature Range on Mortality in a Subtropical Megacity of China

Background

Many studies have found extreme temperature can increase the risk of mortality. However, it is not clear whether extreme diurnal temperature range (DTR) is associated with daily disease-specific mortality, and how season might modify any association.

Objectives

To better understand the acute effect of DTR on mortality and identify whether season is a modifier of the DTR effect.

Methods

The distributed lag nonlinear model (DLNM) was applied to assess the non-linear and delayed effects of DTR on deaths (non-accidental mortality (NAD), cardiovascular disease (CVD), respiratory disease (RD) and cerebrovascular disease (CBD)) in the full year, the cold season and the warm season.

Results

A non-linear relationship was consistently found between extreme DTR and mortality. Immediate effects of extreme low DTR on all types of mortality were stronger than those of extreme high DTR in the full year. The cumulative effects of extreme DTRs increased with the increment of lag days for all types of mortality in cold season, and they were greater for extreme high DTRs than those of extreme low DTRs. In hot season, the cumulative effects for extreme low DTRs increased with the increment of lag days, but for extreme high DTR they reached maxima at a lag of 13 days for all types of mortality except for CBD(at lag6 days), and then decreased.

Conclusions

Our findings suggest that extreme DTR is an independent risk factor of daily mortality, and season is a modifier of the association of DTR with daily mortality.     

A Phase II,Randomized, Double-Blind,Placebo Controlled,Dose-Response Trial of the Melatonin Effect on the Pain Threshold of Healthy Subjects

Background

Previous studies have suggested that melatonin may produce antinociception through peripheral and central mechanisms. Based on the preliminary encouraging results of studies of the effects of melatonin on pain modulation, the important question has been raised of whether there is a dose relationship in humans of melatonin on pain modulation.

Objective

The objective was to evaluate the analgesic dose response of the effects of melatonin on pressure and heat pain threshold and tolerance and the sedative effects.

Methods

Sixty-one healthy subjects aged 19 to 47 y were randomized into one of four groups: placebo, 0.05 mg/kg sublingual melatonin, 0.15 mg/kg sublingual melatonin or 0.25 mg/kg sublingual melatonin. We determine the pressure pain threshold (PPT) and the pressure pain tolerance (PPTo). Quantitative sensory testing (QST) was used to measure the heat pain threshold (HPT) and the heat pain tolerance (HPTo). Sedation was assessed with a visual analogue scale and bispectral analysis.

Results

Serum plasma melatonin levels were directly proportional to the melatonin doses given to each subject. We observed a significant effect associated with dose group. Post hoc analysis indicated significant differences between the placebo vs. the intermediate (0.15 mg/kg) and the highest (0.25 mg/kg) melatonin doses for all pain threshold and sedation level tests. A linear regression model indicated a significant association between the serum melatonin concentrations and changes in pain threshold and pain tolerance (R² = 0.492 for HPT, R² = 0.538 for PPT, R² = 0.558 for HPTo and R² = 0.584 for PPTo).

Conclusions

The present data indicate that sublingual melatonin exerts well-defined dose-dependent antinociceptive activity. There is a correlation between the plasma melatonin drug concentration and acute changes in the pain threshold. These results provide additional support for the investigation of melatonin as an analgesic agent. Brazilian Clinical Trials Registry (ReBec): (U1111-1123-5109). IRB: Research Ethics Committee at the Hospital de Clínicas de Porto Alegre.     

Local ASIC3 modulates pain and disease progression in a rat model of osteoarthritis

Background

Recent data have suggested a relationship between acute arthritic pain and acid sensing ion channel 3 (ASIC3) on primary afferent fibers innervating joints. The purpose of this study was to clarify the role of ASIC3 in a rat model of osteoarthritis (OA) which is considered a degenerative rather than an inflammatory disease.

Methods

We induced OA via intra-articular mono-iodoacetate (MIA) injection, and evaluated pain-related behaviors including weight bearing measured with an incapacitance tester and paw withdrawal threshold in a von Frey hair test, histology of affected knee joint, and immunohistochemistry of knee joint afferents. We also assessed the effect of ASIC3 selective peptide blocker (APETx2) on pain behavior, disease progression, and ASIC3 expression in knee joint afferents.

