Search

Tubulointerstitial fibrosis is a common and diagnostic hallmark of a spectrum of chronic renal disorders. While the etiology varies as to the causative nature of the underlying pathology, persistent TGF-β1 signaling drives the relentless progression of renal fibrotic disease. TGF-β1 orchestrates the multifaceted program of kidney fibrogenesis involving proximal tubular dysfunction, failed epithelial recovery or re-differentiation, capillary collapse and subsequent interstitial fibrosis eventually leading to chronic and ultimately end-stage disease. An increasing complement of non-canonical elements function as co-factors in TGF-β1 signaling. p53 is a particularly prominent transcriptional co-regulator of several TGF-β1 fibrotic-response genes by complexing with TGF-β1 receptor-activated SMADs. This cooperative p53/TGF-β1 genomic cluster includes genes involved in cellular proliferative control, survival, apoptosis, senescence, and ECM remodeling. While the molecular basis for this co-dependency remains to be determined, a subset of TGF-β1-regulated genes possess both p53- and SMAD-binding motifs. Increases in p53 expression and phosphorylation, moreover, are evident in various forms of renal injury as well as kidney allograft rejection. Targeted reduction of p53 levels by pharmacologic and genetic approaches attenuates expression of the involved genes and mitigates the fibrotic response confirming a key role for p53 in renal disorders. This review focuses on mechanisms underlying TGF-β1-induced renal fibrosis largely in the context of ureteral obstruction, which mimics the pathophysiology of pediatric unilateral ureteropelvic junction obstruction, and the role of p53 as a transcriptional regulator within the TGF-β1 repertoire of fibrosis-promoting genes.

Chronic kidney disease affects >15% of the U.S. population and >850 million individuals worldwide. Fibrosis is the common outcome of many chronic renal disorders and, although the etiology varies (i.e., diabetes, hypertension, ischemia, acute injury, and urologic obstructive disorders), persistently elevated renal TGF-β1 levels result in the relentless progression of fibrotic disease. TGF-β1 orchestrates the multifaceted program of renal fibrogenesis involving proximal tubular dysfunction, failed epithelial recovery and redifferentiation, and subsequent tubulointerstitial fibrosis, eventually leading to chronic renal disease. Recent findings implicate p53 as a cofactor in the TGF-β1–induced signaling pathway and a transcriptional coregulator of several TGF-β1 profibrotic response genes by complexing with receptor-activated SMADs, which are homologous to the small worms (SMA) and Drosophilia mothers against decapentaplegic (MAD) gene families. The cooperative p53–TGF-β1 genomic cluster includes genes involved in cell growth control and extracellular matrix remodeling [e.g., plasminogen activator inhibitor-1 (PAI-1; serine protease inhibitor, clade E, member 1), connective tissue growth factor, and collagen I]. Although the molecular basis for this codependency is unclear, many TGF-β1–responsive genes possess p53 binding motifs. p53 up-regulation and increased p53 phosphorylation; moreover, they are evident in nephrotoxin- and ischemia/reperfusion-induced injury, diabetic nephropathy, ureteral obstructive disease, and kidney allograft rejection. Pharmacologic and genetic approaches that target p53 attenuate expression of the involved genes and mitigate the fibrotic response, confirming a key role for p53 in renal disorders. This review focuses on mechanisms whereby p53 functions as a transcriptional regulator within the TGF-β1 cluster with an emphasis on the potent fibrosis-promoting PAI-1 gene.—Higgins, C. E., Tang, J., Mian, B. M., Higgins, S. P., Gifford, C. C., Conti, D. J., Meldrum, K. K., Samarakoon, R., Higgins, P. J. TGF-β1–p53 cooperativity regulates a profibrotic genomic program in the kidney: molecular mechanisms and clinical implications.

Context: Taste and smell abnormalities (TSA) occur throughout the cancer trajectory regardless of cancer primary site and contribute to cancer-associated malnutrition. TSA etiology is poorly understood. Tumor-related inflammation is a possible cause. Objective: This study examined the prevalence, characteristics, and severity of TSA in advanced cancer and explored the relationship between TSA and nutritional status. No previous study combined subjective and objective measures for both taste and smell assessment in this population. Method: Consecutive advanced cancer hospice patients were recruited. A modified version of the “Taste and Smell Survey” assessed subjective TSA. Validated taste strips and “Sniffin’ Sticks” were the objective measures. The abridged patient-generated subjective global assessment evaluated nutritional status. Results: A 93% prevalence of TSA in 30 patients with advanced cancer was identified. When subjective and objective evaluations were combined, 28 had taste abnormalities, 24 smell abnormalities, and 24 both. Taste changes included “persistent bad taste” (n = 18) and changes in how basic tastes were perceived. Half reported smell was not “as strong” as prediagnosis, while more than half (n = 16) had an objective smell abnormality. Most (97%) were at risk of malnutrition. Fatigue, dry mouth, early satiety, and anorexia were common nutrition-impact symptoms. No statistically significant relationship was found between TSA and malnutrition scores. Conclusions: TSA were highly prevalent. Subjective taste and smell changes did not always accord with objective TSA, suggesting both assessments are valuable. TSA characteristics varied, and particular foods tasted and smelled different and were not enjoyed as before. TSA are common, high-impact problems in advanced cancer.

