Multiple skin cancers in a single patient: Multiple pigmented Bowen's disease, giant basal cell carcinoma, squamous cell carcinoma.

Basal cell carcinoma (BCC) and squamous cell carcinoma are the most common type of nonmelanoma skin cancers (NMSCs). Bowen's disease (BD), a premalignant condition, has a marginal potential (3-5%) to progress to invasive carcinoma. We report here a rarest of a rare case of multiple pigmented BD with overlying squamous cell cancer along with a giant neglected BCC on the scalp of a 76-year-old man. The occurrence of multiple BD and NMSC in a single patient compelled us to explore the following hypothesis: (1) The multiple precancerous and cancerous lesions can be due to common etiopathogenesis. Chronic ultraviolet exposure, immunosupresssion, human papillomavirus infection, dietary factors, and environmental factors including arsenic exposure were probed in to. (2) There is evolution of precancerous lesions into a different type of cancers in different time frame. (3) The new cancerous lesions are subsequent cancers that developed after neglected untreated primary cancer.

Proinflammatory Cytokine IL-6 and JAK-STAT Signaling Pathway in Myeloproliferative Neoplasms.

The recent JAK1/2 inhibitor trial in myeloproliferative neoplasms (MPNs) showed that reducing inflammation can be more beneficial than targeting gene mutants. We evaluated the proinflammatory IL-6 cytokine and JAK-STAT signaling pathway related genes in circulating CD34(+) cells of MPNs. Regarding laboratory data, leukocytosis has been observed in polycythemia vera (PV) and JAK2V617F mutation positive versus negative primary myelofibrosis (PMF) patients. Moreover, thrombocytosis was reduced by JAK2V617F allele burden in essential thrombocythemia (ET) and PMF. 261 significantly changed genes have been detected in PV, 82 in ET, and 94 genes in PMF. The following JAK-STAT signaling pathway related genes had augmented expression in CD34(+) cells of MPNs: CCND3 and IL23A regardless of JAK2V617F allele burden; CSF3R, IL6ST, and STAT1/2 in ET and PV with JAK2V617F mutation; and AKT2, IFNGR2, PIM1, PTPN11, and STAT3 only in PV. STAT5A gene expression was generally reduced in MPNs. IL-6 cytokine levels were increased in plasma, as well as IL-6 protein levels in bone marrow stroma of MPNs, dependent on JAK2V617F mutation presence in ET and PMF patients. Therefore, the JAK2V617F mutant allele burden participated in inflammation biomarkers induction and related signaling pathways activation in MPNs.

Basiliximab treatment for autoimmune bowel disease in a pediatric heart transplant patient.

Autoimmune-mediated bowel disease has been reported after pediatric heart transplantation. Recognition and treatment of these patients has been difficult. We describe a patient who responded to steroids and basiliximab therapy after an inflammatory process secondary to abnormal T-cell activation. Our patient is a 28-month-old female who received a heart transplant at five wk of age. At 24 months post-transplant, she developed fever and bloody stools. Initial investigations were significant for an elevated ESR (>120) and CRP (15.2). Symptoms persisted despite bowel rest and mycophenolate discontinuation. Endoscopic evaluation revealed discontinuous ulcerative disease involving esophagus, terminal ileum, right and left colon, necessitating extensive bowel resection. She had additional airway inflammation leading to a TEF at the site of esophageal ulceration, requiring tracheostomy. Immune evaluation revealed autoimmune dysregulation that responded to parenteral methylprednisolone. Chronic basiliximab therapy allowed for successful weaning of steroids with sustained remission. She has been transitioned to sirolimus and tacrolimus maintenance immunosuppression with plans to discontinue basiliximab once off steroids. In conclusion, bowel disease in the setting of pediatric heart transplantation can be severe and refractory to traditional treatment methods. Tailoring immune therapy to activated T cells can result in remission. Basiliximab therapy was used in our patient to maintain steroid-induced remission, but long-term complications of this disease process are unknown.

Acquired subglottic stenosis: aetiological profile and treatment results.

