Local Vascular Changes Research Articles

Sphingosine-1-Phosphate Receptor 4 links neutrophils and early local inflammation to lymphocyte recruitment into the draining lymph node to facilitate robust germinal center formation.

The successful development of germinal centers (GC) relies heavily on innate mechanisms to amplify the initial inflammatory cascade. In addition to their role in antigen presentation, innate cells are essential for the redirection of circulating lymphocytes toward the draining lymph node (dLN) to maximize antigen surveillance. Sphingosine-1-Phosphate (S1P) and its receptors (S1PR1-5) affect various aspects of immunity; however, the role of S1PR4 in regulating an immune response is not well understood. Here we use a footpad model of localized TH1 inflammation to carefully monitor changes in leukocyte populations within the blood, the immunized tissue, and the dLN. Within hours of immunization, neutrophils failed to adequately mobilize and infiltrate into the footpad tissue of S1PR4-/- mice, thereby diminishing the local vascular changes thought to be necessary for redirecting circulating cells toward the inflamed region. Neutrophil depletion with anti-Ly6G antibodies significantly reduced early tissue edema as well as the redirection and initial accumulation of naïve lymphocytes in dLN of WT mice, while the effects were less prominent or absent in S1PR4-/- dLN. Adoptive transfer experiments further demonstrated that the lymphocyte homing deficiencies in vivo were not intrinsic to the donor S1PR4-/- lymphocytes, but were instead attributed to differences within the S1PR4-deficient host. Reduced cell recruitment in S1PR4-/- mice would seed the dLN with fewer antigen-respondent lymphocytes and indeed, dLN hypertrophy at the peak of the immune response was severely diminished, with attenuated GC and activation pathways in these mice. Histological examination of the S1PR4-/- dLN also revealed an underdeveloped vascular network with reduced expression of the leukocyte tethering ligand, PNAd, within high endothelial venule regions, suggesting inadequate growth of the dLN meant to support a robust GC response. Thus, our study reveals that S1PR4 may link early immune modulation by neutrophils to the initial recruitment of circulating lymphocytes and downstream expansion and maturation of the dLN, thereby contributing to optimal GC development during an adaptive response.

Interindividual variability in cold-pressor pain sensitivity is not explained by peripheral vascular responding and generalizes to a C-nociceptor-specific pain phenotype.

Pain sensitivity of healthy subjects in the cold-pressor (CP) test was proposed to be dichotomously distributed and to represent a pain sensitivity trait. Still, it has not been systematically explored which factors influence this pain sensitivity readout. The aim of this study was to distinguish potential contributions of local tissue-related factors such as perfusion and thermoregulation or gain settings in nociceptive systems. Cold-pressor-sensitive and CP-insensitive students screened from a medical student laboratory course were recruited for a CP retest with additional cardiovascular and bilateral local vascular monitoring. In addition, comprehensive quantitative sensory testing according to Deutscher Forschungsverbund Neuropathischer Schmerz standards and a sustained pinch test were performed. Cold pressor was reproducible across sessions (Cohen kappa 0.61 ± 0.14, P < 0.005). At 30 seconds in ice water, CP-sensitive subjects exhibited not only more pain (78.6 ± 26.3 vs 29.5 ± 17.5, P < 0.0001) but also significantly stronger increases in mean arterial blood pressure (12.6 ± 9.3 vs 5.6 ± 8.1 mm Hg, P < 0.05) and heart rate (15.0 ± 8.2 vs 7.1 ± 6.2 bpm, P < 0.005), and lower baroreflex sensitivity, but not local or vasoconstrictor reflex-mediated microcirculatory responses. Cold-pressor-sensitive subjects exhibited significantly lower pain thresholds also for cold, heat, and blunt pressure, and enhanced pain summation, but no significant differences in Aδ-nociceptor-mediated punctate mechanical pain. In conclusion, differences in nociceptive signal processing drove systemic cardiovascular responses. Baroreceptor activation suppressed pain and cardiovascular responses more efficiently in CP-insensitive subjects. Cold-pressor sensitivity generalized to a pain trait of C-fiber-mediated nociceptive channels, which was independent of local thermal and vascular changes in the ice-water-exposed hand. Thus, the C-fiber pain trait reflects gain setting of the nociceptive system.