Background: Systemic anti-cancer treatment (SACT) can improve symptoms and survival in patients with incurable cancer but there may be harmful consequences. Information regarding the use of SACT at the end-of-life and its impact on patients has not been described in Ireland. Aims: The study aimed to quantify and describe the use of SACT at end-of-life. The primary outcome of interest was the number of patients who received treatment in the last 12, 4 and 2 weeks of life. Secondary outcomes included the frequency of admissions and procedures, location of death, and timing of specialist palliative care (SPC) referral. Methods: Retrospective review. Fisher exact testing was used for analyses. Patients were included if they died between January 2015 and July 2017 and received at least 1 dose of treatment for a solid tumor malignancy. Results: Five hundred and eighty two patients were included. Three hundred and thirty eight (58%), 128 (22%) and 36 (6%) received treatment in the last 12, 4 and 2 weeks of life respectively. Patients who received chemotherapy in the last 12 weeks of life were more likely to be admitted to hospital, undergo a procedure, and die in hospital than those who did not (P < 0.001 for all). Median time of SPC referral before death was shorter in those patients who received chemotherapy than those who did not (61 v129 days, p = 0.0001). Conclusion: Patients who received chemotherapy had a higher likelihood of hospital admission, invasive procedure, and in-hospital death. They were less likely to have been referred early to SPC services.

Fibrotic disorders of the renal, pulmonary, cardiac, and hepatic systems are associated with significant morbidity and mortality. Effective therapies to prevent or curtail the advancement to organ failure, however, remain a major clinical challenge. Chronic kidney disease, in particular, constitutes an increasing medical burden affecting >15% of the US population. Regardless of etiology (diabetes, hypertension, ischemia, acute injury, urologic obstruction), persistently elevated TGF-β1 levels are causatively linked to the activation of profibrotic signaling networks and disease progression. TGF-β1 is the principal driver of renal fibrogenesis, a dynamic pathophysiologic process that involves tubular cell injury/apoptosis, infiltration of inflammatory cells, interstitial fibroblast activation and excess extracellular matrix synthesis/deposition leading to impaired kidney function and, eventually, to chronic and endstage disease. TGF-β1 activates the ALK5 type I receptor (which phosphorylates SMAD2/3) as well as non-canonical (e.g., src kinase, EGFR, JAK/STAT, p53) pathways that collectively drive the fibrotic genomic program. Such multiplexed signal integration has pathophysiological consequences. Indeed, TGF-β1 stimulates the activation and assembly of p53-SMAD3 complexes required for transcription of the renal fibrotic genes plasminogen activator inhibitor-1, connective tissue growth factor and TGF-β1. Tubular-specific ablation of p53 in mice or pifithrin-α-mediated inactivation of p53 prevents epithelial G(2)/M arrest, reduces the secretion of fibrotic effectors and attenuates the transition from acute to chronic renal injury, further supporting the involvement of p53 in disease progression. This review focuses on the pathophysiology of TGF- β1-initiated renal fibrogenesis and the role of p53 as a regulator of profibrotic gene expression.

Recreational drug use (RDU) has been reported to be disproportionately higher in men who have sex with men (MSM) when compared to their heterosexual counterparts. To identify RDU, links to risky sexual practices and infections for MSM attending three sexual health clinics across Manchester, United Kingdom, a retrospective case note review was conducted using a random powered sample of service users attending three sites during 2014. Three hundred and fifty-seven case notes were reviewed across three sites. Eighteen per cent of service users reported any type of RDU. Use of at least one of the three drugs associated with chemsex (crystal methamphetamine, mephedrone, gamma hydroxybutyrate/gamma butyrolactone) was reported by 3.6%. A statistically significant difference was identified between non-drug users and any-drug users reporting: group sex (odds ratio [OR] 5.88, p = 0.013), condomless receptive anal intercourse (CRAI) (OR 2.77, p = 0.003) and condomless oral intercourse (OR 2.52, p = 0.016). A statistically significant difference was identified between chemsex-related drug user and non-drug user groups reporting: group sex (OR 13.05, p = 0.023), CRAI (OR 3.69, p = 0.029) and condomless insertive anal intercourse (OR 1.27, p = 0.039). There was also a statistically higher incidence of gonorrhoea infection in chemsex-related drug use compared with those not using drugs (p = 0.002, OR 6.88). This study identifies that substance use is common in MSM attending sexual health clinics in Manchester. High-risk sexual practices and certain sexually transmitted infections are more common in MSM reporting RDU.

To determine the prevalence of newly diagnosed hepatitis C virus (HCV) and associated risk behaviours among men who have sex with men (MSM) in Manchester.A survey among MSM attending four genitourinary medicine clinics in Manchester was carried out over 9 months in 2013. Participants were asked about recent sexual behaviour, recreational drug use and HIV status. All men were offered an HCV test.Overall, 2030 MSM completed a questionnaire and accepted an HCV test. Of whom, 0.9% (18) were newly diagnosed with HCV, including 1.8% (13/735) of HIV-positive MSM, 0.7% (3/440) of MSM of unknown HIV status and 0.2% (2/855) of HIV-negative MSM. HCV positivity was significantly associated with HIV status (p0.001). When compared with HIV-negative MSM, HIV-positive MSM had higher rates of sharing snorting drug equipment, injecting drugs/'slamming' and using recreational drugs (all p0.05) but lower rates of five or more sexual partners and insertive unprotected anal intercourse (p0.05). MSM newly diagnosed with HCV had significantly higher prevalence of unprotected sex, sex with someone HCV positive, fisting, group sex, ever injecting drugs/'slamming' and recreational drug use (p0.002).In this survey, HIV-positive MSM had significantly different drug use behaviour which may explain the higher HCV burden. However, HCV was also associated with HIV-negative MSM engaging in high-risk sexual practices. All MSM attending sexual health clinics must have a risk assessment and HCV screening should be offered based on the risk. Further studies are warranted to explore the interplay between HCV and HIV risk associated with drug use versus sexual practices.