Results

OA rats showed not only weight-bearing pain but also mechanical hyperalgesia outside the knee joint (secondary hyperalgesia). ASIC3 expression in knee joint afferents was significantly upregulated approximately twofold at Day 14. Continuous intra-articular injections of APETx2 inhibited weight distribution asymmetry and secondary hyperalgesia by attenuating ASIC3 upregulation in knee joint afferents. Histology of ipsilateral knee joint showed APETx2 worked chondroprotectively if administered in the early, but not late phase.

Conclusions

Local ASIC3 immunoreactive nerve is strongly associated with weight-bearing pain and secondary hyperalgesia in MIA-induced OA model. APETx2 inhibited ASIC3 upregulation in knee joint afferents regardless of the time-point of administration. Furthermore, early administration of APETx2 prevented cartilage damage. APETx2 is a novel, promising drug for OA by relieving pain and inhibiting disease progression.     

The Concordance of Care for Age Related Macular Degeneration with the Chronic Care Model: A Multi-Centered Cross-Sectional Study

Aims

The aim of the study was to assess the concordance of care for age related macular degeneration with the evidence-based framework for care for chronic medical conditions known as the chronic care model. Furthermore we aimed to identify factors associated with the concordance of care with the chronic care model.

Methods

Multi-centered cross-sectional study. 169 patients beginning medical treatment for age related macular degeneration were recruited and analyzed. Patients completed the Patient Assessment of Chronic Illness Care (PACIC) questionnaire, reflecting accordance to the chronic care model from a patient’s perspective, the National Eye Institute Visual Functioning Questionnaire-25 (NEI-VFQ-25) and Patient Health Questionnaire (PHQ-9). Visual acuity and chronic medical conditions were assessed. Nonparametric tests and correlation analyses were performed, also multivariable regression analysis.

Results

The median PACIC summary score was 2.4 (interquartile range 1.75 to 3.25), the lowest PACIC subscale score was “follow-up/coordination” with a median of 1.8 (interquartile range 1.00 to 2.60). In multivariable regression analysis the presence of diabetes type 2 was strongly associated with low PACIC scores (coefficient = −0.85, p = 0.007).

Conclusion

Generally, care for patients with age related macular degeneration by ophthalmologists is in moderate concordance with the chronic care model. Concerning follow-up and coordination of health service, large improvements are possible. Future research should answer the question how healthcare delivery can be improved effecting relevant benefits to patients with AMD.     

Increased Risk of Acute Pancreatitis in Patients with Chronic Hemodialysis: A 4-Year Follow-Up Study

Background

The risk of acute pancreatitis in patients on long-term peritoneal dialysis is higher as compared to the general population. However, the relationship between long-term hemodialysis and acute pancreatitis has never been established.

Objectives

We investigated the incidence of acute pancreatitis among patients on long-term hemodialysis in Taiwan to evaluate if there is a higher risk of acute pancreatitis in comparison to the general population.

Methods

We utilized a National Health Insurance (NHI) claims data sample containing one million beneficiaries. We followed all adult beneficiaries from January 1, 2007 until December 31, 2010 to see if they had been hospitalized for acute pancreatitis during this period. We further identified patients on chronic hemodialysis and compared their risk of acute pancreatitis with the general population.

Results

This study included 2603 patients with long-term hemodialysis and 773,140 patients without hemodialysis. After controlling for age, gender, Charlson Comorbidity Index Score, geographic region, socioeconomic status and urbanization level, the adjusted hazard ratio was 3.44 (95% Confidence interval, 2.5–4.7).

Conclusions

The risk of acute pancreatitis in patients on long-term hemodialysis is significantly higher in comparison to the general population.     

Participation of myosin Va and Pka type I in the regeneration of neuromuscular junctions

Background

The unconventional motor protein, myosin Va, is crucial for the development of the mouse neuromuscular junction (NMJ) in the early postnatal phase. Furthermore, the cooperative action of protein kinase A (PKA) and myosin Va is essential to maintain the adult NMJ. We here assessed the involvement of myosin Va and PKA in NMJ recovery during muscle regeneration.

Methodology/Principal Findings

To address a putative role of myosin Va and PKA in the process of muscle regeneration, we used two experimental models the dystrophic mdx mouse and Notexin-induced muscle degeneration/regeneration. We found that in both systems myosin Va and PKA type I accumulate beneath the NMJs in a fiber maturation-dependent manner. Morphologically intact NMJs were found to express stable nicotinic acetylcholine receptors and to accumulate myosin Va and PKA type I in the subsynaptic region. Subsynaptic cAMP signaling was strongly altered in dystrophic muscle, particularly in fibers with severely subverted NMJ morphology.