Phytotherapeutic Potential of Natural Herbal Medicines for Management of Psoriasis: Current Status

Pharmacognosy Research,2023,15,1,42-55.DOI:10.5530/097484900261Published:December 2022Type:Review ReportAuthors:Nupur Maheshwari, Neelesh Maheshwari, Dinesh Kumar Mishra, and Anju Goyal Author(s) affiliations:Nupur Maheshwari1, Neelesh Maheshwari2,*, Dinesh Kumar Mishra3, Anju Goyal1 1B.N. Institute of Pharmaceutical Sciences, B.N. University, Udaipur, Rajasthan, INDIA. 2School of Pharmacy, Sangam University, Bhilwara, Rajasthan, INDIA. 3Indore Institute of Pharmacy, Indore, Madhya Pradesh, INDIA. Abstract:Psoriasis is a complex multifunctional inflammatory autoimmune skin disease, which is mainly characterized by activation of T-cell (T-lymphocyte), abnormal proliferation keratinocyte, local vascular changes and activation of the neutrophil. A number of therapies are being used to treat psoriasis including topical, systemic and phototherapy recpectively but none of them is able to cure the disease completely, precluding the long-term serious side effects for the human body. In contrast to these, herbal therapies can play an important role for treatment of psoriasis. With this endeavor, this review reports the recent developments and patent showing potential of herbal therapy for treatment of psoriasis along with future prospect in the field of traditional and novel drug delivery system (NDDS) for treatment of psoriasis. Keywords:Herbal drug, Hyperproliferation, Keratinocyte, Novel drug delivery systems, PsoriasisView:PDF (423.12 KB)

The Deleterious Effects of Impaired Fibrinolysis on Skeletal Development Are Dependent on Fibrin(ogen), but Independent of Interlukin-6.

Chronic diseases in growing children, such as autoimmune disorders, obesity, and cancer, are hallmarked by musculoskeletal growth disturbances and osteoporosis. Many of the skeletal changes in these children are thought to be secondary to chronic inflammation. Recent studies have likewise suggested that changes in coagulation and fibrinolysis may contribute to musculoskeletal growth disturbances. In prior work, we demonstrated that mice deficient in plasminogen, the principal protease of degrading and clearing fibrin matrices, suffer from inflammation-driven systemic osteoporosis and that elimination of fibrinogen resulted in normalization of IL-6 levels and complete rescue of the skeletal phenotype. Given the intimate link between coagulation, fibrinolysis, and inflammation, here we determined if persistent fibrin deposition, elevated IL-6, or both contribute to early skeletal aging and physeal disruption in chronic inflammatory conditions. Skeletal growth as well as bone quality, physeal development, and vascularity were analyzed in C57BL6/J mice with plasminogen deficiency with and without deficiencies of either fibrinogen or IL-6. Elimination of fibrinogen, but not IL-6, rescued the skeletal phenotype and growth disturbances in this model of chronic disease. Furthermore, the skeletal phenotypes directly correlated with both systemic and local vascular changes in the skeletal environment. In conclusion, these results suggest that fibrinolysis through plasmin is essential for skeletal growth and maintenance, and is multifactorial by limiting inflammation and preserving vasculature.

Vasoprotective Endothelial Effects of Chronic Cannabidiol Treatment and Its Influence on the Endocannabinoid System in Rats with Primary and Secondary Hypertension.