These guidelines are an update for 2015 of the 2008 UK guidelines for the management of syphilis. The writing group have piloted the new BASHH guideline methodology, notably using the GRADE system for assessing evidence and making recommendations. We have made significant changes to the recommendations for screening infants born to mothers with positive syphilis serology and to facilitate accurate and timely communication between the teams caring for mother and baby we have developed a birth plan. Procaine penicillin is now an alternative, not preferred treatment, for all stages of syphilis except neurosyphilis, but the length of treatment for this is shortened. Other changes are summarised at the start of the guideline.

Plasminogen activator inhibitor-1 (PAI-1), the primary inhibitor of urokinase-and tissue-type plasminogen activators (uPA and tPA), is an injury-response gene implicated in the development of tissue fibrosis and cardiovascular disease. PAI-1 mRNA and protein levels were elevated in the balloon catheter-injured carotid and in the vascular smooth muscle cell (VSMC)-enriched neointima of ligated arteries. PAI-1/uPA complex formation and PAI-1 antiproteolytic activity can be inhibited, via proteolytic cleavage, by the small molecule antagonist tiplaxtinin which effectively increased the VSMC apoptotic index in vitro and attenuated carotid artery neointimal formation in vivo. In contrast to the active full-length serine protease inhibitor (SERPIN), elastase-cleaved PAI-1 (similar to tiplaxtinin) also promoted VSMC apoptosis in vitro and similarly reduced neointimal formation in vivo. The mechanism through which cleaved PAI-1 (CL-PAI-1) stimulates apoptosis appears to involve the TNF-α family member TWEAK (TNF-α weak inducer of apoptosis) and it’s cognate receptor, fibroblast growth factor (FGF)-inducible 14 (FN14). CL-PAI-1 sensitizes cells to TWEAK-stimulated apoptosis while full-length PAI-1 did not, presumably due to its ability to down-regulate FN14 in a low density lipoprotein receptor-related protein 1 (LRP1)-dependent mechanism. It appears that prolonged exposure of VSMCs to CL-PAI-1 induces apoptosis by augmenting TWEAK/FN14 pro-apoptotic signaling. This work identifies a critical, anti-stenotic, role for a functionally-inactive (at least with regard to its protease inhibitory function) cleaved SERPIN. Therapies that promote the conversion of full-length to cleaved PAI-1 may have translational implications.

Significance: A highly interactive serine protease/plasmin/matrix metalloproteinase axis regulates stromal remodeling in the wound microenvironment. Current findings highlight the importance of stringent controls on protease expression and their topographic activities in cell proliferation, migration, and tissue homeostasis. Targeting elements in this cascading network may lead to novel therapeutic approaches for fibrotic diseases and chronic wounds. Recent Advances: Matrix-active proteases and their inhibitors orchestrate wound site tissue remodeling, cell migration, and proliferation. Indeed, the serine proteases urokinase plasminogen activator and tissue-type plasminogen activator (uPA/tPA) and their major phsyiological inhibitor, plasminogen activator inhibitor-1 (PAI-1; serine protease inhibitor clade E member 1 [SERPINE1]), are upregulated in several cell types during injury repair. Coordinate expression of proteolytic enzymes and their inhibitors in the wound bed provides a mechanism for fine control of focal proteolysis to facilitate matrix restructuring and cell motility in complex environments. Critical Issues: Cosmetic and tissue functional consequences of wound repair anomalies affect the quality of life of millions of patients in the United States alone. The development of novel therapeutics to manage individuals most affected by healing anomalies will likely derive from the identification of critical, translationally accessible, control elements in the wound site microenvironment. Future Directions: Activation of the PAI-1 gene early after wounding, its prominence in the repair transcriptome and varied functions suggest a key role in the global cutaneous injury response program. Targeting PAI-1 gene expression and/or PAI-1 function with molecular genetic constructs, neutralizing antibodies or small molecule inhibitors may provide a novel, therapeutically relevant approach, to manage the pathophysiology of wound healing disorders associated with deficient or excessive PAI-1 levels.

ObjectiveTo determine the prevalence of asymptomatic neurosyphilis (ANS) in HIV-positive individuals after treatment of early syphilis with single-dose benzathine penicillin G (BPG) or oral antibiotic alternatives.MethodsPatients at high risk of neurosyphilis (defined by serum rapid plasma reagin (RPR) titre ≥1:32 and/or peripheral blood CD4 lymphocyte count ≤350/μL) underwent lumbar puncture (LP) at a median time of 8.2 months post treatment. ANS was diagnosed by a reactive cerebrospinal fluid (CSF) RPR test or CSF white blood cells (WBC) >20/μL plus a reactive CSF Treponema pallidum particle agglutination (TPPA) ≥1:640.ResultsOf 133 eligible patients, all were men who have sex with men. Of these, 64 consented to LP. Full CSF results were available for 59 patients. Inclusion criteria were serum RPR (21/59), CD4 count (22/59) and combined RPR and CD4 (16/59). The LP patients were white British (82%), median age 40. Syphilis stages were primary (17%) secondary (43%) and early latent (41%). Syphilis was treated with BPG (47/59), doxycycline 100 mg two times per day for 14 days (10/59) and for 21 days (1/59). Azithromycin 500 mg one time per day for 10 days was given to 1/59. At the time of LP, 100% of patients had achieved serological cure, and 66% were taking antiretroviral treatment. Only 1/59 was diagnosed with ANS. The CSF showed: RPR non-reactive (59/59); TPPA non-reactive in 54/59; WBC ≤5/μL in 51/59.ConclusionsAlthough the number of patients in our study is modest, single-dose BPG appears to be highly effective even in patients at high risk of neurosyphilis.