OBJECTIVES: To analyse the aetiological profile and surgical results of patients with acquired chronic subglottic stenosis, and formulate a surgical scheme based on an audit of various surgical procedures. METHODS: Thirty patients were treated by 65 procedures (31 endoscopic and 34 external) between 2004 and 2009. RESULTS: Isolated subglottic stenosis was noted as unusual in the majority (27 cases), demonstrating contiguous tracheal or glottic involvement. The major aetiologies were intubation injury (n = 8) and external injury (n = 21) (i.e. blunt trauma, strangulation or penetrating injury). Vocal fold immobility and cartilage framework involvement were frequent with external injury and infrequent with intubation injury. Luminal restoration was achieved by endoscopic procedures in 2 cases, external procedures in 19 cases, and external plus adjuvant endoscopic procedures in 8 cases. The preferred surgical options were: endoscopic procedures, restricted to short, recent, grade I or II mucosal stenosis cases; and external procedures for all other stenosis situations, including isolated subglottic (anterior cricoid split plus cartilage graft), subglottic and glottic or high subglottic (anterior plus posterior cricoid split with cartilage graft), and subglottic and tracheal (cricotracheal resection with anastomosis). CONCLUSIONS: External injury stenosis has a worse profile than intubation injury stenosis. Anatomical categorisation of subglottic stenosis guides surgical procedure selection. Endoscopic procedures have limited indications as primary procedures but are useful adjunctive procedures.

Virulence Characterization of International Collections of the Wheat Stripe Rust Pathogen, Puccinia striiformis f. sp. tritici.

Wheat stripe rust (yellow rust [Yr]), caused by Puccinia striiformis f. sp. tritici, is an economically important disease of wheat worldwide. Virulence information on P. striiformis f. sp. tritici populations is important to implement effective disease control with resistant cultivars. In total, 235 P. striiformis f. sp. tritici isolates from Algeria, Australia, Canada, Chile, China, Hungary, Kenya, Nepal, Pakistan, Russia, Spain, Turkey, and Uzbekistan were tested on 20 single Yr-gene lines and the 20 wheat genotypes that are used to differentiate P. striiformis f. sp. tritici races in the United States. The 235 isolates were identified as 129 virulence patterns on the single-gene lines and 169 virulence patterns on the U.S. differentials. Virulences to YrA, Yr2, Yr6, Yr7, Yr8, Yr9, Yr17, Yr25, YrUkn, Yr28, Yr31, YrExp2, Lemhi (Yr21), Paha (YrPa1, YrPa2, YrPa3), Druchamp (Yr3a, YrD, YrDru), Produra (YrPr1, YrPr2), Stephens (Yr3a, YrS, YrSte), Lee (Yr7, Yr22, Yr23), Fielder (Yr6, Yr20), Tyee (YrTye), Tres (YrTr1, YrTr2), Express (YrExp1, YrExp2), Clement (Yr9, YrCle), and Compair (Yr8, Yr19) were detected in all countries. At least 80% of the isolates were virulent on YrA, Yr2, Yr6, Yr7, Yr8, Yr17, YrUkn, Yr31, YrExp2, Yr21, Stephens (Yr3a, YrS, YrSte), Lee (Yr7, Yr22, Yr23), and Fielder (Yr6, Yr20). Virulences to Yr1, Yr9, Yr25, Yr27, Yr28, Heines VII (Yr2, YrHVII), Paha (YrPa1, YrPa2, YrPa3), Druchamp (Yr3a, YrD, YrDru), Produra (YrPr1, YrPr2), Yamhill (Yr2, Yr4a, YrYam), Tyee (YrTye), Tres (YrTr1, YrTr2), Hyak (Yr17, YrTye), Express (YrExp1, YrExp2), Clement (Yr9, YrCle), and Compair (Yr8, Yr19) were moderately frequent (>20 to <80%). Virulence to Yr10, Yr24, Yr32, YrSP, and Moro (Yr10, YrMor) was low (≤20%). Virulence to Moro was absent in Algeria, Australia, Canada, Kenya, Russia, Spain, Turkey, and China, but 5% of the Chinese isolates were virulent to Yr10. None of the isolates from Algeria, Canada, China, Kenya, Russia, and Spain was virulent to Yr24; none of the isolates from Algeria, Australia, Canada, Nepal, Russia, and Spain was virulent to Yr32; none of the isolates from Australia, Canada, Chile, Hungary, Kenya, Kenya, Nepal, Pakistan, Russia, and Spain was virulent to YrSP; and none of the isolates from any country was virulent to Yr5 and Yr15. Although the frequencies of virulence factors were different, most of the P. striiformis f. sp. tritici isolates from these countries shared common virulence factors. The virulences and their frequencies and distributions should be useful in breeding stripe-rust-resistant wheat cultivars and understanding the pathogen migration and evolution.

