Crosstalk between NRF2 and HIPK2 shapes cytoprotective responses.

Homeodomain interacting protein kinase-2 (HIPK2) is a member of the HIPK family of stress-responsive kinases that modulates cell growth, apoptosis, proliferation and development. HIPK2 has several well-characterised tumour suppressor roles, but recent studies suggest it can also contribute to tumour progression, although the underlying mechanisms are unknown. Herein, we have identified novel crosstalk between HIPK2 and the cytoprotective transcription factor NRF2. We show that HIPK2 is a direct transcriptional target of NRF2, identifying a functional NRF2 binding site in the HIPK2 gene locus and demonstrating for the first time a transcriptional mode of regulation for this kinase. In addition, HIPK2 is required for robust NRF2 responsiveness in cells and in vivo. By using both gain-of-function and loss-of-function approaches, we demonstrate that HIPK2 can elicit a cytoprotective response in cancer cells via NRF2. Our results have uncovered a new downstream effector of HIPK2, NRF2, which is frequently activated in human tumours correlating with chemoresistance and poor prognosis. Furthermore, our results suggest that modulation of either HIPK2 levels or activity could be exploited to impair NRF2-mediated signalling in cancer cells, and thus sensitise them to chemotherapeutic drugs.

Majocchi Granuloma of the Breast: A Rare Clinical Entity / Granuloma de Majocchi: Una rara entidad

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KLF6 contributes to myeloid cell plasticity in the pathogenesis of intestinal inflammation.

Inflammatory bowel disease (IBD) is associated with dysregulated macrophage responses, such that quiescent macrophages acquire a pro-inflammatory activation state and contribute to chronic intestinal inflammation. The transcriptional events governing macrophage activation and gene expression in the context of chronic inflammation such as IBD remain incompletely understood. Here, we identify Kruppel-like transcription factor-6 (KLF6) as a critical regulator of pathogenic myeloid cell activation in human and experimental IBD. We found that KLF6 was significantly upregulated in myeloid cells and intestinal tissue from IBD patients and experimental models of IBD, particularly in actively inflamed regions of the colon. Using complementary gain- and loss-of-function studies, we observed that KLF6 promotes pro-inflammatory gene expression through enhancement of nuclear factor κB (NFκB) signaling, while simultaneously suppressing anti-inflammatory gene expression through repression of signal transducer and activator of transcription 3 (STAT3) signaling. To study the in vivo role of myeloid KLF6, we treated myeloid-specific KLF6-knockout mice (Mac-KLF6-KO) with dextran sulfate sodium (DSS) and found that Mac-KLF6-KO mice were protected against chemically-induced colitis; this highlights the central role of myeloid KLF6 in promoting intestinal inflammation. Collectively, our results point to a novel gene regulatory program underlying pathogenic, pro-inflammatory macrophage activation in the setting of chronic intestinal inflammation.

Safe Tummy Tuck: Anatomy and Strategy to Avoid Injury to the Lateral Femoral Cutaneous Nerve During Abdominoplasty.

BACKGROUND: Abdominoplasty is one of the most common aesthetic procedures performed in the United States. While poor contour and unsatisfactory cosmetic result have been recognized, neuropathic pain from lateral femoral cutaneous nerve injury has been poorly described. We aim to improve outcomes by using an anatomical study to develop a strategy to avoid injury to the lateral femoral cutaneous nerve in abdominoplasty. METHODS: Twenty-three fresh cadaver abdomens were dissected to evaluate the course of the lateral femoral cutaneous nerve, using 2.5× loupe magnification. Measurements were taken from the nerve to the anterior superior iliac spine and from the pubic symphysis to the lateral femoral cutaneous nerve. Recordings of the relationship of the nerve to the inguinal ligament and depth at scarpa's fascia were also made. Statistical analysis was performed to find average distances with a standard deviation. RESULTS: On average, the distance from the lateral femoral cutaneous nerve to the anterior superior iliac spine was 3.62 (SD = 1.32) cm and 13.58 (SD = 2.41) cm from the pubic symphysis in line with the inguinal ligament. The lateral femoral cutaneous nerve was found at the inguinal ligament 80% of the time and 20% of the time superior to the ligament and always deep to scarpa's fascia. CONCLUSION: Abdominoplasty carries a high patient and surgeon satisfaction rate. The plastic surgeon is continuously challenged to identify ways to improve outcomes, efficiency, and morbidity. Minimal and careful dissection in the area around 4 cm of the anterior superior iliac spine in addition to preserving scarpa's fascia near the inguinal ligament may serve as key strategies to avoiding lateral femoral cutaneous nerve injury.