Chronic kidney disease constitutes an increasing medical burden affecting 26 million people in the United States alone. Diabetes, hypertension, ischemia, acute injury, and urological obstruction contribute to renal fibrosis, a common pathological hallmark of chronic kidney disease. Regardless of etiology, elevated TGF-β1 levels are causatively linked to the activation of profibrotic signaling pathways initiated by angiotensin, glucose, and oxidative stress. Unilateral ureteral obstruction (UUO) is a useful and accessible model to identify mechanisms underlying the progression of renal fibrosis. Plasminogen activator inhibitor-1 (PAI-1), a major effector and downstream target of TGF-β1 in the progression of several clinically important fibrotic disorders, is highly up-regulated in UUO and causatively linked to disease severity. SMAD and non-SMAD pathways (pp60(c-src), epidermal growth factor receptor [EGFR], mitogen-activated protein kinase, p53) are required for PAI-1 induction by TGF-β1. SMAD2/3, pp60(c-src), EGFR, and p53 activation are each increased in the obstructed kidney. This review summarizes the molecular basis and translational significance of TGF-β1-stimulated PAI-1 expression in the progression of kidney disease induced by ureteral obstruction. Mechanisms discussed here appear to be operative in other renal fibrotic disorders and are relevant to the global issue of tissue fibrosis, regardless of organ site.

Background The National Chlamydia Screening Programme in Greater Manchester (NCSP-GM) commissioned an evaluation of the management of gonorrhoea cases identified using the Gen-Probe APTIMA Combo 2 assay (AC2). Methods NCSP-GM provided data on gonorrhoea cases from a 6-month period (September 2007–February 2008). Data were collected from patient referral pathways to genitourinary medicine (GUM) clinics, including confirmatory testing, antibiotic resistance patterns and contact tracing. The AC2 positive predictive value (PPV) was calculated. Results 111 individuals tested positive for gonococcal infection using AC2 (0.7% of 16 028 individuals tested). Of these, 96 (0.6% of all tested) known index cases were seen at Greater Manchester GUM clinics. 78/96 (14 men, 64 women) underwent confirmatory microscopy and gonococcal culture. Confirmatory tests were positive in 14 men (100%) but only 40 women (63%). Thus the PPV of AC2 was 69% (54/78). Sensitivity in women may have been reduced by limited partner information and sample-taking (only 28% had a full gonorrhoea screen). Conclusion Gonorrhoea screening in an NCSP-targeted population identified gonorrhoea in a low-risk population. Subsequent management in GUM clinics was variable and limited sample-taking may have decreased the sensitivity of confirmatory testing in women. Appropriate antibiotic sensitivity tests or, in their absence, a test of cure may be needed to ensure effective treatment.

Elevated levels of plasminogen activator inhibitor type-1 (PAI-1) often occur in concert with the conversion of non-motile epithelial elements into a more migratory phenotype. While essential during embryonic development, this restructuring process, referred to as epithelial-to-mesenchymal-transition (EMT) is limited in the adult organism, occurring normally during wound repair or more atypically in tumor progression. Cell motility, the focal point of EMT, requires the coordinate regulation of multiple mechanisms which ensure proper communication between cell surface receptors and the extracellular environment. PAI-1, through multifaceted interactions with both extracellular matrix (ECM) and cell surface constituents plays a critical role in modulating many of these events. This review focuses on the complex role of PAI-1 in the cellular motile program.

Increased transforming growth factor-β(TGF-β) expression and epidermal growth factor receptor (EGFR) amplification accompany the emergence of highly aggressive human carcinomas. Cooperative signaling between these two growth factor/receptor systems promotes cell migration and synthesis of stromal remodeling factors (i.e., proteases, protease inhibitors) that, in turn, regulate tumor invasion, neo-angiogenesis and inflammation. ranscript profiling of transformed human cells revealed that genes encoding wound healing, matrix remodeling and cell cycle proteins (i.e., the “tissue repair” transcriptome) are significantly up-regulated early after growth factor stimulation. The major inhibitor of plasmin generation, plasminogen activator inhibitor-1 (PAI-1), is among the most highly induced transcripts during the phenotypic transition initiated by TGF-βmaximal expression requires EGFR signaling. PAI-1 induction occurs early in the progression of incipient epidermal squamous cell carcinoma (SCC) and is a significant indicator of poor prognosis in epithelial malignancies. Mouse modeling and molecular genetic analysis of complex systems indicates that PAI-1 regulates the temporal/spatial control of pericellular proteolysis, promotes epithelial plasticity, inhibits capillary regression and facilitates stromal invasion. Defining TGF-β1-initiated signaling events that cooperate with an activated EGFR to impact the protease-protease inhibitor balance in the tumor microenvironment is critical to the development of novel therapies for the clinical management of human cancers.