Local drug delivery agents as adjuncts to endodontic and periodontal therapy.

In the treatment of intracanal and periodontal infections, the local application of antibiotics and other therapeutic agents in the root canal or in periodontal pockets may be a promising approach to achieve sustained/controlled drug release, high antimicrobial activity and low systemic side effects. The conventional method for the elimination of subgingival microbial infection includes mechanical debridement, irrigation with antimicrobial agents or surgical access. But, the effectiveness of conventional nonsurgical treatment is limited by lack of accessibility to bacteria in deeper periodontal pockets, and/or does not completely eliminate intracanal microorganisms. Surgical intervention may be beneficial but cannot be done in all cases, medically compromised cases and also in patients not willing to be subjected to surgical therapy. Development of local drug delivery systems provides an answer to all such difficulties. This comprehensive review tries to cover the detailed information about the latest advances in the various local drug delivery systems, their indications, contraindications and their advantages over systemic drug therapy.

Molecular Characterization of Fusarium Head Blight Pathogens Sampled from a Naturally Infected Disease Nursery Used for Wheat Breeding Programs in China.

Fusarium head blight (FHB) is an important disease of wheat and barley worldwide. The disease is primarily caused by members of the Fusarium graminearum species complex, consisting of at least 14 phylogenetically distinct species. To determine the population structure of the FHB pathogens in a naturally infected disease nursery located at Jianyang, Fujian province, China, 160 isolates of the F. graminearum complex were recovered from symptomatic wheat spike samples collected in two consecutive years (2008 and 2009) and characterized using species- and chemotype-specific polymerase chain reaction as well as variable number tandem repeat (VNTR) markers. All isolates analyzed were identified as F. asiaticum except for one isolate, which was identified as F. avenaceum. Among the 159 F. asiaticum isolates, 126 (79%) isolates were of the nivalenol (NIV) type while 29 (18%) isolates were of the 15-acetyl deoxynivalenol type and only 4 (3%) isolates were of the 3-acetyl deoxynivalenol type. The 10 VNTR markers revealed 124 distinct haplotypes and 76 polymorphic alleles across the whole population. The two subpopulations (FA-08 and FA-09) grouped based on the year of collection exhibited low genetic differentiation (Fst = 0.032) and high gene flow (Nm = 15.13). However, a significant genetic differentiation was found within the NIV-type isolates as revealed by the Structure software. The pairwise linkage disequilibrium tests did not support the hypothesis of random mating in the population because half (48.8%) of the locus pairs showed a linkage disequilibrium (P > 0.05). Our results suggest that FHB in this nursery was caused by a genetically homogenous and non-random mating population of F. asiaticum in 2008 and 2009, which consisted of all three trichothecene types with various levels of aggressiveness.

Phosphoinositide 3-kinase δ inhibitor suppresses interleukin-17 expression in a murine asthma model.

Phosphoinositide 3-kinases (PI3Ks) contribute to the pathogenesis of asthma by regulating the activation of inflammatory mediators, inflammatory cell recruitment and immune cell function. Recent findings have indicated that PI3Ks also regulate the expression of interleukin (IL)-17, which has been recognised as an important cytokine involved in airway inflammation. In the present study, we investigated a role of PI3Kδ in the regulation of IL-17 expression in allergic airway disease using a murine model of asthma. After ovalbumin inhalation, administration of a selective p110δ inhibitor, IC87114, significantly attenuated airway infiltration of total cells, lymphocytes, neutrophils and eosinophils, as well as airway hyperresponsiveness, and attenuated the increase in IL-17 protein and mRNA expression. Moreover, IC87114 reduced levels of IL-4, -5 and -13, expression of keratinocyte chemoattractant protein and mRNA, and nuclear factor (NF)-κB activity. In addition, a NF-κB inhibitor, BAY 11-7085 substantially reduced the increase in IL-17 protein levels. Our results also showed that inhibition of IL-17 activity with an anti-IL-17 antibody remarkably reduced airway inflammation and hyperresponsiveness. These findings suggest that inhibition of the p110δ signalling pathway suppresses IL-17 expression through regulation of NF-κB activity and, thus, has therapeutic potential in asthma.