Our study aimed to examine the endothelium (vascular)-protecting effects of chronic cannabidiol (CBD) administration (10 mg/kg once daily for 2 weeks) in aortas and small mesenteric (G3) arteries isolated from deoxycorticosterone-induced hypertensive (DOCA-salt) rats and spontaneously hypertensive rats (SHR). CBD reduced hypertrophy and improved the endothelium-dependent vasodilation in response to acetylcholine in the aortas and G3 of DOCA-salt rats and SHR. The enhancement of vasorelaxation was prevented by the inhibition of nitric oxide (NO) with L-NAME and/or the inhibition of cyclooxygenase (COX) with indomethacin in the aortas and G3 of DOCA-salt and SHR, respectively. The mechanism of the CBD-mediated improvement of endothelial function in hypertensive vessels depends on the vessel diameter and may be associated with its NO-, the intermediate-conductance calcium-activated potassium channel- or NO-, COX-, the intermediate and the small-conductance calcium-activated potassium channels-dependent effect in aortas and G3, respectively. CBD increased the vascular expression of the cannabinoid CB1 and CB2 receptors and aortic levels of endocannabinoids with vasorelaxant properties e.g., anandamide, 2-arachidonoylglycerol and palmitoyl ethanolamide in aortas of DOCA-salt and/or SHR. In conclusion, CBD treatment has vasoprotective effects in hypertensive rats, in a vessel-size- and hypertension-model-independent manner, at least partly via inducing local vascular changes in the endocannabinoid system.

Imaging diagnostics in acute pancreatitis

Abdominal imaging is an important component of the diagnostics of acute pancreatitis. In addition to the clinical features and the laboratory constellation, it serves to establish the diagnosis or the exclusion of other diseases and also the identification and assessment of the course of local complications and vascular changes that can arise during the course of acute pancreatitis. Due to the numerous imaging examination methods that are available, their combination options and the different examination times, there are diverse application options that have to be taken into account, such as the severity and duration of the disease, concomitant diseases and complications of acute pancreatitis. Arational use of imaging is an important prerequisite for high quality and at the same time cost-effective patient care. This review summarizes the current importance of imaging in acute pancreatitis, with particular reference to the updated S3 guidelines on acute pancreatitis.

The analysis of the lipid levels in patients with coronary artery disease after percutaneous coronary intervention: a one-year follow-up observational study

BackgroundCoronary heart disease (CHD) is one of the leading causes of death worldwide. Percutaneous coronary intervention (PCI) has been an important technology for the treatment of CHD. Blood lipid management is critical for PCI patients because not only should local vascular pathological changes be considered but the whole atherosclerotic process should be considered as well.MethodsA total of 522 patients diagnosed with CHD (including acute myocardial infarction and unstable angina) successfully underwent stent implantation in acute or elective PCI in the cardiology department of one general hospital in Guangzhou from June 2015 to December 2017. The 2016 Chinese Guideline for the Management of dyslipidaemia in Adults and the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report (NCEP-ATP III) were used to classify total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) levels.ResultsA total of 522 patients were recruited for the study. The mean values of TC, TG, LDL-C, and HDL-C at baseline were 4.76, 1.80, 2.93 and 1.03 mmol/L, respectively. After 1 year of follow-up, the mean values of TC, TG, LDL-C, and HDL-C were 3.94, 1.62, 2.26 and 1.01 mmol/L, respectively. The prevalence of high TC, high TG, high LDL-C and low HDL-C at baseline was 12.05, 21.80, 10.90 and 56.79%, respectively, and the prevalence at follow-up was 4.59, 15.68, 3.25 and 59.85%, respectively. Logistic regression revealed that gender was risk factor for high TC (≥ 6.22 mmol/L), low HDL-C (< 1.04 mmol/L) and high LDL-C (≥ 4.14 mmol/L) at follow-up. Age was the factor associated with high TG (≥ 2.26 mmol/L) and low HDL-C (< 1.04 mmol/L) at follow-up. Besides, smoking and diet control were risk factors for low HDL-C (< 1.04 mmol/L) and high LDL-C (≥ 4.14 mmol/L) at follow-up, respectively.ConclusionThe patients with PCI at follow-up experienced lower mean values of lipids and prevalence of dyslipidaemia than those at baseline. Gender, age, smoking and diet control were the risk factors associated with elevated lipids. Improvement in lipid management at follow up demonstrated that such intervention can be effective.

Evaluation of vascular tissue disorders and regional bleeding under chronic reduced preparative atphosis

At present, the biochemical and morphological phases of the development of inflammation in the area of tissue damage are distinguished, in particular, the rate of formation of vasoactive and chemotactic substances that determine the stereotypical nature of local vascular and tissue changes (1,4,5,6). Concerning the dynamics of the release of inflammatory mediators in the alteration zone, the initiating role of histamine should be noted.