TGF-β1 and its target gene encoding plasminogen activator inhibitor-1 (PAI-1) are major regulators of capillary outgrowth, vessel maturation and angiogenic network stability. The increasing realization of the complexity of PAI-1 action in the vascular system requires analysis of specific signaling events that impact its expression in a physiologically-relevant cell system. PAI-1 was required for tubular differentiation and maintenance of cellular survival in complex gels since targeted disruption of PAI-1 synthesis or activity with antisense constructs or function-blocking antibodies resulted in network regression. Indeed, serum-deprivation-induced apoptosis of tubulogenic T2 cells was concentration-dependently inhibited by addition of a stable PAI-1 mutant protein consistent with the established pro-survival role of PAI-1 in vascular endothelial cells. PAI-1 induction and ERK pathway activation in response to TGF-β1 was attenuated by EGFR signaling blockade (with AG1478) or preincubation with the MMP/ADAM inhibitor GM6001. The combination of AG1478 + GM6001 completely ablated both responses suggesting that EGFR transactivation is important in PAI-1 gene control and may, at least partially, involve ligand shedding. TGF-β1-stimulated PAI-1 induction was preceded, in fact, by EGFR phosphorylation on Y845 (a src kinase target residue). EGFR1 knockdown with lentiviral shRNA constructs, moreover, effectively decreased (by >75%) TGF-β1-stimulated PAI-1 expression whereas infection with control (i.e. GFP) viruses had no effect. TGF-β1 failed to induce PAI-1 synthesis in EGFR-deficient fibroblasts while introduction of a wild-type EGFR1 construct in EGFR -/- cells rescued the PAI-1 response to TGF-β1 confirming, at a genetic level, the targeted knockdown data. The continued clarification of novel cooperative signaling cascades that impact expression of important angiogenic genes (e.g. PAI-1) may provide therapeutically useful targets to manage the pathophysiology of human neoplastic and vascular diseases.

Summary The Clinical Effectiveness Group of the British Association for Sexual Health has updated their methodology for the production of national guidelines for the management of sexually transmitted infections and related conditions. The main changes are the adoption of the GRADE system for assessing evidence and making recommendations and the introduction of a specific Conflict of Interests policy for Clinical Effectiveness Group members and guideline authors. This new methodology has been piloted during the production of the 2015 British Association for Sexual Health & HIV guideline on the management of syphilis.

We report the case of an 18-year-old woman presenting with ulceration of the cervix caused by primary type 2 herpes simplex infection in the absence of skin lesions. The differential diagnosis included cervical cancer and we referred the patient for urgent colposcopy. However, laboratory tests proved the viral aetiology of the cervical ulceration and the cervix had healed completely 3 weeks later. The case highlights the need to consider herpes simplex infection in the differential diagnosis of ulceration of the cervix even when there are no cutaneous signs of herpes.

We report a case in which an HIV-positive man developed general malaise, skin rash and biochemical hepatitis within days of starting a nevirapine-based antiretroviral treatment regimen. At the same time, his syphilis serology proved positive. We discuss the diagnostic dilemma: was this a nevirapine hypersensitivity reaction, secondary syphilis or both?

Background Insomnia involves difficulty with sleep onset, maintenance, early morning wakening or non-restorative sleep. Prevalence is 30%–75% in cancer. Consequences include fatigue and impaired memory or concentration. It is under-reported, overlooked and severely impairs quality of life. ?Subjective sleep diaries underestimate insomnia. Objective measurements previously required dedicated sleep laboratories. Wireless medical technology enables objective sleep measurement in the natural environment. Aims Conduct a feasibility study to examine if a wireless monitor can measure sleep in cancer. Evaluate acceptability in: Patient Nurse Family Correlate objective device results with subjective reports. Methods A prospective observational study recruited 10 consecutive hospice inpatients (IP) and 20 consecutive community participants (CP) with cancer. Insomnia Severity Index recorded subjective sleep pattern. Participants used a wireless non-contact bedside sleep monitor for 3 nights. Three insomnia features were examined (sleep onset, maintenance, early awakening). A daily sleep diary was completed. Acceptability questionnaires were completed by patient, nurse and family. Statistical analysis was undertaken with SPSS version 22. Results The device successfully recorded sleep patterns in all 30 participants. Inpatients: Mean age was 63 years (range 47–61). 7/10 were positive for one or more insomnia features. Delayed sleep onset was most common (7/10). Community Participants: Mean age was 64 years (range 47–84). 15/20 were positive for one or more insomnia features. Fragmented sleep was most common. 14/20 recorded over 30 min awake overnight with more than 2 awakenings. Early morning wakening was not present in either cohort. Poor sleep hygiene was noted in community participants compared to inpatients. Correlation between subjective and objective measures was not significant (IP: p=0.07; CP: p=0.106). Patients, nurses and family members reported 100% device acceptability. Conclusions A wireless bedside monitor effectively measures sleep in cancer. High patient acceptability supports clinical use. Cancer-related insomnia features were common in both cohorts. Objective measurements correlated poorly with subjective.

Plasminogen activator inhibitor-1 (PAI-1; SERPINE1) is a member of the serine protease inhibitor (SERPIN) superfamily and the predominant physiologic inhibitor of urokinase (uPA) and tissue-type (tPA) plasmingen activators. This system effectively restricts, both spatially and temporally, the conversion of plasminogen to plasmin, thereby regulating physiologic and pathophysiologic stromal remodeling. Dysregulation of this cascade frequently results in anomalies of the tissue repair response. Elevated PAI-1 levels are a causative factor in various forms of vascular disease and tissue fibrotic syndromes. Independent of its role in proteolysis, PAI-1 stimulates cell motility via interacting with low-density lipoprotein receptor-related protein-1 (LRP1) activating several cellular signaling pathwaays. PAI-1 also regulates the availability of cell-surface integrins by promoting their endocytosis in an LRP-1- dependent manner via PAI-1/uPA/uPAR (uPA receptor)/LRPI/integrin complexes. This process fine tunes the special control of pericellular proteolysis and the overall cadence of cell detachment/re-adhesion required for efficient cell migration. These data suggest that PAI-1 modulates cell motility under several contexts, both via by its established anti-proteolytic properties and as a signaling initiator.