Conclusions/Significance

Our data show a correlation between the subsynaptic accumulation of myosin Va and PKA type I on the one hand and NMJ regeneration status and morphology, AChR stability and specificity of subsynaptic cAMP handling on the other hand. This suggests an important role of myosin Va and PKA type I for the maturation of NMJs in regenerating muscle.     

Stress-Induced Allodynia – Evidence of Increased Pain Sensitivity in Healthy Humans and Patients with Chronic Pain after Experimentally Induced Psychosocial Stress

Background

Experimental stress has been shown to have analgesic as well as allodynic effect in animals. Despite the obvious negative influence of stress in clinical pain conditions, stress-induced alteration of pain sensitivity has not been tested in humans so far. Therefore, we tested changes of pain sensitivity using an experimental stressor in ten female healthy subjects and 13 female patients with fibromyalgia.

Methods

Multiple sensory aspects of pain were evaluated in all participants with the help of the quantitative sensory testing protocol before (60 min) and after (10 and 90 min) inducing psychological stress with a standardized psychosocial stress test (“Trier Social Stress Test”).

Results

Both healthy subjects and patients with fibromyalgia showed stress-induced enhancement of pain sensitivity in response to thermal stimuli. However, only patients showed increased sensitivity in response to pressure pain.

Conclusions

Our results provide evidence for stress-induced allodynia/hyperalgesia in humans for the first time and suggest differential underlying mechanisms determining response to stressors in healthy subjects and patients suffering from chronic pain. Possible mechanisms of the interplay of stress and mediating factors (e.g. cytokines, cortisol) on pain sensitivity are mentioned. Future studies should help understand better how stress impacts on chronic pain conditions.     

Repeated autologous intraarticular blood injections as an animal model for joint pain in haemophilic arthropathy

Introduction

Haemophilic arthropathy following recurrent joint bleedings is one of the major disease-related complications in people with haemophilia (PWH), leading to mostly chronic joint pain. Since many antinociceptive principles interfere with the clotting system, PWH are restricted in treatment options, thereby defining a medical need for novel therapeutic principles. However, we lack the availability of an animal model for joint pain in haemophilic arthropathy for testing these.

Methods

In this study, we aimed to validate the rat model of repeated autologous intraarticular blood injections specifically for pain-related behavior. During an observation period of 50 days, groups of animals were injected weekly into one knee joint with either whole blood or cellular/plasma components.

Results

Injections induced primary hyperalgesia starting after the third injection, accompanied by mild functional gait changes and joint swelling. Secondary hyperalgesia and quantitative gait disturbances were not observed. This phenotype was most prominent in whole blood injected animals, with effect sizes of cells and plasma being additive. In order to differentiate haemophilia-related arthropathy from traumatic joint bleeding, another group was injected with whole blood only once, which did not cause any alterations.

Conclusions

Repeated autologous intraarticular injections of blood showed a time course, inflammatory response and reduction in pain thresholds similar to the signs and symptoms observed in PWH. Therefore, this model may be utilised in the future for testing novel antinociceptive principles in haemophilia-associated joint pain.     

Increased Brain White Matter Axial Diffusivity Associated with Fatigue,Pain and Hyperalgesia in Gulf War Illness

Background

Gulf War exposures in 1990 and 1991 have caused 25% to 30% of deployed personnel to develop a syndrome of chronic fatigue, pain, hyperalgesia, cognitive and affective dysfunction.

Methods

Gulf War veterans (n = 31) and sedentary veteran and civilian controls (n = 20) completed fMRI scans for diffusion tensor imaging. A combination of dolorimetry, subjective reports of pain and fatigue were correlated to white matter diffusivity properties to identify tracts associated with symptom constructs.

Results

Gulf War Illness subjects had significantly correlated fatigue, pain, hyperalgesia, and increased axial diffusivity in the right inferior fronto-occipital fasciculus. ROC generated thresholds and subsequent binary regression analysis predicted CMI classification based upon axial diffusivity in the right inferior fronto-occipital fasciculus. These correlates were absent for controls in dichotomous regression analysis.