Systemic Transcriptional Responses to Hemarthrosis and FVIII Replacement in FVIII-Deficient Mice

IntroductionHemarthrosis in patients with hemophilia (PWH) leads to local inflammation and vascular changes in the joint, but little is known about the extent and nature of systemic responses to joint bleeding. Since the spleen is a major systemic immune-modulatory organ, we quantified changes in splenic gene expression profiles in FVIII-deficient mice at baseline and after induced hemarthrosis, and in the presence and absence of FVIII replacement therapy.MethodsHemarthrosis was induced in FVIII-deficient mice by sub-patellar needle puncture +/- 100 IU/kg recombinant human FVIII (rhFVIII) intravenously 2 hours before and 6 hours after injury. Spleens were harvested on day 3 or 2 weeks post-injury (n=3-5). Spleens from uninjured mice +/- rhFVIII treatment served as controls. RNA libraries were prepared using the NEBNext Ultra II Directional RNA Library Prep Kit and sequenced on an Illumina NextSeq500 platform (single-end; 75bp reads). The limma-voom method (R Bioconductor) was used for differential expression analyses. The criteria for differential expression were: i) a log fold-change (logFC) >1 or <-1, and ii) an adjusted p value <0.05. Functional enrichment was performed using Signaling Pathway Impact Analysis and the STRING database of protein-protein interactions.ResultsKnee injury in FVIII-deficient mice caused gross hemarthrosis that was largely prevented with rhFVIII prophylaxis (day 2 hematocrit: 26.4% and 46.3%). Pronounced alterations in splenic gene expression profiles occurred in vehicle-treated mice on day 3 post-injury, with 4227 differentially expressed genes (DEG) and 41 perturbed pathways. This response was markedly improved with rhFVIII treatment (386 DEG; 5 pathways), and almost entirely corrected by 2 weeks. Multiple pathways relating to immune processes, inflammation, and cell survival were highly perturbed on day 3 post-injury, including cytokine-cytokine receptor interactions (pNDE=1.4x10-6) and cell cycle (pNDE=5.3x10-5). The cell cycle pathway remained significantly altered despite rhFVIII treatment (pNDE=3.5x10-6), while other pathways were comparable to uninjured mice. Analysis of the top 50 DEG that are mutual to both treatment groups revealed a striking difference in directionality, with up-regulation in the vehicle group, and down-regulation in the rhFVIII group. Together, these findings demonstrate a significant effect of rhFVIII treatment on systemic transcriptional responses to joint bleeding. Treatment with rhFVIII in the absence of hemarthrosis resulted in only 97 DEG on day 3 by the same criteria, and 233 DEG after lowering the logFC threshold from (-)1 to (-)0.5. Of these 233 genes, STRING analysis revealed perturbation of the platelet activation pathway (FDR: 7.7x10-10) for up-regulated genes (93 DEG) and the T cell receptor signaling pathway (FDR: 1.3x10-8) for down-regulated genes (140 DEG), which may corroborate a role of T cell responses to rhFVIII treatment in the development of inhibitors. These responses to rhFVIII were unique to uninjured mice and did not occur in mice with induced hemarthrosis and rhFVIII treatment.ConclusionsJoint bleeding in hemophilic mice leads to acute, profound changes in multiple systemic pathways, including immune and inflammatory processes, as shown by gene expression profiling. Prophylactic treatment with rhFVIII largely corrects this response to hemarthrosis. Interestingly, in the absence of hemarthrosis, rhFVIII treatment affects platelet activation and T cell receptor signaling, whereby further analyses are required to determine if these effects stimulate or dampen immune responses. This approach can be used to explore the systemic mechanisms contributing to progressive hemophilic arthropathy in PWH, elucidate immune responses that may facilitate inhibitor formation, and lead to development of novel therapeutic strategies. Disclosuresvon Drygalski:UniQure BV, Bayer, Bioverativ/Sanofi, Pfizer, Novo Nordisk, Biomarin, Shire, CSL Behring: Consultancy.

Functional Neuroimaging of Nociceptive and Pain-Related Activity in the Spinal Cord and Brain: Insights From Neurovascular Coupling Studies.