Summary: We evaluated Cobas AmplicorTM, a highly automated polymerase chain reaction (PCR) system, to test first-void urine (FVU) and urethral swab specimens for Chlamydia trachomatis and Neisseria gonorrhoeae in men attending a sexually transmitted infection (STI) clinic. Results were compared against an inhouse radioimmune dot blot (DB) test for C. trachomatis and selective culture for N. gonorrhoeae . Three hundred and ninety sets of specimens were obtained from 378 consecutive new and returned-new patients. Gonorrhoea prevalence was 9.49%, with no significant difference in sensitivity or specificity between culture and PCR. Chlamydia prevalence was 15.4%, with sensitivities of: DB 55%, PCR of FVU 86.7%, urethral swab PCR 90%. The specificity of PCR on FVU and urethral swabs was 100%. We have shown that Cobas AmplicorTM PCR is highly sensitive and specific in the diagnosis of chlamydia and gonorrhoea in men attending an STI clinic. Further economic and scientific studies are needed to determine the costeffectiveness of this technique for screening in primary care settings.

Spatial and temporal regulation of the pericellular proteolytic environment by local growth factors, such as EGF and TGF-β, initiates a wide repertoire of cellular responses coupled to a plasmin/matrix metalloproteinase (MMP) dependent stromal-remodeling axis. Cell motility and invasion, tumor metastasis, wound healing, and organ fibrosis, for example, represent diverse events controlled by expression of a subset of genes that encode various classes of tissue remodeling proteins. These include members of the serine protease and MMP families that functionally constitute a complex system of interacting protease cascades and titrated by their respective inhibitors. Several structural components of the extracellular matrix are upregulated by TGF-β as are matrix-active proteases (e.g., urokinase (uPA), plasmin, MMP-1, -3, -9, -10, -11, -13, -14). Stringent controls on serine protease/MMP expression and their topographic activity are essential for maintaining tissue homeostasis. Targeting individual elements in this highly interactive network may lead to novel therapeutic approaches for the treatment of cancer, fibrotic diseases, and chronic wounds.

Interstitial fibrosis, resulting in renal tissue destruction and progressive impairment of organ function, is a hallmark of end-stage kidney disease [1]. The primary sources of matrix synthesis during renal fibrogenesis are activated fibroblasts or myofibroblasts. While their origin remains uncertain, this cell type-predictor of disease progression likely derives largely from resident fibroblasts and epithelial-to-mesenchymal transdifferentiated (EMT) tubular epithelial cells [2]. The transforming growth factor-β (TGF-β)/SMAD system is a potent, perhaps the most well-characterized, inducer of myofibroblast differentiation and EMT. TGF-β drives EMT in renal epithelial cells and promotes fibrosis in animal models by engaging effector pathways and their downstream target genes that impact both the inflammatory and scarring stages of the injury response [3]. SMAD-mediated signaling initiated by TGF-β is pivotal for induction of EMT, fibroblast activation and renal fibrosis [2,3]. SMAD3, in particular, appears critical in several in vivo models of renal fibrosis. This was, indeed, confirmed by the finding that SMAD3-deficient mice are significantly protected from disease progression. TGF-β also activates non-SMAD-dependent pathways [4] that impact the expression of pro-fibrotic genes. The continued characterization of such highly-interactive transduction events initiated by TGF-β/TGF-β receptor interactions will likely lead to identification of novel opportunities for anti-fibrotic therapy.

Malignant transformation of mammalian cells withrasfamily oncogenes results in dramatic changes in cellular architecture and growth traits. The generation of flat revertants of v-K-ras-transformed renal cells by exposure to the histone deacetylase inhibitor sodium butyrate (NaB) was previously found to be dependent on transcriptional activation of the PAI-1 (SERPINE1) gene (encoding the type-1 inhibitor of urokinase and tissue-type plasminogen activators). NaB-initiated PAI-1 expression preceded induced cell spreading and entry into G1arrest. To assess the relevance of PAI-1 induction to growth arrest in this cell system more critically, two complementary approaches were used. The addition of a stable, long half-life, recombinant PAI-1 mutant to PAI-1-deficient v-K-ras-/c-Ha-ras-transformants or to PAI-1 functionally null, NaB-resistant, 4HH cells (engineered by antisense knockdown of PAI-1 mRNA transcripts) resulted in marked cytostasis in the absence of NaB. The transfection ofras-transformed cells with the Rc/CMVPAI expression construct, moreover, significantly elevated constitutive PAI-1 synthesis (10- to 20-fold) with a concomitant reduction in proliferative rate. These data suggest that high-level PAI-1 expression suppresses growth of chronicras-oncogene transformed cells and is likely a major cytostatic effector of NaB exposure.

Cellular migration, over simple surfaces or through complex stromal barriers, requires coordination between detachment/re-adhesion cycles, involving structural components of the extracellular matrix and their surface-binding elements (integrins), and the precise regulation of the pericellular proteolytic microenvironment. It is now apparent that several proteases and protease inhibitors, most notably urokinase plasminogen activator (uPA) and plasminogen activator inhibitor type-1 (PAI-1), also interact with several cell surface receptors transducing intracellular signals that significantly affect both motile and proliferative programs. These events appear distinct from the original function of uPA/PAI-1 as modulators of the plasmin-based proteolytic cascade. The multifaceted interactions of PAI-1 with specific matrix components (i.e., vitronectin), the low-density lipoprotein receptor-related protein-1 (LRP1), and the uPA/uPA receptor complex have dramatic consequences on the migratory phenotype and may underlie the pathophysiologic sequalae of PAI-1 deficiency and overexpression. This paper focuses on the increasingly intricate role of PAI-1 as a major mechanistic determinant of the cellular migratory phenotype.