Idiopathic Acquired Leukonychia Totalis of the Fingernails in a Child Treated Successfully with Zinc and Amino Acid Supplementation / Leuconiquia totalis idiopática, adquirida de las unas de las manos tratada con éxito mediante suplementos de zinc y aminoácidos

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Nrf2 is controlled by two distinct ß-TrCP recognition motifs in its Neh6 domain, one of which can be modulated by GSK-3 activity.

Identification of regulatable mechanisms by which transcription factor NF-E2 p45-related factor 2 (Nrf2) is repressed will allow strategies to be designed that counter drug resistance associated with its upregulation in tumours that harbour somatic mutations in Kelch-like ECH-associated protein-1 (Keap1), a gene that encodes a joint adaptor and substrate receptor for the Cul3-Rbx1/Roc1 ubiquitin ligase. We now show that mouse Nrf2 contains two binding sites for ß-transducin repeat-containing protein (ß-TrCP), which acts as a substrate receptor for the Skp1-Cul1-Rbx1/Roc1 ubiquitin ligase complex. Deletion of either binding site in Nrf2 decreased ß-TrCP-mediated ubiquitylation of the transcription factor. The ability of one of the two ß-TrCP-binding sites to serve as a degron could be both increased and decreased by manipulation of glycogen synthase kinase-3 (GSK-3) activity. Biotinylated-peptide pull-down assays identified DSGIS(338) and DSAPGS(378) as the two ß-TrCP-binding motifs in Nrf2. Significantly, our pull-down assays indicated that ß-TrCP binds a phosphorylated version of DSGIS more tightly than its non-phosphorylated counterpart, whereas this was not the case for DSAPGS. These data suggest that DSGIS, but not DSAPGS, contains a functional GSK-3 phosphorylation site. Activation of GSK-3 in Keap1-null mouse embryonic fibroblasts (MEFs), or in human lung A549 cells that contain mutant Keap1, by inhibition of the phosphoinositide 3-kinase (PI3K)-protein kinase B (PKB)/Akt pathway markedly reduced endogenous Nrf2 protein and decreased to 10-50% of normal the levels of mRNA for prototypic Nrf2-regulated enzymes, including the glutamate-cysteine ligase catalytic and modifier subunits, glutathione S-transferases Alpha-1 and Mu-1, haem oxygenase-1 and NAD(P)H:quinone oxidoreductase-1. Pre-treatment of Keap1(-/-) MEFs or A549 cells with the LY294002 PI3K inhibitor or the MK-2206 PKB/Akt inhibitor increased their sensitivity to acrolein, chlorambucil and cisplatin between 1.9-fold and 3.1-fold, and this was substantially attenuated by simultaneous pre-treatment with the GSK-3 inhibitor CT99021.

Gingival crevicular fluid and plasma levels of neuropeptide Substance-P in periodontal health, disease and after nonsurgical therapy.