Spinal cord and brain processes underlie pain perception, which produces systemic cardiovascular changes. In turn, the autonomic nervous system regulates vascular function in the spinal cord and brain in order to adapt to these systemic changes, while neuronal activity induces local vascular changes. Thus, autonomic regulation and pain processes in the brain and spinal cord are tightly linked and interrelated. The objective of this topical review is to discuss work on neurovascular coupling during nociceptive processing in order to highlight supporting evidence and limitations for the use of cerebral and spinal fMRI to investigate pain mechanisms and spinal nociceptive processes. Work on functional neuroimaging of pain is presented and discussed in relation to available neurovascular coupling studies and related issues. Perspectives on future work are also discussed with an emphasis on differences between the brain and the spinal cord and on different approaches that may be useful to improve current methods, data analyses and interpretation. In summary, this review highlights the lack of data on neurovascular coupling during nociceptive stimulation and indicates that hemodynamic and BOLD responses measured with fMRI may be biased by nonspecific vascular changes. Future neuroimaging studies on nociceptive and pain-related processes would gain further understanding of neurovascular coupling in the brain and spinal cord and should take into account the effects of systemic vascular changes that may affect hemodynamic responses. Anat Rec, 301:1585-1595, 2018. © 2018 Wiley Periodicals, Inc.

The Role of Kallikrein-kinin System in Complex Regional Pain Syndrome I (CRPS I) Pathophysiologic Mechanisms

Inflammation, edema and local vascular permeability changes are essential features of the complex regional pain syndrome type I (CRPS I). The role of kallikrein-kinin system components as the major mediators in the development of these symptoms is poorly investigated.&#x0D; The objective: to investigate the role of kallikrein-kinin system in pathophysiologic mechanisms of CRPS I.&#x0D; Patients and methods. We have investigated level of prekallikrein (PK), activity of fast-reacting (FRI) and time-dependent (TDI) inhibitors of plasma kallikrein, and blood plasma proteolytic activity (BPPA) in 45 patients with CRPS I and 15 healthy volunteers.&#x0D; Results. Analysis of kininogenesis activity and sympathetic-adrenal system revealed their close interdependence. Our data corresponds well with the literature information about depressive effect of sympathetic nervous system on kininase activity. This leads to the accumulation of vasoactive peptides in the injures segment of the extremity. Decrease of neurogenic effects at the later stages of CRPS I leads to the fall of the basal kininogenesis level.&#x0D; Conclusion. Local humoral factors such as the components of kallikrein-kinin system play an important role in CRPS I pathophysiologic mechanisms and are dependent on sympathetic-adrenal system activity.

Beyond BOLD: optimizing functional imaging in stroke populations.

Blood oxygenation level-dependent (BOLD) signal changes are often assumed to directly reflect neural activity changes. Yet the real relationship is indirect, reliant on numerous assumptions, and subject to several sources of noise. Deviations from the core assumptions of BOLD contrast functional magnetic resonance imaging (fMRI), and their implications, have been well characterized in healthy populations, but are frequently neglected in stroke populations. In addition to conspicuous local structural and vascular changes after stroke, there are many less obvious challenges in the imaging of stroke populations. Perilesional ischemic changes, remodeling in regions distant to lesion sites, and diffuse perfusion changes all complicate interpretation of BOLD signal changes in standard fMRI protocols. Most stroke patients are also older than the young populations on which assumptions of neurovascular coupling and the typical analysis pipelines are based. We present a review of the evidence to show that the basic assumption of neurovascular coupling on which BOLD-fMRI relies does not capture the complex changes arising from stroke, both pathological and recovery related. As a result, estimating neural activity using the canonical hemodynamic response function is inappropriate in a number of contexts. We review methods designed to better estimate neural activity in stroke populations. One promising alternative to event-related fMRI is a resting-state-derived functional connectivity approach. Resting-state fMRI is well suited to stroke populations because it makes no performance demands on patients and is capable of revealing network-based pathology beyond the lesion site.

