Timing of radiotherapy (RT) after radical prostatectomy (RP): long-term outcomes in the RADICALS-RT trial (NCT00541047).

BACKGROUND: The optimal timing of radiotherapy (RT) after radical prostatectomy for prostate cancer has been uncertain. RADICALS-RT compared efficacy and safety of adjuvant RT versus an observation policy with salvage RT for prostate-specific antigen (PSA) failure. PATIENTS AND METHODS: RADICALS-RT was a randomised controlled trial enrolling patients with ≥1 risk factor (pT3/4, Gleason 7-10, positive margins, preoperative PSA≥10 ng/ml) for recurrence after radical prostatectomy. Patients were randomised 1:1 to adjuvant RT ('Adjuvant-RT') or an observation policy with salvage RT for PSA failure ('Salvage-RT') defined as PSA≥0.1 ng/ml or three consecutive rises. Stratification factors were Gleason score, margin status, planned RT schedule (52.5 Gy/20 fractions or 66 Gy/33 fractions) and treatment centre. The primary outcome measure was freedom-from-distant-metastasis (FFDM), designed with 80% power to detect an improvement from 90% with Salvage-RT (control) to 95% at 10 years with Adjuvant-RT. Secondary outcome measures were biochemical progression-free survival, freedom from non-protocol hormone therapy, safety and patient-reported outcomes. Standard survival analysis methods were used; hazard ratio (HR)<1 favours Adjuvant-RT. RESULTS: Between October 2007 and December 2016, 1396 participants from UK, Denmark, Canada and Ireland were randomised: 699 Salvage-RT, 697 Adjuvant-RT. Allocated groups were balanced with a median age of 65 years. Ninety-three percent (649/697) Adjuvant-RT reported RT within 6 months after randomisation; 39% (270/699) Salvage-RT reported RT during follow-up. Median follow-up was 7.8 years. With 80 distant metastasis events, 10-year FFDM was 93% for Adjuvant-RT and 90% for Salvage-RT: HR=0.68 [95% confidence interval (CI) 0.43-1.07, P=0.095]. Of 109 deaths, 17 were due to prostate cancer. Overall survival was not improved (HR=0.980, 95% CI 0.667-1.440, P=0.917). Adjuvant-RT reported worse urinary and faecal incontinence 1 year after randomisation (P=0.001); faecal incontinence remained significant after 10 years (P=0.017). CONCLUSION: Long-term results from RADICALS-RT confirm adjuvant RT after radical prostatectomy increases the risk of urinary and bowel morbidity, but does not meaningfully improve disease control. An observation policy with salvage RT for PSA failure should be the current standard after radical prostatectomy. TRIAL IDENTIFICATION: RADICALS, RADICALS-RT, ISRCTN40814031, NCT00541047.

Addition of docetaxel to hormonal therapy in low- and high-burden metastatic hormone sensitive prostate cancer: long-term survival results from the STAMPEDE trial.

BACKGROUND: STAMPEDE has previously reported that the use of upfront docetaxel improved overall survival (OS) for metastatic hormone naïve prostate cancer patients starting long-term androgen deprivation therapy. We report on long-term outcomes stratified by metastatic burden for M1 patients. METHODS: We randomly allocated patients in 2 : 1 ratio to standard-of-care (SOC; control group) or SOC + docetaxel. Metastatic disease burden was categorised using retrospectively-collected baseline staging scans where available. Analysis used Cox regression models, adjusted for stratification factors, with emphasis on restricted mean survival time where hazards were non-proportional. RESULTS: Between 05 October 2005 and 31 March 2013, 1086 M1 patients were randomised to receive SOC (n = 724) or SOC + docetaxel (n = 362). Metastatic burden was assessable for 830/1086 (76%) patients; 362 (44%) had low and 468 (56%) high metastatic burden. Median follow-up was 78.2 months. There were 494 deaths on SOC (41% more than the previous report). There was good evidence of benefit of docetaxel over SOC on OS (HR = 0.81, 95% CI 0.69-0.95, P = 0.009) with no evidence of heterogeneity of docetaxel effect between metastatic burden sub-groups (interaction P = 0.827). Analysis of other outcomes found evidence of benefit for docetaxel over SOC in failure-free survival (HR = 0.66, 95% CI 0.57-0.76, P < 0.001) and progression-free survival (HR = 0.69, 95% CI 0.59-0.81, P < 0.001) with no evidence of heterogeneity of docetaxel effect between metastatic burden sub-groups (interaction P > 0.5 in each case). There was no evidence that docetaxel resulted in late toxicity compared with SOC: after 1 year, G3-5 toxicity was reported for 28% SOC and 27% docetaxel (in patients still on follow-up at 1 year without prior progression). CONCLUSIONS: The clinically significant benefit in survival for upfront docetaxel persists at longer follow-up, with no evidence that benefit differed by metastatic burden. We advocate that upfront docetaxel is considered for metastatic hormone naïve prostate cancer patients regardless of metastatic burden.