BACKGROUND AND OBJECTIVE: The level of Substance-P in gingival crevicular fluid has been found to correlate with clinical measures of periodontal disease. The present study was designed to assess the relationship between clinical parameters and levels of Substance-P in the gingival crevicular fluid from inflamed gingiva, periodontitis sites and after treatment of periodontitis sites, and to correlate them to the Substance-P levels of plasma. MATERIAL AND METHODS: Thirty, age- and gender-matched subjects were divided into three groups (healthy, gingivitis and chronic periodontitis) based on modified gingival index scores and clinical attachment loss. A fourth group consisted of 10 subjects from the periodontitis group, 6-8 wk after initial therapy. Plasma and gingival crevicular fluid samples were collected and quantified for Substance-P using an enzyme immunoassay. RESULTS: The mean concentration of Substance-P, both in gingival crevicular fluid and plasma, was observed to be highest in the periodontitis group (45.13 pg/mL in gingival crevicular fluid and 67.8 pg/mL in plasma) and lowest in the healthy group (6.07 pg/mL in gingival crevicular fluid and below the detection level in plasma). The mean Substance-P concentration in the gingivitis group (11.42 pg/mL in gingival crevicular fluid and 38.8 pg/mL in plasma) and in the after-treatment group (7.58 pg/mL in gingival crevicular fluid and 39.7 pg/mL in plasma) lay between the highest and lowest values. In all groups the gingival crevicular fluid levels showed a statistically significant positive correlation with that of plasma and clinical attachment loss. CONCLUSION: Substance-P levels were highest in the gingival crevicular fluid from sites with periodontal destruction; however, periodontal treatment resulted in the reduction of Substance-P levels. Gingival crevicular fluid and plasma Substance-P levels showed a positive correlation in all of the groups.

Detection of adeno-associated virus type 2 genome in cervical carcinoma.

Adeno-associated virus (AAV) can impair the replication of other viruses. Adeno-associated virus seroprevalences have been reported to be lower among women with cervical cancer. In-vitro, AAV can interfere with the production of human papillomavirus virions. Adeno-associated virus-2 DNA has also been detected in cervical cancer tissue, although not consistently. To evaluate the role of AAV infection in relation to invasive cervical cancer, we performed a nested case-control study within a retrospectively followed population-based cohort. A total of 104 women who developed invasive cervical cancer on average 5.6 years of follow-up (range: 0.5 months-26.2 years) and 104 matched control-women who did not develop cervical cancer during the same follow-up time were tested for AAV and human papillomavirus by polymerase chain reaction. At baseline, two (2%) case-women and three (3%) control-women were positive for AAV-2 DNA. At the time of cancer diagnosis, 12 (12%) case-women and 3 (3%) matched control-women were positive for AAV-2 DNA. Persisting AAV infection was not evident. In conclusion, AAV-2 DNA was present in a low proportion of cervical cancers and we found no evidence that the presence of AAV in cervical smears of healthy women would be associated with reduced risk of cervical cancer.

Reducing the pain of open groin hernia repair.

Pain after open mesh repair of groin hernia has a multifactorial etiology. Suturing technique for anchoring the mesh is important. Sutures placed too tightly, a common practice, are often the site of pain and point tenderness. These "pain points" are often precisely felt by patients and may vary in their intensity and duration. We believe that this type of suturing-technique-related pain can be significantly reduced by an "air-knotting" technique described below. The mesh was anchored with sutures tied in a subtle air-knot. In the event of accidentally incorporating a nerve in the knot, an air knot is less likely to cause the distressing symptoms of entrapment neuralgia. All knots are tied above the mesh and not across the edge of the mesh. Using this technique, we believe a significant reduction in the sharp, well-localized point pain can be achieved.

Parakeratosis pustulosa--a distinct but less familiar disease.

Parakeratosis pustulosa (PP) is a distinct but less commonly known skin disease, which is frequently seen, in young girls. We describe the clinical and histological features of PP in a 7 month old female baby. Further, it is stressed that unless carefully looked for, this entity may be easily misdiagnosed as chronic paronychia, acrodermatitis of Hallopeau, pustular psoriasis, atopic dermatitis, tinea pedis or dry fissured eczematoid dermatitis and mistreated subsequently.

Rising quinolone resistance in Neisseria gonorrhoeae isolates from New Delhi.