Declaration of Helsinki, 2008: implications for stakeholders in research.

The Declaration of Helsinki (DoH) was adopted by the World Medical Association (WMA) in 1964, as a statement of ethical principles, to provide guidance to physicians and other participants in medical research involving human subjects. Having undergone several amendments, the most recent version was approved on 18 October 2008, by the WMA General Assembly at Seoul, South Korea, replacing all previous versions. This version highlights issues such as, participant safety, the need to include participants from otherwise underrepresented groups, clinical trial registration, post-study access, usage of data and human tissues, compensating participants with research-related injury, and usage of placebo. In this article, we discuss the major aspects of the 2008 version, including the impact of this version on all stakeholders in research, including, investigators, ethics committee members, sponsors, authors, editors, and reviewers.

Structural and functional abnormalities in lungs in patients with achalasia.

Dilatation and oesophageal body aperistalsis in achalasia can lead to stasis which in turn can induce repeated microaspiration. It is therefore conceivable that patients with achalasia may also have abnormalities in lungs secondary to repeated episodes of microaspiration. There is a lack of systematic study on involvement of lungs in patients with achalasia. Thirty patients with achalasia underwent pulmonary function tests (spirometry, and carbon mono-oxide diffusion capacity) and high resolution computerized tomography (HRCT) of the chest. The mean age of patients and mean duration of disease were 33.5 +/- 10.9 years and 28.1 +/- 27.3 months respectively. Regurgitation was present in 22 (73.3%) of them. Respiratory symptoms in them were dry cough in 17 (56.6%), and chest pain in 18 (60%). The oesophagus was dilated in 26 (86.6%) and 13 (43.3%) had residue in oesophagus. Sixteen (53.3%) patients had either anatomical changes as seen on HRCT or functional changes as observed on pulmonary function tests. Of those with functional abnormalities, five (16.6%) and one (3.3%) had restrictive and obstructive airways disease respectively. While evidence of tracheo-bronchial compression by dilated oesophagus was present in eight (26.6%), 10 (33.3%) patients had parenchymal lung disease [nodular opacities in five (16.6%), ground glass appearance six (20%), patchy pulmonary fibrosis five (16.6%), air trapping two (6.6%), consolidation and bronchiectasis one (3.3%) each]. There was a significant association between presence of regurgitation and dilatation of oesophagus (P = 0.032). More than half (53.3%) of patients with achalasia have structural and/or functional abnormalities in lungs.

Endoscopic ultrasound and fine needle aspiration for the diagnosis of hepatocellular carcinoma.

Liver cancer is one of the most frequent solid cancers. The major risk factor associated with the development of hepatocellular carcinoma (HCC) is cirrhosis caused by hepatitis B, hepatitis C virus or chronic alcohol consumption. The overall prognosis of patients with HCC is very poor and this is mainly due to the advanced stages of cancer at presentation and also because of underlying cirrhosis. When HCC is diagnosed at early stages, prognosis is better with five-year disease free survival of around 50% with resection, or local ablative treatments such as radio-frequency ablation or percutaneous ethanol injection, and 70-80% with liver transplantation. Therefore, systematic screening of all the high-risk patients is the key to an early diagnosis of small HCC and the use of an appropriate treatment modality. The currently available tools for the screening, surveillance and diagnosis of HCC in the presence of cirrhosis remain sub-optimal. The advancements made in the past 10 years, however, have made HCC a potentially curable disease in a highly selected group of patients. This review will briefly discuss the current guidelines for surveillance and diagnosis of HCC in high-risk subjects and then review the potential role of endoscopic ultrasound and fine needle aspiration for the diagnosis of small HCC.

Linear porokeratosis.

