Epidemiology of Escherichia coli bacteraemia in England: results of an enhanced sentinel surveillance programme.

BACKGROUND: Escherichia coli causes more than one-third of the bacteraemia cases in England each year, and the incidence of these infections is increasing. AIM: To determine the underlying risk factors associated with E. coli bacteraemia. METHODS: A three-month enhanced sentinel surveillance study involving 35 National Health Service hospitals was undertaken in the winter of 2012/13 to collect risk factor information and further details on the underlying source of infection to augment data already collected by the English national surveillance programme. Antimicrobial susceptibility results for E. coli isolated from blood and urine were also collected. FINDINGS: A total of 1731 cases of E. coli bacteraemia were included. The urogenital tract was the most frequently reported source of infection (51.2% of cases) with previous treatment for a urinary tract infection being the largest independent effect associated with this infection source. Half of all patients had previous healthcare exposure in the month prior to the bacteraemia with antimicrobial therapy and urinary catheterization being reported in one-third and one-fifth of these patients, respectively. Previous healthcare exposure was associated with a higher proportion of antibiotic non-susceptibility in the blood culture isolates (P=0.001). CONCLUSION: Analysis of risk factors suggests the potential benefit of community- and hospital-related interventions, especially the better use of urinary catheters and improved antibiotic management of urinary tract infections. As part of the latter strategy, antibiotic resistance profiles need to be closely monitored to ensure that treatment guidelines are up to date to limit inappropriate empiric therapy.

Population structure of Escherichia coli causing bacteraemia in the UK and Ireland between 2001 and 2010.

OBJECTIVES: Escherichia coli is the most common agent of bacteraemia, bacterial gastroenteritis and urinary tract infections (UTIs). Lineages causing UTIs and gastrointestinal disease are well defined, but less is known about those causing bacteraemia. We therefore investigated the population structure of E. coli from bacteraemia in the UK and Ireland between 2001 and 2010. METHODS: E. coli isolates (n = 2166) were submitted to the BSAC Bacteraemia Surveillance Programme from 18 UK and Irish centres from 2001 to 2010. Genotypes were analysed by MLST using the Achtman scheme; MICs, blaCTX-M group and patient demographics were previously determined in the BSAC surveillance. RESULTS: Four hundred and forty-eight STs were identified, but five of these, and their associated clonal complexes (CCs), accounted for 58.4% (1264 of 2166) of isolates: CC73 was the most common (20.7%), followed by CC131 (13.9%), CC95 (11.3%), CC69 (6.9%) and CC12 (5.5%). All these, except CC69 (group D), belong to phylogenetic group B2. CC131 isolates were much more often MDR than other STs were: they rose from 2.9% of isolates in 2001 to 20.5%-20.7% in 2007-08 and then declined to 14.3% in 2010. Resistance rates to cephalosporins, aminoglycosides and fluoroquinolones remained below 10% in other major CCs throughout. CONCLUSIONS: The five most prevalent bacteraemia STs have all been associated previously with UTIs. They dominated in all years, but their proportions fluctuated, most notably for ST131, a globally disseminated high-risk clone that is often MDR.

Thirty day all-cause mortality in patients with Escherichia coli bacteraemia in England.

Escherichia coli is the commonest cause of bacteraemia in England, with an incidence of 50.7 cases per 100 000 population in 2011. We undertook a large national study to estimate and identify risk factors for 30-day all-cause mortality in E. coli bacteraemia patients. Records for patients with E. coli bacteraemia reported to the English national mandatory surveillance system between 1 July 2011 and 30 June 2012 were linked to death registrations to determine 30-day all-cause mortality. A multivariable regression model was used to identify factors associated with 30-day all-cause mortality. There were 5220 deaths in 28 616 E. coli bacteraemia patients, a mortality rate of 18.2% (95% CI 17.8-18.7%). Three-quarters of deaths occurred within 14 days of specimen collection. Factors independently associated with increased mortality were: age < 1 year or > 44 years; an underlying respiratory or unknown infection focus; ciprofloxacin non-susceptibility; hospital-onset infection or not being admitted; and bacteraemia occurring in the winter. Female gender and a urogenital focus were associated with a reduction in mortality. This is the first national study of mortality among E. coli bacteraemia patients in England. Interventions to reduce mortality need to be multifaceted and include both primary and secondary healthcare providers. Greater awareness of the risk factors for and symptoms of E. coli bacteraemia may prompt earlier diagnosis and treatment. Changes in antimicrobial resistance patterns need to be monitored for their potential impact on infection and mortality.