Adding abiraterone or docetaxel to long-term hormone therapy for prostate cancer: directly randomised data from the STAMPEDE multi-arm, multi-stage platform protocol.

Background: Adding abiraterone acetate with prednisolone (AAP) or docetaxel with prednisolone (DocP) to standard-of-care (SOC) each improved survival in systemic therapy for advanced or metastatic prostate cancer: evaluation of drug efficacy: a multi-arm multi-stage platform randomised controlled protocol recruiting patients with high-risk locally advanced or metastatic PCa starting long-term androgen deprivation therapy (ADT). The protocol provides the only direct, randomised comparative data of SOC + AAP versus SOC + DocP. Method: Recruitment to SOC + DocP and SOC + AAP overlapped November 2011 to March 2013. SOC was long-term ADT or, for most non-metastatic cases, ADT for ≥2 years and RT to the primary tumour. Stratified randomisation allocated pts 2 : 1 : 2 to SOC; SOC + docetaxel 75 mg/m2 3-weekly×6 + prednisolone 10 mg daily; or SOC + abiraterone acetate 1000 mg + prednisolone 5 mg daily. AAP duration depended on stage and intent to give radical RT. The primary outcome measure was death from any cause. Analyses used Cox proportional hazards and flexible parametric models, adjusted for stratification factors. This was not a formally powered comparison. A hazard ratio (HR) <1 favours SOC + AAP, and HR > 1 favours SOC + DocP. Results: A total of 566 consenting patients were contemporaneously randomised: 189 SOC + DocP and 377 SOC + AAP. The patients, balanced by allocated treatment were: 342 (60%) M1; 429 (76%) Gleason 8-10; 449 (79%) WHO performance status 0; median age 66 years and median PSA 56 ng/ml. With median follow-up 4 years, 149 deaths were reported. For overall survival, HR = 1.16 (95% CI 0.82-1.65); failure-free survival HR = 0.51 (95% CI 0.39-0.67); progression-free survival HR = 0.65 (95% CI 0.48-0.88); metastasis-free survival HR = 0.77 (95% CI 0.57-1.03); prostate cancer-specific survival HR = 1.02 (0.70-1.49); and symptomatic skeletal events HR = 0.83 (95% CI 0.55-1.25). In the safety population, the proportion reporting ≥1 grade 3, 4 or 5 adverse events ever was 36%, 13% and 1% SOC + DocP, and 40%, 7% and 1% SOC + AAP; prevalence 11% at 1 and 2 years on both arms. Relapse treatment patterns varied by arm. Conclusions: This direct, randomised comparative analysis of two new treatment standards for hormone-naïve prostate cancer showed no evidence of a difference in overall or prostate cancer-specific survival, nor in other important outcomes such as symptomatic skeletal events. Worst toxicity grade over entire time on trial was similar but comprised different toxicities in line with the known properties of the drugs. Trial registration: Clinicaltrials.gov: NCT00268476.

Low-temperature plasma treatment induces DNA damage leading to necrotic cell death in primary prostate epithelial cells.