Conclusion

The right inferior fronto-occipital fasciculus may be a potential biomarker for Gulf War Illness. This tract links cortical regions involved in fatigue, pain, emotional and reward processing, and the right ventral attention network in cognition. The axonal neuropathological mechanism(s) explaining increased axial diffusivity may account for the most prominent symptoms of Gulf War Illness.     

Incidence and Outcome of Early Acute Kidney Injury in Critically-Ill Trauma Patients

Objective

To determine the incidence and effect on mortality of early acute kidney injury in severely injured trauma patients using the Acute Kidney Injury Network creatinine criteria.

Design

A retrospective cohort study of severely injured trauma patients admitted to the shock trauma intensive care unit.

Setting

Texas Trauma Institute, a state designated level I trauma unit certified by the American College of Surgeons Committee on Trauma.

Patients

901 severely injured trauma patients admitted over a 15 month period to the shock trauma intensive care unit.

Interventions

Retrospective analysis of prospectively collected data abstracted from an electronic trauma database.

Measurements and Main Results

Of 901 eligible patients admitted to the shock trauma intensive care unit after traumatic injury, 54 patients (6%) developed acute kidney injury, of whom 10 (19%) required renal replacement therapy. The 30-day mortality rate for the entire cohort was 83/901 (9.2%). Patients with early acute kidney injury had a mortality rate of 16/54 (29.6%). When corrected for multiple covariates including injury severity scores, the development of early acute kidney injury was associated with a significantly higher risk of death at 30 days with an OR of 3.4 (95% CI 1.6-7.4).

Conclusions

Applying the Acute Kidney Injury Network creatinine criteria in severely injured trauma patients, the incidence of early acute kidney injury was 6%. After correction for injury severity, development of early acute kidney injury was independently associated with significantly higher 30-day mortality.     

Physiology, morphology and phenology of seed dormancy break and germination in the endemic Iberian species Narcissus hispanicus (Amaryllidaceae)

Background and Aims

Only very few studies have been carried out on seed dormancy/germination in the large monocot genus Narcissus. A primary aim of this study was to determine the kind of seed dormancy in Narcissus hispanicus and relate the dormancy breaking and germination requirements to the field situation.

Methods

Embryo growth, radicle emergence and shoot growth were studied by subjecting seeds with and without an emerged radicle to different periods of warm, cold or warm plus cold in natural temperatures outdoors and under controlled laboratory conditions.

Key Results

Mean embryo length in fresh seeds was approx. 1·31 mm, and embryos had to grow to 2·21 mm before radicle emergence. Embryos grew to full size and seeds germinated (radicles emerged) when they were warm stratified for 90 d and then incubated at cool temperatures for 30 d. However, the embryos grew only a little and no seeds germinated when they were incubated at 9/5, 10 or 15/4 °C for 30 d following a moist cold pre-treatment at 5, 9/5 or 10 °C. In the natural habitat of N. hispanicus, seeds are dispersed in late May, the embryo elongates in autumn and radicles emerge (seeds germinate) in early November; however, if the seeds are exposed to low temperatures before embryo growth is completed, they re-enter dormancy (secondary dormancy). The shoot does not emerge until March, after germinated seeds are cold stratified in winter.

Conclusion

Seeds of N. hispanicus have deep simple epicotyl morphophysiological dormancy (MPD), with the dormancy formula C_1bB(root) – C₃(epicotyl). This is the first study on seeds with simple MPD to show that embryos in advanced stages of growth can re-enter dormancy (secondary dormancy).     

Reliability study of thermal quantitative sensory testing in healthy Chinese

Background: Test–retest reliability is important to establish for any diagnostic tool. The reliability of quantitative sensory testing (QST) in the trigeminal region has recently been described in Caucasians as well as differences in absolute thresholds and responses between Caucasians and Chinese. However, the test–retest reliability has not been determined in a Chinese population.

Objective: To provide novel information on the test–retest reliability of thermal QST in the trigeminal and spinal system in healthy Chinese.

Methods: Twenty healthy volunteers (10 women and 10 men) participated. Cold detection threshold (CDT), warm detection threshold (WDT), cold pain threshold (CPT), and heat pain threshold (HPT) were measured at two sites: the surface of the left hand and the left masseter. The testing was performed over three consecutive stimuli trials, three sessions conducted on one day and repeated one week later. Data were analyzed with intra-tester reliability test and four-way analysis of variance (ANOVA) for repeated measures.