The impact in the UK of the Central and Eastern European HIV epidemics.

Despite increasing migration, the impact of HIV epidemics from Central and Eastern Europe (C&EE) on the UK HIV epidemic remains small. C&EE-born adults comprised 1.2% of adults newly diagnosed with HIV in the UK between 2000 and 2007. Most C&EE-born women probably acquired their infection heterosexually in C&EE. In contrast, 59% of C&EE-born men reported sex with men, half of whom probably acquired their infection in the UK. Previously undiagnosed HIV prevalence in C&EE-born sexual-health-clinic attendees was low (2007, 0.5%) as was overall HIV prevalence in C&EE-born women giving birth in England (2007, <0.1%). The high proportion of men who have sex with men (MSM) suggests under-reporting of this group in C&EE HIV statistics and/or migration of MSM to the UK. In addition to reducing HIV transmission in injecting drug users, preventative efforts aimed at C&EE-born MSM both within their country of origin and the UK are required.

Heroin-related deaths in Sydney, Australia. How common are they?

The objective of this article was to determine the number of recent deaths caused by accidental illicit drug overdoses seen at the NSW Institute of Forensic Medicine, Glebe (Sydney). All Forensic cases (3559) were reviewed during the period July 1995-February 1997. Any that were classified as accidental illicit drug overdose were followed up, and demographic and toxicological data were collected for analysis. Our results found that one hundred and forty three accidental illicit drug overdoses were identified from 3359 autopsies during the 20 month data collection period (4%). Male to female ratio was 5:1, but females predominated in the methadone toxicity group. Most of the cases were under 40 years of age. Toxicological results showed that 80% of the deaths were associated with morphine (heroin) levels in the toxic range, although 91% had morphine present at some level. Only 35% of cases had significant levels of bile morphine, suggesting "chronic" usage. In many cases, multiple illicit substances and/or alcohol were thought to be important contributing factors. Cocaine was found in 13% of cases, and all of these had morphine (heroin) in their blood. Methadone was found in 13% of cases, and 13/19 had toxic levels--9/19 also had morphine in their blood. Only two cases had amphetamines or methamphetamines in their blood. The authors conclude that Heroin overdose is by far the most common cause of accidental illicit drug overdose. Those at greatest risk are naive users and those who are not tolerant. There is an urgent need for increased awareness and further education concerning the dangers of heroin use, particularly of multiple drug use (including alcohol). Only about one-third of these cases appear to be "chronic" users.

A painful cutaneous nodule as the presentation of metastatic transitional cell carcinoma of the renal pelvis.

We report a 43-year-old man with HIV who presented with a painful, vascular-appearing nodule as the initial manifestation of metastasis of a prior transitional cell carcinoma of the renal pelvis. The transitional cell carcinoma had been treated by nephroureterectomy 4 years before the appearance of the nodule. Histopathologic comparison of the nodule with the prior transitional cell carcinoma and immunoperoxidase staining with monoclonal antibodies confirmed that the nodule was a metastasis of the original transitional cell carcinoma. In general, metastasis of transitional cell carcinoma to the skin is quite uncommon. This case is the first reported episode of transitional cell carcinoma of the renal pelvis metastasizing to the skin in the form of a vascular-appearing nodule. The significance of this unusual metastasis occurring in a person with HIV is unknown.