BACKGROUND: In recent years, the rapidly advancing field of low-temperature atmospheric pressure plasmas has shown considerable promise for future translational biomedical applications, including cancer therapy, through the generation of reactive oxygen and nitrogen species. METHOD: The cytopathic effect of low-temperature plasma was first verified in two commonly used prostate cell lines: BPH-1 and PC-3 cells. The study was then extended to analyse the effects in paired normal and tumour (Gleason grade 7) prostate epithelial cells cultured directly from patient tissue. Hydrogen peroxide (H2O2) and staurosporine were used as controls throughout. RESULTS: Low-temperature plasma (LTP) exposure resulted in high levels of DNA damage, a reduction in cell viability, and colony-forming ability. H2O2 formed in the culture medium was a likely facilitator of these effects. Necrosis and autophagy were recorded in primary cells, whereas cell lines exhibited apoptosis and necrosis. CONCLUSIONS: This study demonstrates that LTP treatment causes cytotoxic insult in primary prostate cells, leading to rapid necrotic cell death. It also highlights the need to study primary cultures in order to gain more realistic insight into patient response.

HDAC inhibitor confers radiosensitivity to prostate stem-like cells.

BACKGROUND: Radiotherapy can be an effective treatment for prostate cancer, but radiorecurrent tumours do develop. Considering prostate cancer heterogeneity, we hypothesised that primitive stem-like cells may constitute the radiation-resistant fraction. METHODS: Primary cultures were derived from patients undergoing resection for prostate cancer or benign prostatic hyperplasia. After short-term culture, three populations of cells were sorted, reflecting the prostate epithelial hierarchy, namely stem-like cells (SCs, α2ß1integrin(hi)/CD133(+)), transit-amplifying (TA, α2ß1integrin(hi)/CD133(-)) and committed basal (CB, α2ß1integrin(lo)) cells. Radiosensitivity was measured by colony-forming efficiency (CFE) and DNA damage by comet assay and DNA damage foci quantification. Immunofluorescence and flow cytometry were used to measure heterochromatin. The HDAC (histone deacetylase) inhibitor Trichostatin A was used as a radiosensitiser. RESULTS: Stem-like cells had increased CFE post irradiation compared with the more differentiated cells (TA and CB). The SC population sustained fewer lethal double-strand breaks than either TA or CB cells, which correlated with SCs being less proliferative and having increased levels of heterochromatin. Finally, treatment with an HDAC inhibitor sensitised the SCs to radiation. INTERPRETATION: Prostate SCs are more radioresistant than more differentiated cell populations. We suggest that the primitive cells survive radiation therapy and that pre-treatment with HDAC inhibitors may sensitise this resistant fraction.

The natural history of low-risk non-muscle-invasive bladder cancer: a collaborative multi-centre study.

BACKGROUND: International guidelines vary in terms of their definition and recommendation for management of low-risk non-muscle-invasive bladder cancer (LRNMIBC). The ideal management for this large subset of bladder cancer patient remains unclear. OBJECTIVE: To evaluate long-term outcomes of patients with LRNMIBC. As a secondary objective, to assess for intergroup heterogeneity in disease-specific outcomes between G1 and G2LG diseases. METHODS: A multi-centre, retrospective study of patients who met the 2015 NICE definition of LRNMIBC. Timeline of diagnosis ranged from 01/01/2012 to 30/06/2016. RESULTS: A total 390 patients had available follow-up data (G1: 142, G2LG: 249). Over a median follow-up time of 36 months (IQR 25-50), 29.2% of the patients developed a recurrence. G2LG patients were statistically more likely to develop a recurrence (G1: 26.8%, G2LG: 33.7%, p < 0.05). 51.8% of recurrences occurred after 1 year of surveillance. Progression to high-grade disease occurred in 1.8% (n = 7, G1: 3, G2LG: 4) and a further 1.0% (n = 4, G1:3, G2LG: 1) of patients developed muscle-invasive bladder cancer (MIBC). CONCLUSION: The majority of recurrences occurred after 1 year of surveillance. The risk of disease progression was low; however, this was observed in a cohort of patients with regular cystoscopic follow-up. The risk may be higher if patients were pre-maturely discharged. If a 5-year surveillance programme were to be followed, 96.5% of recurrences would be captured. Lastly, there appears to be intergroup heterogeneity within LRNMIBC with G2LG patients having a statistically higher risk of recurrence compared to G1.

Use of granulated sugar therapy in the management of sloughy or necrotic wounds: a pilot study.