Bilateral pupillary dilatation with normal intracranial pressure

Sir, The standard management of non-operable severe head injury is ventilation with intracranial pressure (ICP) monitoring (brain trauma foundation).[1] Since the patient is often sedated for ventilation, neurological monitoring is restricted to examination of the pupils. We report the case of a patient who almost forced a fundamental change in our management protocol. A 50-year-old diabetic female patient was admitted 2 h following a road traffic accident with a Glasgow coma scales core of 8/15, minimally asymmetric, but briskly reacting pupils and no lateralizing deficit. A computerized tomography (CT) scan of the brain showed bilateral frontal and a small right temporal contusion with preserved basal cisterns [Figure 1]. She was managed conservatively with ventilation and ICP monitoring. The ICP remained below 15 mmHg for the 1st 3 days and then showed a minimal increase up to a maximum of 18 mmHg. It was therefore decided to repeat a CT scan before weaning from the ventilator. The CT scan was performed 76 h after the trauma showed resolving contusions with increased edema around them [Figure 2]. Hence, mannitol was started and later vasopressors were added to maintain an adequate cerebral perfusion pressure. Figure 1 Axial computerized tomography scan 3 h following trauma showing bilateral frontal contusions adjacent to the falx with some surrounding edema. cerebrospinal fluid cisterns are seen Figure 2 Computerized tomography scan 3 days later showing a decrease in the volume of hemorrhage and an increase in the edema. CSF cisterns are better visualized than in the earlier scan At 16 h after the second scan, her pupils became large and non-reacting, though ICP remained below 20 mmHg. Assuming the ICP values were wrong, patient was taken up for a bifrontal decompressive craniectomy. After craniectomy, dura and brain were lax, excluding raised ICP. After craniectomy, blood pressure dropped further and had severe metabolic acidosis with a pH of 6.91 and a chloride of 123 mmol/L. Despite vigorous treatment of acidosis, blood pressure never recovered and she died 4 h later. This report highlights the importance of hemodynamic changes and escalating needs of vasoactive drugs while managing a severe head injury with ICP monitoring. The hypotension was assumed to be due to the effects of acidosis on the heart and vasculature.[2] Though hyperchloremic acidosis is not fatal, Kellum et al. have reported that saline resuscitation significantly shortened survival. The survival time inversely correlated with the decrease in pH and the rise in serum chloride.[3] Ritter et al. demonstrated reduced blood flow in the midbrain in patients with pupillary dilatation, independent of the ICP and brainstem lesions on CT scan and concluded that brainstem ischemia was an important causal factor in pupillary dilatation.[4] It is possible that the severe acidosis could have caused local vascular changes in the region of brainstem in our patient resulting in pupillary dilatation since there were no clinical or surgical features of raised ICP or herniation. In conclusion, we wish to reiterate that pupillary changes in head injury need not always be caused by herniation. This case also shows that excessive importance given to one parameter (in our case, ICP) can result in decreased attention to other equally important clinical and laboratory findings and less than optimal care.

Acquired Localized Hypertrichosis Induced by Internal Fixation and Plaster Cast Application

Hypertrichosis refers to increased vellus hair growth and is independent to androgen excess. The acquired localized hypertrichosis (ALH) is one of the typical hypertrichosis, which mainly results from chronic irritation, inflammation, friction, and occlusion by plaster of Paris. Here, we report a young boy who had ALH on his right hand following a closed fracture with internal fixation and plaster cast application. The case is unusual because the hairy area is limited to the operative region of internal fixation. We suggest that the local vascular changes and skin inflammation induced by internal fixation and plaster cast application may be associated with ALH.

Diabetic Foot Infections: The Role of Microbiology and Antibiotic Treatment

Diabetes mellitus is a major risk factor for the development of foot infections. Among the risk factors that contribute to the development of diabetic foot infections are local neuropathy, vascular changes and depressed local host defenses. The microbiology of these infections is often complex and can be polymicrobial. Treatment of these infections depends on the severity and extent of infection. Treatment should involve a multi-disciplinary team approach involving surgeons and infectious disease specialists. The current recommendations for treatment are primarily based on expert opinion and consensus rather than clinical trials. No single agent or combination of agents has been shown to be superior to others. The aim of this review is to provide valid options of therapy, especially with regard to newer agents that are currently available for treatment of both soft tissue infections and osteomyelitis.