The neutral cysteine protease bleomycin hydrolase is essential for epidermal integrity and bleomycin resistance.

The papain superfamily member bleomycin hydrolase (Blmh) is a neutral cysteine protease with structural similarity to a 20S proteasome. Bleomycin (BLM), a clinically used glycopeptide anticancer agent, is deaminated in vitro by Blmh. We used gene targeting to generate mice that lack Blmh and demonstrated that Blmh is the sole enzyme required for BLM deamination. Although some Blmh null mice were viable and reproduced, only about 65% of the expected number survived the neonatal period, revealing an important role for Blmh in neonatal survival. Mice lacking Blmh exhibited variably penetrant tail dermatitis that resembled rodent ringtail. The histopathology of the tail dermatitis was similar to skin lesions in humans with pellagra, necrolytic migratory erythema, and acrodermatitis enteropathica. Compared with controls, Blmh null mice were more sensitive to acute BLM lethality and developed pulmonary fibrosis more readily following BLM treatment. Thus, we have established that Blmh is an essential protectant against BLM-induced death and has an important role in neonatal survival and in maintaining epidermal integrity.

Systemic interferon-alpha (IFN-alpha) treatment leads to Stat3 inactivation in melanoma precursor lesions.

BACKGROUND: In the setting of familial melanoma, the presence of atypical nevi, which are the precursors of melanoma, is associated with a nearly 100% risk of developing primary melanoma by age 70. In patients with sporadic melanoma, it is estimated that 40-60% of melanomas develop in contiguous association with atypical nevi. Currently, the only way to prevent atypical nevi from progressing to melanoma is to monitor and excise them as soon as they exhibit changes in their clinical features. Activation of the transcription factor, Stat3, has been linked to abnormal cell growth and transformation as well as to interferon alpha (IFN-alpha)-mediated growth suppression in vitro. MATERIALS AND METHODS: To determine whether IFN-alpha, used for adjuvant therapy of high-risk, resected melanoma, induces changes in Stat3 in atypical nevi, patients with a clinical history of melanoma who have multiple atypical nevi were treated for 3 months with low-dose IFN-alpha. Thereupon, the new technology of microscopic spectral imaging and biochemical assays such as electrophoretic mobility shift assays (EMSAs) and immunoblot analysis were used for the study of atypical nevi, obtained before and after IFN-alpha treatment. RESULTS: The results of the investigations provided evidence that, as a result of systemic IFN-alpha treatment, Stat1 and Stat3, which are constitutively activated in melanoma precursor lesions, lose their ability to bind DNA, and as shown in the case of Stat3, become dephosphorylated. CONCLUSIONS: Unlike primary and metastatic melanomas, melanoma precursor lesions cannot be established as cell cultures. Thus, the only way to explore pathways and treatment regimens that might help prevent progression to melanoma is within the context of a melanoma precursor lesion study conducted prospectively. The findings presented here suggest that down-regulation of the transcription factors Stat1 and Stat3 by systemic IFN-alpha treatment may represent a potential pathway to prevent the activation of gene(s) whose expression may be required for atypical nevus cells to progress to melanoma.

Macroscopic spectral imaging and gene expression analysis of the early stages of melanoma.