OBJECTIVE: To determine the in vitro antimicrobial efficacy of three types of sugar and conduct a pilot clinical study with a view to developing a protocol for a randomised controlled trial (RCT). METHOD: In the in vitro studies three types of granulated sugar (Demerara, granulated beet sugar and granulated cane sugar) were tested to determine their minimum inhibitory concentrations (MICs) against 18 Gram-negative and Gram-positive bacteria in a micro-titre broth dilution assay; growth inhibition of Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa in different concentrations of sugar (0.38-25%) was also tested over 12-hours in an agar diffusion assay. The pilot clinical study selected patients from a vascular surgical ward and a vascular outpatient department. All had acute or chronic exuding wounds, some of which were infected. White granulated sugar was applied to the wounds. The following parameters were assessed: surface area; wound characteristics including pain, malodour, appearance (slough/granulation); exudate level; pain level and bacterial load. Patients with diabetes had their blood sugar levels checked daily. All patients completed a short health questionnaire at the start and end of the study. Staff completed a satisfaction questionnaire at the end of the study. The study period was 21 days. RESULTS: In vitro tests demonstrated that sugar inhibits bacterial growth. All three types of sugars had MICs ranging from 6-25% in the bacterial strains tested. The diffusion tests showed that strains were able to grow well in low concentrations of sugar but were completely inhibited in higher concentrations. The two granulated sugars were found to be slightly more effective than Demerara sugar, so the latter was excluded from the clinical pilot study. Twenty-two patients (20 inpatients and two outpatients) with sloughy or necrotic wounds were recruited into the clinical study. Two patients had MRSA and two had Staphylococcus colonisation at baseline. Blood sugar levels remained stable in the seven patients with insulin-dependent diabetes mellitus. All wounds were clean/debrided in a mean of 11.13 days. Pain and malodour reduced markedly. Patient and staff surveys revealed overwhelming support for the sugar therapy. CONCLUSION: The pilot study achieved its aim of developing a protocol for a RCT. Preliminary data suggest that sugar is an effective wound cleansing and is safe to use in patients with insulin-dependent diabetes. In vitro studies demonstrate that sugar inhibits bacterial growth. CONFLICT OF INTEREST: None.

The genetic basis of colorectal cancer in a population-based incident cohort with a high rate of familial disease.

BACKGROUND AND AIMS: Colorectal cancer (CRC) is the second most frequent cancer in developed countries. Newfoundland has the highest incidence of CRC in Canada and the highest rate of familial CRC yet reported in the world. To determine the impact of mutations in known CRC susceptibility genes and the contribution of the known pathways to the development of hereditary CRC, an incident cohort of 750 patients with CRC (708 different families) from the Newfoundland population was studied. METHODS: Microsatellite instability (MSI) testing was performed on tumours, together with immunohistochemistry analysis for mismatch repair (MMR) genes. Where indicated, DNA sequencing and multiplex ligation-dependent probe amplifications of MMR genes and APC was undertaken. DNA from all patients was screened for MUTYH mutations. The presence of the BRAF variant, p.V600E, and of MLH1 promoter methylation was also tested in tumours. RESULTS: 4.6% of patients fulfilled the Amsterdam criteria (AC), and an additional 44.6% fulfilled the revised Bethesda criteria. MSI-high (MSI-H) was observed in 10.7% (n=78) of 732 tumours. In 3.6% (n=27) of patients, CRC was attributed to 12 different inherited mutations in six known CRC-related genes associated with chromosomal instability or MSI pathways. Seven patients (0.9%) carried a mutation in APC or biallelic mutations in MUTYH. Of 20 patients (2.7%) with mutations in MMR genes, 14 (70%) had one of two MSH2 founder mutations. 17 of 28 (61%) AC families did not have a genetic cause identified, of which 15 kindreds fulfilled the criteria for familial CRC type X (FCCTX). CONCLUSIONS: Founder mutations accounted for only 2.1% of cases and this was insufficient to explain the high rate of familial CRC. Many of the families classified as FCCTX may have highly penetrant mutations segregating in a Mendelian-like manner. These families will be important for identifying additional CRC susceptibility loci.

Surgical treatment of the neuroischemic foot.