Linear porokeratosis is a rare variant. It can be present at birth or can develop in adult life. Lesions of linear porokeratosis are grouped and linearly arranged along the lines of Blaschko. On the extremities it affects the distal portion more than the proximal areas. On the trunk these can be zosteriform in distribution. Lesions of linear porokeratosis probably result from an abnormal clone of epidermal precursors. A 20 year old male presented with annular plaques in linear pattern following the lines of Blaschko over the left upper limb extending up to the axilla present since childhood. The lesions had atrophic centre and raised hyperkeratotic borders. The lesions were more proximal than distal. Few scattered lesions were present on left side of trunk. There was no family history of such lesions. Systemic examination of patient was normal. On histopathological examination there was hyperkeratosis and parakeratosis. A coronoid lamella was present. At the base of coronoid lamella thinned out granular layer and necrotic keratinocytes were also seen. In the dermis pigment incontinence and perivascular lymphocytic infiltrate were present. This case is being reported because of its rarity. It is an atypical presentation because the lesions were disposed more over proximal than distal area of upper limb. Linear porokeratosis is associated with an increased risk of malignant transformation.

Incidence of various causes of vaginal discharge among sexually active females in age group 20-40 years.

The present study was undertaken to know incidence of various causes of vaginal discharge in sexually active females of age group 20-40 years. One hundred sexually active females in the age group of 20-40 years, with vaginal discharge, were selected for this study at random. A detailed clinical history and a thorough examination of all the cases was done. After making the clinical diagnosis, appropriate tests for diagnosing candidiasis, trichomoniasis, gonorrhoea and bacterial vaginosis were done. The present study showed 45% incidence of bacterial vaginosis, 31% vulvovaginal candidiasis, 2% trichomoniasis, 3% gonorrhoea, 5% non-specific urogenital causes, and 14% with other causes.

Evaluation of causes of vaginal discharge in relation to pregnancy status.

The purpose of this study was to determine incidence of vaginal discharge in pregnant and non-pregnant sexually active females of age group 20-40 years presenting with the chief complaint of vaginal discharge. One hundred sexually active females in the age group of 20-40 years, with vaginal discharge, were selected for this study at random. A detailed clinical history and a thorough examination of all the cases were done. After making the clinical diagnosis, appropriate tests for diagnosing candidiasis, trichomoniasis, gonorrhoea and bacterial vaginosis were done. It was observed that out of 100 cases, 13 (13%) patients were pregnant and 87 (87%) were non-pregnant.

Giant hairy 'bathing trunk' naevus with multiple congenital melanocytic naevi.

A 23-day-old male infant had hairy 'bathing trunk' naevus covering, neck and upper trunk along with multiple congenital melanocytic naevi scattered all over the body.

Mammalian-cell-produced neurturin (NTN) is more potent than purified Escherichia coli-produced NTN.

Neurturin (NTN) is a recently identified homologue of glial-cell-line-derived neurotrophic factor. Both factors promote the survival of dopaminergic (DA) neurons. We investigated the biological activity of mammalian-cell-produced NTN versus purified Escherichia coli-produced NTN. Baby hamster kidney cells were engineered to stably secrete mature human NTN. Mammalian-cell-derived NTN enhanced the activity of embryonic DA neurons in vitro, with greater potency (maximum effect achieved in the picogram range) than purified E. coli-produced NTN. Cell-based delivery of NTN (less than 10 ng/day) was also shown to be biologically active in vivo. These results suggest that mammalian-cell-derived NTN, synthesized de novo and delivered in small quantities to the parenchyma at the target site, may be as active as much larger quantities of purified, E. coli-produced NTN, delivered by other means.

Management of neurogenic bladder dysfunction with incontinent ileovesicostomy.

OBJECTIVES: Incontinent ileovesicostomy is an alternative form of urinary management applied to patients with neurogenic vesical dysfunction who are either unable or unwilling to perform clean intermittent self-catheterization or assisted catheterization. We review our operative results, urodynamic data, and complications observed in patients who underwent creation of incontinent ileovesicostomy at our institution. METHODS: Thirteen patients (mean age 43.2 years) with neurogenic bladder dysfunction underwent an incontinent ileovesicostomy between 1994 and 1998. The etiologies of the neurogenic bladder dysfunction were spinal cord injury in 8 patients, multiple sclerosis in 4 patients, and tuberculous meningitis in 1 patient. The preoperative data, surgical records, urodynamic findings, and postoperative complications were assessed. RESULTS: All patients experienced complications of their pretreatment bladder management. The mean operating room time was 242 minutes (range 170 to 395), including 14 additional procedures in 1 1 patients. The mean estimated blood loss was 403.8 mL (range 50 to 2000). No patient required blood transfusion. There were no intraoperative complications. Only 1 patient required reoperation for stomal revision. One patient had a ureteral stone 2 years after surgery; 1 patient has continued to have urinary tract infections despite a negative workup. The mean follow-up was 23 months (range 6 to 57). The mean bladder leak point pressure through the stoma was 8.2 cm H2O. CONCLUSIONS: The incontinent ileovesicostomy is a useful technique in the treatment of patients with neurogenic bladder unable to perform clean intermittent catheterization. It provides patients with a low-pressure urinary conduit that empties readily without an in dwelling catheter.