Background Plasminogen activator inhibitor-1 (PAI-1), a major regulator of the plasmin-based pericellular proteolytic cascade, is significantly increased in human arterial plaques contributing to vessel fibrosis, arteriosclerosis and thrombosis, particularly in the context of elevated tissue TGF-β1. Identification of molecular events underlying to PAI-1 induction in response to TGF-β1 may yield novel targets for the therapy of cardiovascular disease. Principal Findings Reactive oxygen species are generated within 5 minutes after addition of TGF-β1 to quiescent vascular smooth muscle cells (VSMCs) resulting in pp60c-src activation and PAI-1 expression. TGF-β1-stimulated Src kinase signaling sustained the duration (but not the initiation) of SMAD3 phosphorylation in VSMC by reducing the levels of PPM1A, a recently identified C-terminal SMAD2/3 phosphatase, thereby maintaining SMAD2/3 in an active state with retention of PAI-1 transcription. The markedly increased PPM1A levels in triple Src kinase (c-Src, Yes, Fyn)-null fibroblasts are consistent with reductions in both SMAD3 phosphorylation and PAI-1 expression in response to TGF-β1 compared to wild-type cells. Activation of the Rho-ROCK pathway was mediated by Src kinases and required for PAI-1 induction in TGF-β1-stimulated VSMCs. Inhibition of Rho-ROCK signaling blocked the TGF-β1-mediated decrease in nuclear PPM1A content and effectively attenuated PAI-1 expression. TGF-β1-induced PAI-1 expression was undetectable in caveolin-1-null cells, correlating with the reduced Rho-GTP loading and SMAD2/3 phosphorylation evident in TGF-β1-treated caveolin-1-deficient cells relative to their wild-type counterparts. Src kinases, moreover, were critical upstream effectors of caveolin-1Y14 phosphoryation and initiation of downstream signaling. Conclusions TGF-β1-initiated Src-dependent caveolin-1Y14 phosphorylation is a critical event in Rho-ROCK-mediated suppression of nuclear PPM1A levels maintaining, thereby, SMAD2/3-dependent transcription of the PAI-1 gene.

BACKGROUND--The incidence of tuberculosis is increased in HIV positive patients. Purified protein derivative (PPD, tuberculin) testing has not been performed routinely on patients infected with HIV in the UK and its usefulness in diagnosing tuberculosis in these patients is unclear. METHODS--198 HIV positive patients were Tine tested and a CD4+ lymphocyte count and chest radiograph were performed. Of the 179 male patients 164 were homosexual or bisexual, 11 were injecting drug users (IDUs), and four were both homosexual and IDUs. Of 19 women 14 were heterosexual and five were IDUs. Patients assessed their own skin reactions at 72 hours, recording the grade on a card which was returned by post. Patients with a grade 0 reaction were requested to have a second test one month later. RESULTS--Details were available on 168 of the 198 patients. Grade 0 reactions occurred in 89 of the 168 patients, requiring a second Tine test, and 73 completed Tine 2 results were received. Of 57 patients with CD4+ lymphocyte counts below 200/mm3, low grade PPD reactivity was seen in 18 on Tine 1 and nine on Tine 2. No history of BCG immunisation of tuberculosis was found in 33 Tine positive patients. Two patients treated for tuberculosis in the previous six months were PPD positive with CD4+ counts of 60/mm3 and 4/mm3 respectively. CONCLUSIONS--PPD reactivity may be maintained despite a CD4+ count of 100/mm3 or less when there is a history of tuberculosis or BCG immunisation.

Antiretroviral (ARV) therapy in HIV patients can cause hyperlipidaemia, glucose intolerance and insulin resistance, which increase the risk of cardiovascular disease (CVD). An audit carried out in Manchester found that CVD risk factors were common among HIV patients receiving ARVs; however, the management of risk factors was not satisfactory. Adopting a formal system to identify and manage CVD risk factors as well as appropriate referral for specialist management of complications of ARV therapy would improve patient care.

Cutaneous tissue injury, both in vivo and in vitro, initiates activation of a "wound repair" transcriptional program. One such highly induced gene encodes plasminogen activator inhibitor type-1 (PAI-1, SERPINE1). PAI-1-GFP, expressed as a fusion protein under inducible control of +800 bp of the wound-activated PAI-1 promoter, prominently "marked" keratinocyte migration trails during the real-time of monolayer scrape-injury repair. Addition of active recombinant PAI-1 to wounded wild-type keratinocyte monolayers as well as to PAI-1(-/-) MEFs and PAI-1(-/-) keratinocytes significantly stimulated directional motility above basal levels in all cell types. PAI-1 expression knockdown or antibody-mediated functional inhibition, in contrast, effectively attenuated injury repair. The defect in wound-associated migratory activity as a consequence of antisense-mediated PAI-1 down-regulation was effectively reversed by addition of recombinant PAI-1 immediately after scrape injury. One possible mechanism underlying the PAI-1-dependent motile response may involve fine control of the keratinocyte substrate detachment/re-attachment process. Exogenous PAI-1 significantly enhanced keratinocyte spread cell "footprint" area while PAI-1 neutralizing antibodies, but not control non-immune IgG, effectively inhibited spreading with apoptotic hallmarks evident within 24 h. Importantly, PAI-1 not only stimulated keratinocyte adhesion and wound-initiated planar migration but also rescued keratinocytes from plasminogen-induced substrate detachment/anoikis. The early transcriptional response of the PAI-1 gene to monolayer trauma and its prominence in the injury repair genetic signature are consistent with its function as both a survival factor and regulator of the time course of epithelial migration as part of the cutaneous injury response program.