As many as 1% of older people in the Western world are at risk of developing a foot ulcer as a complication of diabetes mellitus. The resultant debility and disability constitutes a burden for both individuals and their health services. When peripheral arterial insufficiency complicates neuropathy there is a tenfold risk of ulceration progressing to infection, gangrene and amputation. Patient education and the vigilant implementation of preventive measures offer the best prospects for containment of the problem. Patients faced with ulceration and limb loss require access to a co-ordinated and comprehensive diabetic foot service offering detailed assessment and a full range of social, medical and surgical therapies.

Long-term results of surgical repair of popliteal artery aneurysm.

OBJECTIVE: To determine the long-term outcome of surgical repair of popliteal artery aneurysms (PAA). METHODS: A retrospective review of consecutive patients who underwent surgical PAA repair in two vascular surgery units between 1988 and 2006 was performed. Primary and secondary graft patency, limb salvage and patient survival rates were determined using Kaplan-Meier methods. RESULTS: 48 patients underwent repair of 63 PAAs (ligation and bypass=45, interposition grafting=18). The 5-year primary graft patency, secondary graft patency, limb salvage and patient survival rates were 75%, 95%, 98% and 81%, respectively. The 10-year primary graft patency rates were significantly lower for emergency cases (59%) compared with elective cases (66%) (p=0.0023). Thirteen patients (16 PAAs) required a total of 20 late re-interventions. Duplex ultrasound was available in 33 of 45 PAAs treated by ligation and bypass. Five (15%) PAAs demonstrated perfusion of the aneurysm sac at median (range) follow up of 75 (1-246) months after primary repair and two of these required emergency re-operation. CONCLUSIONS: These data demonstrate that surgical PAA repair is associated with excellent long-term durability and provide an important benchmark with which to compare results of endovascular PAA repair. Patients treated using the ligation and bypass technique should be enrolled in an aneurysm sac surveillance program.

The management of lymph node metastasis from bladder cancer.

AIM: The presence of pelvic lymph node metastasis from bladder cancer has traditionally been associated with a very poor prognosis. The aim of this paper is to review the literature with regard to the management of patients with nodal disease, particularly gross nodal metastasis and suggest a strategy for management of these patients. METHODS: We performed a literature search in the PubMed database and the reference lists of relevant papers describing the management of locally advanced bladder cancer. FINDINGS: There are no randomised studies relating specifically to the management of nodal metastasis in bladder cancer. It is clear however that a significant number of patients with micrometastatic nodal disease may be cured. Few studies exist which address the management of patients with gross nodal disease and consist of series from a limited number of institutions. In patients with gross nodal disease detected pre-operatively or at the time of surgery, a multimodality approach consisting of surgery, chemotherapy and possibly radiotherapy seems appropriate. The prognosis of such patients relates to the pathological stage of the primary tumour and the degree of lymph node involvement. In addition a good response to neoadjuvant chemotherapy may identify patients who are likely to survive longer. CONCLUSIONS: The prognosis for patients with gross nodal disease from bladder cancer is poor although cure may be possible in a small number of patients. In such cases a multimodality approach is appropriate and management decisions should be made on an individual patient basis.

Well leg compartment syndrome after pelvic and perineal surgery in the lithotomy position.

OBJECTIVE: Lower limb compartment syndrome after prolonged surgical procedures performed in the lithotomy position is a rare but potentially devastating complication. It is recognised after urological, colorectal, and gynaecological procedures. Sixteen cases of compartment syndrome after urological surgery have been reported. The objective of this study was to estimate the incidence of this complication in urological practice and identify risk factors for its development. DESIGN: A postal survey of UK consultant urologists was conducted. RESULTS: Replies were received from 261 consultants. In total there were 65 cases of compartment syndrome. Compartment syndrome occurred after radical cystectomy and urinary diversion in 51 cases and was rare in procedures lasting less than four hours. The incidence of compartment syndrome after cystectomy was estimated at around 1 in 500 cases. Risk factors for its development included perioperative blood loss, peripheral vascular disease, and obesity. CONCLUSIONS: Compartment syndrome after use of the lithotomy position may be more common than is generally appreciated and has been underreported in the past. All staff should be aware of this serious complication and adopt strategies for its avoidance.

Thrombosis in the emergency department: use of a clinical diagnosis model to safely avoid the need for urgent radiological investigation.