BACKGROUND: The stages of melanocytic progression are defined as atypical (dysplastic) nevus, melanoma in situ, melanoma in the radial growth phase (RGP), melanoma in the vertical growth phase (VGP), and melanoma in the metastatic growth phase (MGP). Melanoma in situ and RGP melanoma often develop in contiguous association with atypical nevi. This frequently poses a problem with respect to their early detection. Furthermore, unlike cells obtained from VGP and MGP melanomas, cells derived from melanoma in situ and RGP melanoma do not proliferate in vitro. Thus, compared to the late stages of the disease, less information is available regarding genes expressed in the early stages. MATERIALS AND METHODS: To determine whether spectral imaging, a recently developed optical imaging technique, can detect melanoma in situ and RGP melanoma arising in melanoma precursor lesions, atypical nevi in patients with a clinical history of melanoma were subjected to noninvasive macroscopic spectral imaging. To determine at what stage in the progression pathway of melanoma genes having important biological functions in VGP and MGP melanomas are activated and expressed, lesions of melanoma in situ were analyzed by immunohistochemistry and in situ hybridization for expression of some of these known molecular and immunologic markers. RESULTS: The present study demonstrates the capability of noninvasive spectral imaging to detect melanoma in situ and RGP melanoma that arise in contiguous association with atypical nevi. Furthermore, the study provides evidence that genes and antigens expressed in VGP and MGP melanoma are also expressed in melanoma in situ. CONCLUSIONS: Because of the dark and variegated pigmentation of atypical nevi, melanoma in situ and RGP melanoma that arise in these melanoma precursor lesions are often difficult to recognize and thus frequently go unnoticed. The application of new optical screening techniques for early detection of melanoma and the identification of genes expressed in the early stages of melanoma development are two important avenues in the pursuit of melanoma prevention. The investigations presented here document that macroscopic spectral imaging has the potential to detect melanoma in its early stage of development and that genes essential for the proliferation and cell adhesion of VGP and MGP melanoma are already expressed in melanoma in situ.

Second-harmonic generation in a direct-bonded periodically poled LiNbO(3) buried waveguide.

We report the fabrication of a 12-mum -thick periodically poled LiNbO(3) planar waveguide buried in LiTaO(3) by direct bonding of precision-polished surfaces. Frequency doubling of the 1064-nm output of a cw diode-pumped Nd:YAG laser was performed in a 5.5-mm-long device with a 6.50-mum -period grating at an elevated temperature of 174 degrees C. The resultant green second-harmonic output exhibited fundamental-spatial-mode characteristics at a 4.3%W(-1) conversion efficiency.

Mixed Merkel cell carcinoma and squamous cell carcinoma of the skin.

Four mixed Merkel cell and squamous cell carcinomas of the skin are described. The patients ranged in age from 74 to 90 years and demonstrated or had a history of previous ultraviolet or infrared damage to the skin, manifested by basal cell carcinoma, squamous cell carcinoma, actinic keratoses, solar elastosis, and erythema ab igne. Light microscopic examination of all 4 cases revealed invasive neoplasms consisting of 2 distinct but admixed cell types. The predominant cell type was consistent with Merkel cell carcinoma and was characterized by scant cytoplasm, a small dark polygonal nucleus with granular chromatin, a high mitotic rate, and cytokeratin 20 positivity. In each case, the Merkel cell component merged with a cytokeratin 20 negative squamous component characterized by abundant eosinophilic cytoplasm, intercellular bridges, and keratinization with focal squamous pearl formation. Immunohistochemical staining patterns were consistent with the usual pattern for that cell type; transitional cells were not demonstrated. The intimate admixture of the 2 antigenically different neoplastic cell types, and common etiologic role of ultraviolet and possibly infrared damage, lend support to the theory that some Merkel cell carcinomas and squamous cell carcinomas may arise from a pluripotent epidermal stem cell.

Gompertzian mortality originates in the winding-down of the mitotic clock.

UNLABELLED: Gompertz' age-related exponential increase in mortality rate and the obdurately flat mortality trajectory of Drosophila are paradoxical notions for metazoan aging theory. A multiclonal model of Gompertzian organisms provides a resolution by assuming that (a) conception initiates a stochastic process producing a train of replications of fixed length (the Hayflick limit); (b) unique stem cells arise early on to generate multiple vital clones; (c) life continues until one such clone critically depletes its replicative potential. Lifespan is thus governed by the time it takes to reach the terminal branches of the mitotic tree. Although these times are not independent, asymptotic independence can be justified. This clears the way for asymptotic extreme-value theory to guarantee: (1) a non-increasing failure rate, under unlimited replicability; (2) an exponentially increasing failure rate, under limited replicability. However, to obtain an exact fit to the human force-of-mortality function also requires the inclusion of the phenomenon of mitotic deceleration (implemented with a lognormal model of replication). CONCLUSION: the sine qua non of Gompertzian mortality is cellular aging, expressed through these two mitotic phenomena. Conversely, those metazoa with unlimited cellular replicability, by staving off clonal failure would succumb only to catastrophic, age-independent events, yielding a constant mortality rate, the signature of a mitotic clock that does not run down.