The Olfactory Glomerulus: A Model for Neuro-Glio-Vascular Biology

The cellular basis of brain imaging is emerging as a new frontier in current neuroscience. In this issue of Neuron, Petzold et al. analyze a model system, the olfactory glomerulus, to show how neurovascular coupling involves an elaborate dance between axon terminals, presynaptic and postsynaptic dendrites, glial cells, and the capillary network.

Rash in a Patient Treated with Pemetrexed for Relapsed Non-small Cell Lung Cancer

A 66-year-old man was treated with platinum-based induction chemotherapy (three cycles) followed by thoracic radiotherapy for stage IIIB non-small cell lung cancer. Because of the extent of the disease, high-dose thoracic radiotherapy was not feasible, and 36 Gy/3 Gy fractions on the originally involved areas, with a boost of 12 Gy/3 Gy to the region of residual uptake on positron emission tomography scan after chemotherapy was given. Six months after the initial therapy, the patient experienced anorexia, thoracic pain and cough, based on a local relapse. Administration of the first cycle of second-line pemetrexed (after standard premedication) was complicated 5 days later by a painful, itchy, CTC-NCI grade 2, rash on the thoracic wall (Figure 1). The skin was red, warm, painful, and edematous in an area matching the radiation portal (Figure 2). A skin biopsy revealed a moderate perivascular infiltrate of lymphocytes and eosinophils of the superficial dermis and to a lesser extent of the deeper dermis, compatible with urticarial drug reaction (Figure 3). Treatment with local corticosteroids resulted in complete resolution of the rash within 3 days and the further pemetrexed administration was uneventful.FIGURE 2Radiation field with the delivered dose of 36 Gy in 3 Gy fractions on the originally involved areas, with a boost of 12 Gy/3Gy to the region of residual uptake on positron emission tomography scan after chemotherapy.View Large Image Figure ViewerDownload (PPT)FIGURE 3Skin biopsy reveals a perivascular infiltrate of lymphocytes (arrow head) and many eosinophils (arrow) in the dermis, the epidermis is normal.View Large Image Figure ViewerDownload (PPT) We describe a case of radiation recall dermatitis (RRD) occurring during second-line pemetrexed in a patient treated 6 months after the end of thoracic radiotherapy. RRD is a rare, well known, but poorly understood phenomenon. After administration of some antineoplastic drugs, there is “recalling” of an effect similar to an acute radiation reaction in a previously irradiated field and it is characterized by a mixed nonspecific inflammatory skin reaction. Many hypotheses such as epithelial stem cell inadequacy, local vascular changes, epithelial stem cell sensitivity, or idiosyncratic drug hypersensitivity reaction have been proposed to explain RRD.1Azria D Magne N Zouhair A et al.Radiation recall: a well recognized but neglected phenomenon.Cancer Treat Rev. 2005; 31: 555-570Abstract Full Text Full Text PDF PubMed Scopus (139) Google Scholar RRD usually occurs at first exposure to the responsible drug and should be differentiated from radiosensitization. There is little literature evidence on the incidence of RRD, and most information is on the use of doxorubicin.1Azria D Magne N Zouhair A et al.Radiation recall: a well recognized but neglected phenomenon.Cancer Treat Rev. 2005; 31: 555-570Abstract Full Text Full Text PDF PubMed Scopus (139) Google Scholar Factors increasing the risk of development of RRD are a higher dose of radiotherapy, a shorter time interval between radiotherapy and chemotherapy administration, and the specific dose-timing combinations used. Although in one report the median interval between radiotherapy and chemotherapy was reported to be 39.5 days,2Camidge R Price A Characterizing the phenomenon of radiation recall dermatitis.Radiother Oncol. 2001; 59: 237-245Abstract Full Text Full Text PDF PubMed Scopus (215) Google Scholar the time needed between radiotherapy an chemotherapy to avoid RRD is largely unknown. Usually, patients are not rechallenged with the drug, but in cases of further exposure, the reaction is often milder than the initial presentation. When the drug is stopped, skin reactions usually resolve within a few days. The role of steroids or antihistamines in the resolution remain unclear. To our knowledge, reports of RRD after administration of pemetrexed are very rare. One case was described in a patient with mesothelioma 19 days after radiation therapy (21 Gy/7 Gy fractions) on the thoracoscopy and drainage orifices.3Hureaux J Le GY Tuchais C Savary L Urban T Radiation recall dermatitis with pemetrexed.Lung Cancer. 2005; 50: 255-258Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar Given the short interval, pemetrexed could also have been acting as a radiosensitizing agent some weeks after the radiotherapy. In contrast to our patient, one other report mentioned unsuccessful rechallenge with pemetrexed.4Barlesi F Tummino C Tasei AM Astoul P Unsuccessful rechallenge with pemetrexed after a previous radiation recall dermatitis.Lung Cancer. 2006; 54: 423-425Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar As the use of pemetrexed for second line therapy in non-small cell lung cancer—also after chemoradiation—is increasing, it is important to recognize the pattern of RRD induced by pemetrexed. If there are no good therapeutic alternatives in a certain clinical situation, careful rechallenge may be warranted.