CONTEXT: The management of patients presenting to hospital emergency departments with suspected deep vein thrombosis (DVT) is problematic because urgent diagnostic imaging capability is sometimes unavailable. Experienced physicians using clinical skills alone can classify patients with suspected DVT into low-, moderate-, and high-probability categories. OBJECTIVES: To determine the accuracy of an explicit clinical model for the diagnosis of DVT when applied by emergency department physicians and to assess the safety and feasibility of a management strategy based on the clinical pretest probability for patients presenting to the emergency department with suspected DVT outside of regular hospital staff work hours. METHODS: A prospective cohort study was performed in the emergency departments of 2 tertiary care institutions involving 344 patients with suspected DVT. Patient conditions were evaluated by an emergency department physician who determined the pretest probability for DVT to be low, moderate, or high using an explicit clinical model. Patients for whom DVT was considered a low pretest probability were discharged from the emergency department and returned the following day for venous compression ultrasound imaging of the affected leg. Patients for whom DVT was considered a moderate pre-test probability received a single, weight-adjusted dose of subcutaneous unfractionated heparin sodium (between 12 500 and 20 000 U), were discharged from the emergency department, and returned the next morning to undergo ultrasonography. Patients for whom DVT was considered a high pretest probability were admitted to the hospital, administered intravenous unfractionated heparin, and ultrasonography was arranged within 24 hours. Patients with positive ultrasonographic findings were diagnosed with DVT, except for those with low pretest probability for whom confirmatory venography was performed. Patients with DVT excluded in the initial evaluation period did not receive anticoagulant therapy. All patients were followed up for 90 days to monitor development of thromboembolic or bleeding complications. RESULTS: Twenty-four (49.0% [95% confidence interval (CI), 34.5%-63.6%]) of 49 patients in the high-probability category, 15 (14.3% [95% CI, 8.3%-22.4%]) of 105 in the moderate-, and 6 (3.2% [95% CI, 1.2%-6.7%]) of 190 in the low-probability category were confirmed to have DVT. Overall, 45 (13.1%) of 344 patients were confirmed to have DVT. No patient developed pulmonary embolism or major bleeding complications within 48 hours of initial evaluation in the emergency department. Of the 301 patients who had DVT excluded during the initial evaluation period, only 2 (0.7% [95% CI, 0.1%-2.3%]) developed venous thromboembolic complications (calf vein thromboses in both) in the 3-month follow-up period. CONCLUSIONS: Using an explicit clinical model, emergency department physicians can accurately classify patients with suspected DVT into high-, moderate-, and low-probability groups. A management plan based on probability for DVT that avoids the need for urgent diagnostic imaging is safe and feasible in the emergency department setting.

FAST on operational military deployment.

BACKGROUND AND OBJECTIVE: Handheld ultrasound, because of its light weight, size, rugged design, and relative simplicity of use is ideal for use on operational military deployment. These machines have been used in the diagnosis of a range of traumatic conditions including abdominal, thoracic, and extremity trauma in the hospital environment, yet few data exist on their use during military operations. This paper presents experience of handheld focused assessment with sonography for trauma (FAST) on operational military deployment. METHOD: Over a two month period, handheld FAST was performed by a single surgeon during the circulation phase of the primary survey in trauma patients presenting to the British Military Hospital in Iraq. RESULTS: Fifteen from casualties underwent a FAST examination. Ten were victims of blunt trauma, two had received injuries anti-personnel mines, and three had penetrating injuries from ballistic trauma. There was one positive FAST, confirmed at laparotomy as bleeding from a liver injury. Thirteen scans were negative and remained negative on repeat FAST at 6 hours. One further patient with a negative FAST underwent laparotomy because of transectory, there was no intra-abdominal blood or fluid at surgery. CONCLUSION: Handheld FAST is a valuable technique for investigating abdominal or thoracic bleeding in single or multiple casualty events on operational military deployment.

Comparative analysis of catalases: spectral evidence against heme-bound water for the solution enzymes.