Surgical management of giant nonmelanoma skin neoplasia.

BACKGROUND: Management of advanced integumentary malignancy has been controversial. We have evaluated and treated 10 patients with giant nonmelanoma skin neoplasias more than 8 cm in diameter. METHODS: Aggressive surgical ablation was prospectively recommended to treat giant basal cell or mixed basosquamous tumors and two purely squamous cell tumors. Radiation therapy was given in three surgical patients. Our data are analyzed retrospectively. RESULTS: Survival of the two patients who refused surgery was measured in weeks. One patient who refused adequate surgery survived 9 months before dying. All of the adequately treated surgical patients are alive as of this writing, including one who had subsequent resection of pulmonary metastases. Three patients required free tissue transfer. The average survival of surgically treated patients was 2.7 years. CONCLUSION: An aggressive surgical approach to the management of advanced/giant skin neoplasia is justifiable and the only treatment that may produce long-term survivability.

Mucocutaneous criteria for the diagnosis of Behçet's disease: an analysis of clinicopathologic data from multiple international centers.

BACKGROUND: Although four of five of the new international criteria for the diagnosis of Behçet's disease relate to mucocutaneous lesions, disagreement exists as to the exact nature of cutaneous lesions (e.g., vessel-based vs follicular). OBJECTIVE: Our purpose was to review clinical data, clinical photographs, and skin biopsy specimens from multiple medical centers throughout the world to monitor current practice in the implementation of mucocutaneous diagnostic criteria for Behçet's disease. METHODS: Ten medical centers responded to a request to collaborate by sending clinical data, photographs of cutaneous lesions, and biopsy specimens from 22 patients. RESULTS: Of specimens from 22 patients, 14 revealed a histopathologic pattern of neutrophils containing perivascular and interstitial inflammation, whereas specimens from three patients revealed only mononuclear cells in a vessel-based pattern. Biopsy specimens from three patients revealed primarily folliculocentric inflammation and an additional two specimens were from erythema nodosum-like lesions. CONCLUSION: Perivascular inflammation was the predominant histopathologic finding in specimens of cutaneous lesions in this clinical series. Folliculocentric lesions could not be predicted on the basis of review of clinical photographs. Histopathologic assessment of cutaneous lesions is crucial if the proposal is accepted that exclusion of folliculocentric lesions is important to ensure accurate implementation of diagnostic criteria in patients with suspected Behçet's disease.

Epidermotropic metastatic malignant melanoma simulating melanoma in situ. A report of 10 examples from two patients.

Epidermotropic metastatic malignant melanoma (EMMM) is a well-recognized entity that can simulate primary malignant melanoma, and in the past reports of numerous (> or = 100) such lesions were misconstrued as multiple primary lesions. We present the cases of two patients who had not only numerous epidermotropic metastases that simulated primary melanomas but also 10 lesions that mimicked melanoma in situ. After removal of a primary malignant melanoma, the two patients developed 35 and 22 epidermotropic metastases over a 4-year period before dying with brain and pulmonary metastases, respectively. In these patients, 29 and 22 of the skin lesions were excised, respectively. All had epidermotropic metastases, of which seven and three showed pagetoid melanocytes in a pagetoid pattern exclusively within the epidermis and epithelial structures of adnexa, an "epidermal only" (in situ) pattern. Other lesions showed a continuum of dermal involvement, from the more conventional description of EMMM with the extent of dermal involvement > or = epidermal (n = 2) to epidermal involvement > dermal disease (n = 36). This histologic spectrum of dermal versus epidermal involvement in conjunction with the extremely small size (2.8 mm average histologic diameter), symmetry, large number, and time course of development argues strongly that these lesions represent metastases rather than multiple primary melanomas. The lesions illustrate the diagnostic dilemma posed by EMMM that simulates primary melanoma and further exhibits an "epidermal only" (melanoma in situ) pattern.