The kinetics and shear threshold of transient and rolling interactions of L-selectin with its ligand on leukocytes.

The kinetics of rolling and transient adhesions through selectins may depend on the kinetics and mechanical properties of the selectin:ligand bond, as well as on cellular properties including receptor-anchoring to the cell membrane and cytoskeleton. Kinetics are known to depend on the selectin and may also be ligand dependent. Here, we study the kinetics of transient and rolling interactions of leukocytes with L-selectin immobilized on a substrate. Remarkably, all properties examined are similar to those seen when the sidedness is opposite, i.e., when the L-selectin ligand is on the substrate and when the ligand is isolated from HEV rather than present on leukocytes. The similar properties include rolling velocity, a threshold shear stress above 0.4 dyn/cm2 required to support rolling, a k degreesoff of 7.0 to 6.8 s-1 for the L-selectin tether bond, and a mechanical bond length of 0.24 to 0.20 A. Our results argue against a model in which L-selectin shedding mediates rolling. Furthermore, the fast and force-resistant kinetic properties suggest that L-selectin is specialized dynamically for tethering leukocytes to vessel walls and adherent leukocytes.

Carbohydrate specificity and quaternary association in basic winged bean lectin: X-ray analysis of the lectin at 2.5 A resolution.

The structure of basic Winged Bean Agglutinin (WBAI) with two dimeric molecules complexed with methyl-alpha-D-galactopyranoside in the asymmetric unit, has been determined by the molecular replacement method and refined with 2.5 A X-ray intensity data. The polypeptide chain of each monomer has the characteristic legume lectin tertiary fold. The structure clearly defines the lectin-carbohydrate interactions. It reveals how the unusually long variable loop in the binding region endows the lectin with its characteristic sugar specificity. The lectin forms non-canonical dimers of the type found in Erythrina corallodendron lectin (EcorL) even though glycosylation, unlike in EcorL, does not prevent the formation of canonical dimers. The structure thus further demonstrates that the mode of dimerisation of legume lectins is not necessarily determined by the covalently bound carbohydrate but is governed by features intrinsic to the protein. The present analysis and our earlier work on peanut lectin (PNA), show that legume lectins are a family of proteins in which small alterations in essentially the same tertiary structure lead to wide variations in quaternary association. A relationship among the non-canonical modes of dimeric association in legume lectins is presented.

Modifying the mechanical property and shear threshold of L-selectin adhesion independently of equilibrium properties.

Interactions between adhesion molecules on two different cells differ from interactions between receptors and soluble ligands in that the adhesion molecule interaction (bond) is often subjected to force. It is widely assumed by cell biologists that the 'strength' of a bond is a simple function of the affinity of one adhesion molecule for the other, whereas biophysicists suggest that bonds have 'mechanical properties' that affect their strength. Mechanical properties are a function of the shape of the energy landscape related to bond formation and dissociation, whereas affinity is related only to the net energy change. Mechanical properties determine the amount by which the kinetics and affinity of bonds are altered by applied force. To date there has been no experimental manipulation of an adhesion molecule that has been shown to affect mechanical properties. L-selectin is an adhesion molecule that mediates lymphocyte binding to, and rolling on, high endothelial venules; these are prerequisites for the emigration of lymphocytes from the bloodstream into lymph nodes. Here we report a selective and reversible chemical modification of a mucin-like ligand that alters the mechanical properties of its bond with L-selectin. The effect of force on the rate of bond dissociation, that is, on a mechanical property, is altered, whereas there is little or no effect of the modification on the rate of bond dissociation in the absence of force. Moreover, the puzzling requirement for hydrodynamic shear flow above a threshold level for L-selectin interactions is dramatically altered.