BACKGROUND & OBJECTIVES: Treatment for gonorrhoea with fluoroquinolones is recommended. However, reduced susceptibility and treatment failure with fluoroquinolones has recently been reported. We undertook to study the antibiotic susceptibility pattern and the incidence of quinolone resistance in 36 consecutive isolates of Neisseria gonorrhoeae from April to November 2000. METHOD: Antibiotic susceptibility testing was performed by the Kirby Bauer disc diffusion technique and minimum inhibitory concentration (MIC) of ciprofloxacin was determined by the agar dilution method. Penicillinase producing N. gonorrhoeae (PPNG) were identified by using the nitrocefin disc method. RESULTS: Thirty six strains of N. gonorrhoeae obtained from 44 consecutive male patients (81.9%) were studied. By the disc diffusion method, only 3 (8.3%) of these isolates were found to be sensitive to ciprofloxacin. All isolates were sensitive to ceftriaxone while 23 (63.9%) were sensitive to tetracycline and 12 (33.3%) to penicillin. Four (11.1%) of the N. gonorrhoeae isolates were PPNG. Twenty seven (75%) isolates were found to be resistant to ciprofloxacin by MIC determination. INTERPRETATION & CONCLUSION: Incidence of ciprofloxacin resistance amongst N. gonorrhoeae isolates is on the rise in New Delhi. Periodic monitoring of antimicrobial susceptibility pattern of N. gonorrhoeae to antimicrobials other than quinolones is essential to prevent treatment failure in patients with gonorrhoea.

High incidence of treatment failure of Neisseria gonorrhoeae isolates to ciprofloxacin in male gonococcal urethritis in Delhi.

Several treatment failures and widespread antimicrobial resistance to ciprofloxacin have been documented, subsequent to its initial recommendation in 1989 as a single dose alternative therapy for gonorrhoea. Still, it continues to be part of various treatment schedules in National STD control guidelines including India. This prompted us to study the current status of this drug in the treatment of gonorrhoea. Thirty-five male patients with gonococcal urethritis were included in the study. The susceptibility to penicillin, tetracycline, ciprofloxacin and ceftriaxone was determined by Kirby-Bauer disc diffusion method and minimum inhibitory concentration (MIC) of ciprofloxacin by agar plate dilution method. The clinical and bacteriological response was assessed on day 5 after treatment with single dose ciprofloxacin, 500 mg. The sensitivity pattern of Neisseria gonorrhoeae was observed to be: ceftriaxone 100%, azithromycin 100%, tetracycline 65.7%, penicillin 40% and ciprofloxacin 5.7% by disc diffusion method. The MIC for ciprofloxacin was below 0.06 microg/mL (sensitive) in one (2.5%) isolate only. On the fifth day a large number of treatment failures (88.5%) were seen with ciprofloxacin while none was noted one week after re-treatment with ceftriaxone. The location of endemic quinolone-resistant N. gonorrhoeae (QRNG) in New Delhi has increased alarmingly, resulting in an extremely high proportion of therapeutic failures, and thus requiring appropriate alterations in the presently recommended treatment regimens.

The mechanism of a bacterial plasminogen activator intermediate between streptokinase and staphylokinase.

The therapeutic properties of plasminogen activators are dictated by their mechanism of action. Unlike staphylokinase, a single domain protein, streptokinase, a 3-domain (alpha, beta, and gamma) molecule, nonproteolytically activates human (h)-plasminogen and protects plasmin from inactivation by alpha(2)-antiplasmin. Because a streptokinase-like mechanism was hypothesized to require the streptokinase gamma-domain, we examined the mechanism of action of a novel two-domain (alpha,beta) Streptococcus uberis plasminogen activator (SUPA). Under conditions that quench trace plasmin, SUPA nonproteolytically generated an active site in bovine (b)-plasminogen. SUPA also competitively inhibited the inactivation of plasmin by alpha(2)-antiplasmin. Still, the lag phase in active site generation and plasminogen activation by SUPA was at least 5-fold longer than that of streptokinase. Recombinant streptokinase gamma-domain bound to the b-plasminogen.SUPA complex and significantly reduced these lag phases. The SUPA-b.plasmin complex activated b-plasminogen with kinetic parameters comparable to those of streptokinase for h-plasminogen. The SUPA-b.plasmin complex also activated h-plasminogen but with a lower k(cat) (25-fold) and k(cat)/K(m) (7.9-fold) than SK. We conclude that a gamma-domain is not required for a streptokinase-like activation of b-plasminogen. However, the streptokinase gamma-domain enhances the rates of active site formation in b-plasminogen and this enhancing effect may be required for efficient activation of plasminogen from other species.