Purification and characterization of a UDP-GalNAc:polypeptide N-acetylgalactosaminyltransferase specific for glycosylation of threonine residues.

A UDP-GalNAc:polypeptide N-acetylgalactosaminyltransferase from porcine submaxillary glands was purified to electrophoretic homogeneity. IgG prepared from antisera against the pure enzyme immunoprecipitated the transferase in Triton X-100 extracts of submaxillary glands. The submaxillary transferase is a membrane-bound enzyme in contrast to the pure bovine colostrum enzyme, which is soluble in the absence of detergents. Both transferases have similar properties but also differ significantly. Examination of the acceptor substrate specificity of the submaxillary gland transferase showed that it specifically transferred N-acetylgalactosamine from UDP-GalNAc to the hydroxyl group of threonine and was devoid of transferase activity toward serine-containing peptides. These results imply that more than one transferase is involved in forming the GalNAc-threonine and the GalNAc-serine linkages found in O-linked oligosaccharides in glycoproteins. The amino acid sequence adjacent to glycosylated threonine residues may influence the rate of glycosylation by the pure transferase. For example, the second threonine residue in the sequence, Thr-Thr, appears to be glycosylated about twice as fast as the first and more rapidly than single, isolated threonine residues. However, no unique consensus sequence for glycosylation of threonine residues is evident, and any accessible threonine residue appears to be a potential acceptor substrate.

Porcine submaxillary mucin contains a cystine-rich, carboxyl-terminal domain in addition to a highly repetitive, glycosylated domain.

The sequence of a 3.65-kilobase cDNA encoding a large portion of the polypeptide chain of porcine submaxillary mucin (apomucin) has been completed. The encoded polypeptide contains 1150 residues with the carboxyl-terminal 240 residues forming a globular domain that is rich in half-cystine, but deficient in sites for oligosaccharide attachment. The remaining 910 residues preceding the half-cystine-rich domain appear devoid of secondary structures, but they are rich in serine and threonine to which the O-linked oligosaccharides are bound. The first 391 residues of apomucin contain several tandemly repeated, identical sequences of 81 residues. Blots of genomic DNA partially digested with restriction nucleases show that at least 25 of these identical repeats are present in apomucin. The amino acid composition of apomucin isolated in the absence of protease inhibitors was shown earlier (Eckhardt, A. E., Timpte, C. S., Abernethy, J. L., Toumadje, A., Johnson, W. C., Jr., and Hill, R. L. (1987) J. Biol. Chem. 282, 11339-11344) to be devoid of half-cystine. In contrast, the amino acid composition of mucin purified in the presence of protease inhibitors contains half-cystine in amounts predicted by the cDNA sequence and also suggests that this mucin has about 25 tandem repeats. Thus, apomucin contains at least 2800 amino acid residues. Moreover, immunoblots of apomucin prepared in the presence or the absence of protease inhibitors, with antibodies specific for the half-cystine-rich domains or the tandem repeat sequences, show that the half-cystine-rich domain is absent in apomucin unless protease inhibitors are present throughout. Both types of mucin, however, contain the highly repetitive sequences. The molecular weight of undegraded apomucin has not been established exactly, but gel filtration in 6 M guanidine hydrochloride suggests that it is considerably higher than 250,000. RNA blot analysis shows that apomucin mRNA is large and polydisperse in accord with the message size necessary to synthesize the large apomucin polypeptide. These structural features of apomucin suggest a model for the structure of the mucin molecule that correlates well with its reported properties.