A comparative study of Cyclofem® and depot medroxyprogesterone acetate (DMPA) effects on endometrial vasculature

ObjectivesThe most common reason for discontinuation of long-acting progestogen-only contraceptives is irregular bleeding following local endometrial vascular changes. To reduce unpredictable bleeding episodes among depot medroxyprogesterone acetate (DMPA) users, the...

Unsuccessful rechallenge with pemetrexed after a previous radiation recall dermatitis

Radiation recall dermatitis is characterized by an inflammatory reaction within a previously irradiated volume after administration of a drug. Antineoplastic drugs have mainly been involved in radiation recall reactions. This phenomenon is well known but poorly understood. Many hypotheses as stem-cell depletion in the radiotherapy field, heritable mutations within surviving stem cells, local vascular changes as well as a drug hypersensitivity reaction have been proposed to explain these reactions. In this report, we describe a non-small cell lung cancer patient treated with a carboplatin plus gemcitabine combination chemotherapy as first line followed by pemetrexed as second line therapy. Twenty-five years ago, she completed radiation therapy for breast cancer. Three days after the first cycle of pemetrexed, she presented with a radiation recall dermatitis. As EGFR-staining was negative, we rechallenged the patient with pemetrexed. Unfortunately, although less intense, we faced a recurrence of the skin reaction and pemetrexed was no longer continued.

Defective acute inflammation in Crohn's disease: a clinical investigation

The cause of Crohn's disease has not been mechanistically proven. We tested the hypothesis that the disease is a form of immunodeficiency caused by impaired innate immunity. We investigated inflammatory responses in patients and controls by quantifying neutrophil recruitment and cytokine production after acute trauma, interleukin 8 secretion by cultured monocyte-derived macrophages after exposure to inflammatory mediators, and local inflammatory and vascular changes in response to subcutaneous injection of heat-killed Escherichia coli. In patients with Crohn's disease, trauma to rectum, ileum, or skin led to abnormally low neutrophil accumulation (differences from healthy individuals of 79%, n=8, p=0.0003; 57%, n=3, p=0.05; 50%, n=13, p<0.0001, respectively) and lower production of proinflammatory interleukin 8 (63%, n=7, p=0.003; 63%, n=3, p=0.05; 45%, n=8, p<0.0001) and interleukin 1beta (50%, n=8, p=0.0005). Interleukin 8 secretion by cultured macrophages was reduced after exposure to acute wound fluid (38%, n=50, p<0.0001), C5a (48%, n=41, p=0.0005), or tumour necrosis factor alpha (52%, n=27, p<0.0001). Local inflammatory reaction to inoculation with E coli was attenuated, as quantified by changes in bloodflow (ileal disease 50%, n=6, p=0.01; colonic disease 77%, n=6, p=0.0003). This response was mediated by nitric oxide in controls, was increased by sildenafil in patients, and was not related to CARD15 genotype. In Crohn's disease, a constitutionally weak immune response predisposes to accumulation of intestinal contents that breach the mucosal barrier of the bowel wall, resulting in granuloma formation and chronic inflammation. Polymorphisms in CARD15 do not underlie this phenotype, but incapacitate the NOD2 pathway that can compensate for impairment of innate inflammation. Current treatment of secondary chronic inflammation might exaggerate the underlying lesion and promote chronic disease.