Results: There was a tendency for the first trial in CDT (p?=?0.005), CPT (p?=?0.02), and HPT (p?p?=?0.003) and HPT (p?=?0.045) with higher sensitivity at the masseter muscle. There were significant gender differences with higher sensitivity in women for CPT (p?=?0.001) and HPT (p?=?0.001).

Conclusion: Test site and gender affect thermal thresholds substantially. The test–retest reliability of most thermal threshold measures were acceptable for assessing somatosensory function, however, innocuous thresholds appear to be associated with larger variability than noxious thresholds in a Chinese population.     

A bacterial cytotoxin identifies the RhoA exchange factor Net1 as a key effector in the response to DNA damage

Background

Exposure of adherent cells to DNA damaging agents, such as the bacterial cytolethal distending toxin (CDT) or ionizing radiations (IR), activates the small GTPase RhoA, which promotes the formation of actin stress fibers and delays cell death. The signalling intermediates that regulate RhoA activation and promote cell survival are unknown.

Principal Findings

We demonstrate that the nuclear RhoA-specific Guanine nucleotide Exchange Factor (GEF) Net1 becomes dephosphorylated at a critical inhibitory site in cells exposed to CDT or IR. Expression of a dominant negative Net1 or Net1 knock down by iRNA prevented RhoA activation, inhibited the formation of stress fibers, and enhanced cell death, indicating that Net1 activation is required for this RhoA-mediated responses to genotoxic stress. The Net1 and RhoA-dependent signals involved activation of the Mitogen-Activated Protein Kinase p38 and its downstream target MAPK-activated protein kinase 2.

Significance

Our data highlight the importance of Net1 in controlling RhoA and p38 MAPK mediated cell survival in cells exposed to DNA damaging agents and illustrate a molecular pathway whereby chronic exposure to a bacterial toxin may promote genomic instability.     

The Association between Cold Spells and Pediatric Outpatient Visits for Asthma in Shanghai, China

Background

Asthma is a serious global health problem. However, few studies have investigated the relationship between cold spells and pediatric outpatient visits for asthma.

Objective

To examine the association between cold spells and pediatric outpatient visits for asthma in Shanghai, China.

Methods

We collected daily data on pediatric outpatient visits for asthma, mean temperature, relative humidity, and ozone from Shanghai between 1 January 2007 and 31 December 2009. We defined cold spells as four or more consecutive days with temperature below the 5^th percentile of temperature during 2007–2009. We used a Poisson regression model to examine the impact of temperature on pediatric outpatient visits for asthma in cold seasons during 2007 and 2009. We examined the effect of cold spells on asthma compared with non-cold spell days.

Results

There was a significant relationship between cold temperatures and pediatric outpatient visits for asthma. The cold effects on children''s asthma were observed at different lags. The lower the temperatures, the higher the risk for asthma attacks among children.

Conclusion

Cold temperatures, particularly cold spells, significantly increase the risk of pediatric outpatient visits for asthma. The findings suggest that asthma children need to be better protected from cold effects in winter.     

Variability in the precursor proteins of collagen I and III in different stages of COPD

Background

Levels of precursor proteins of collagen I and III are increased in fibrotic pulmonary diseases. This study determined whether the expression of precursors of type I and III collagen proteins would be increased in small and large airways of COPD patients in various stages of the disease reflecting fibrogenesis.

Methods

The levels of precursor proteins of collagen I and III were studied by immunohistochemistry and quantified by image analysis in lung tissue of 16 non-smokers, 20 smokers with normal lung function, 20 smokers with stage I-II COPD and 8 ex-smokers with stage IV COPD.

Results

In large airways, the subepithelial layer which was positive for precursor proteins of collagen I and III was thicker in smokers and in stage I-II COPD compared to non-smokers. Large airways in stage IV COPD showed reduced expression of precursor protein of collagen I whereas precursor of collagen III was increased. The amount of precursor protein of collagen III was increased in small airways of smokers and stage I-II COPD but reduced in stage IV COPD.

Conclusions

Precursor proteins of collagen I and III revealed different expression profiles in large and small airways in various stages of COPD. Smoking enhanced expression of both precursors in large airways with a positive correlation with pack-years.