The classical lesion of primary syphilis is a solitary, indurated, painless chancre. Atypical presentations, such as herpetiform ulceration, are well recognized. However, there are few references in the medical literature to primary syphilis presenting as balanitis or balanoposthitis. We report two cases of primary syphilitic balanitis in homosexual men.

Background/introduction Benzathine penicillin G (BPG) does not cross the blood-brain barrier. Some experts believe that BPG may be ineffective when treating patients co-infected with HIV and syphilis. Aim(s)/objectives To establish the risk of asymptomatic neurosyphilis (ANS) after treatment of early syphilis in HIV positive patients with single dose BPG. Methods HIV patients with early syphilis were offered a post-treatment lumbar puncture if their CD4 count was 16. Patients with clinical neurosyphilis were excluded. ANS was defined as a positive CSF RPR, or CSF white blood cells >20/mm 3 plus CSF TPPA >1:320. Results 64 patients participated (median CD4 417/mm 3 , range 84–1100). 50 of the patients were treated with single dose BPG. Only one patient had ANS (prevalence 1.56% 95 CI 0.04–8.4) with CSF RPR negative, CSF TPPA 1:1280 and lymphocytes 45/mm 3 . Two patients had a pleocytosis (50 and 22 white cells/mm 3 respectively) with negative CSF RPR and CSF TPPA and thus did not meet diagnostic criteria for ANS per protocol. Discussion/conclusion Our study suggests that single dose BPG is effective treatment for early syphilis in HIV co-infected patients. We will present more data to support this conclusion.

The city of Manchester has seen a sustained increase in reported cases of early (infectious) syphilis since the late 1990s. We audited the management of patients presenting with early syphilis to North Manchester General Hospital, with reference to the UK national guidelines. Between January 1999 and December 2001 72 cases of early syphilis were identified. Most (90%) occurred in men who have sex with men, 50% of whom were HIV-positive. Serology and polymerase chain reaction testing of lesions were useful diagnostic tests. Treatment regimens followed the national guidelines in 63% of cases, with adherence to the guidelines improving as the outbreak continued. The majority of patients were treated with intramuscular penicillin (78%), with only three discontinuing this treatment due to side effects. Only 4% of sexual contacts identified were traced and screened, an indication of high levels of both anonymous sex and partner change in this group.

A 41-year-old HIV-positive man who has sex with men (MSM) with a family history of deep vein thrombosis (DVT) presented to the emergency department with an acutely swollen lower limb. The initial clinical diagnosis was of a possible DVT and the patient was anticoagulated. However, investigations subsequently excluded DVT and sexually acquired reactive arthropathy (SARA) was eventually diagnosed. This complication followed an earlier attendance at the emergency department, where proctitis due to lymphogranuloma venereum (LGV) infection went unrecognized. This is the first reported case of LGV infection mimicking a DVT. Prompt recognition and treatment of the initial proctitis may have prevented the development of SARA.

Syphilis is on the increase again. Lorraine Doherty and colleagues report on four recent localised outbreaks and recall the features of infectious syphilis, its treatment, and the public health measures needed to contain it Infectious syphilis is a disease of considerable public health importance, with overwhelming health effects if it is not treated. These include cardiovascular and neurological disease and adverse pregnancy outcomes, such as stillbirth and congenital syphilis. Further, concurrent infection with syphilis can facilitate transmission of HIV.1 Syphilis is most infectious through sexual contact during the primary or secondary stages (see box 1), but transmission can also occur during the early latent stage.2 Syphilis is preventable, and treatable with effective and inexpensive antibiotics. The possible resurgence of infectious syphilis, a disease previously believed to be close to eradication, is a matter of increasing global concern.3–6 This article outlines recent changes in the epidemiology of infectious syphilis in England, including the features of a number of outbreaks. It aims to increase health professionals' awareness of the clinical features of infectious syphilis, and to consider approaches to the investigation and control of syphilis and other outbreaks of sexually transmitted infection. #### Summary points Untreated infectious syphilis may have a number of very serious health effects Recently there has been an upward trend in incidence, partly due to several localised outbreaks affecting homosexual men and heterosexual men and women These outbreaks have emphasised the importance of investigating wider sexual networks as well as tracing individual contacts to identify further cases and prevent further spread The general public, certain groups at risk, and relevant health professionals should be aware of the risks of acquiring syphilis and the symptoms and signs of acute infection Between the 1960s and the late 1970s homosexually acquired syphilitic infection increased, in keeping with liberalisation of …

A man previously treated for tuberculous arthritis presented with acute meningoencephalitis. Cerebrospinal fluid tests suggested infection with Mycobacterium tuberculosis, but a diagnosis of early neurosyphilis was subsequently made.

Summary: We evaluated the management of antiretroviral treatment (ART)-naïve HIV-positive patients in Greater Manchester against the 2005 British HIV association (BHIVA) guidelines. Fifty-seven HIV patients (median age 36 years, 61% males, 53% black Africans) commenced their first ART regimen between 1 October and 31 December 2005. Most of them presented with advanced HIV disease (74% had CD4 lymphocytes

McCartney is right that much patient information is of poor quality and dubious provenance,1 but not all is doom and gloom. The British Association for Sexual Health and HIV (BASHH) produces patient information leaflets through a rigorous development process before publication. Its …

EDITOR—In their excellent clinical review on caring for patients with genital herpes, Drake and colleagues rightly mentioned the need to consider screening patients with genital herpes for other …