A recent X-ray structural analysis of M. luteus catalase indicates heme-bound H2O trans to the proximal tyrosinate ligand, a finding in contrast to previous X-ray data reporting a 5-coordinate heme for bovine liver catalase. The presence of heme-bound H2O, requiring displacement prior to substrate-binding, is likely to be catalytically significant for catalases. We have used magnetic circular dichroism (MCD) spectroscopy, a highly accurate method for assignment of heme spin- and coordination-states, to study native, solution forms of bovine liver, M. luteus, and A. niger catalases. All three enzymes display similar spectral features with the weak (approximately 5 delta epsilon M [moles.cm.Tesla]-1) intensity typical of a 5-coordinate high-spin ferric heme. No evidence for H2O-ligation, inducing a 6-coordinate heme, occurred upon variation of pH or buffer composition. Therefore, we suggest that the catalytically significant structure of catalases has an unoccupied heme binding site trans to the proximal tyrosinate heme ligand.

An analysis of 110 serious enterococcal infections. Epidemiology, antibiotic susceptibility, and outcome.

A prospective, observational study of 110 patients with serious infections due to Enterococcus spp. in 6 university and community teaching hospitals in Connecticut was conducted to define the epidemiology of community and nosocomial serious enterococcal infections and to determine risk factors, including antibiotic resistances, that contribute to outcome. Serious community and nosocomial enterococcal infections involved a variety of sites, and antibiotic resistance was common. Types of infection by major organ system were cardiovascular, 54% (catheter-related bacteremia 28%, primary bacteremia 18%, endocarditis 6%, septic thrombophlebitis 1%); intra-abdominal, 13% (including cholangitis, 6%); renal, 13%; skin and soft tissue, 5%; bone and joint, 4%; pleuropulmonary, 4%; central nervous system, 3%; deep surgical wound, 3%; and endometritis, 2%. Sixty-one percent of infections were nosocomial; 48% of these occurred in the intensive care unit. Enterococcus faecium was responsible for 20% of all infections. Antibiotic resistances among the infections included high-level gentamicin resistance (26%), ampicillin resistance (10%), and vancomycin resistance (8%). Clinical cure was achieved in 64% of patients; 6.8% of patients relapsed, 6.8% had recurrence of the infection with a different pathogen, and overall mortality was 23%. Ampicillin resistance and a high acute physiology and chronic health evaluation (APACHE) II score were highly predictive of lack of cure.

Cefoperazone versus ceftazidime monotherapy of nosocomial pneumonia.

Cefoperazone and ceftazidime monotherapy were compared in a randomized, prospective evaluation of patients with nosocomial pneumonia. These antibiotics were equally effective, with an overall successful treatment rate of 45 of 62 (73 percent) for cefoperazone-treated patients and 50 of 63 (79 percent) for ceftazidime-treated patients (p = 0.41). There was no difference in the incidence of side effects (including hypoprothrombinemia), superinfections, or colonization of the oropharynx with yeast, enterococcus, Staphylococcus aureus, or resistant gram-negative bacilli. When antibiotic administration, and laboratory costs are considered, cefoperazone is less expensive than ceftazidime. Both cefoperazone and ceftazidime are effective therapy for nosocomial pneumonia.

Specialized assessments for children in foster care.

OBJECTIVE: To investigate the differences in health problems identified and health services received by children newly entering foster care who participated in a comprehensive multidisciplinary program, compared with children newly entering foster care who received customary community-based services. METHODS: Using a 2-group quasiexperimental design, 120 young children entering foster care were enrolled in a multidisciplinary intervention program (n = 62) or were followed by customary care providers (n = 58). An interview with the foster parent; a complete medical examination; and a battery of developmental, psychological, speech/language, and motor assessments were completed for each child at baseline. Children in both groups participated in follow-up assessments at 6 and 12 months. RESULTS: No significant differences between the 2 groups existed in medical, educational, developmental, or mental health problems identified by foster mothers. However, children in the intervention group were more likely to be identified with developmental (56.5% vs 8.6%) and mental health problems (37.1% vs 13.8%) by providers than children in the comparison group. Children in the intervention group were also more likely to be referred for health services at baseline (71.0% vs 43.1%) and receive follow-up care at 6 and 12 months of age than children in the comparison group. CONCLUSIONS: Findings indicate that community providers identify medical and educational needs but do not recognize developmental and mental health needs of young children newly entering foster care. The discrepancies in the number of recommended services and follow-up care between the 2 groups make a case for the establishment of specialized services for children entering out-of-home care.