Occupational Outcomes of Obesity Surgery-Do the Employed Return to Work, and Do the Unemployed Find Work?

BACKGROUND: Bariatric surgery offers excellent weight loss results and improvement in obesity-associated comorbidities. Many patients undergoing surgery are of working age, and so an understanding of any relationship between occupational outcomes and surgery is essential. The aim of this study was to ascertain the occupational outcomes of patients undergoing bariatric surgery at a high-volume centre. METHODS: A retrospective search was performed of a prospectively maintained consecutive electronic database. We collected data on patient demographics and employment status before and after bariatric surgery. All patients with a documented employment status within 30 months of surgery were included. Patients were divided into three groups: within 6 months post-operatively, 7-18 months post-operatively, and 19-30 months post-operatively. RESULTS: A total of 1011 patients were included. Median age was 47 years (range 18-78). Pre-operatively, 59.5% (444/746) were employed compared to 69.9% (707/1011) post-operatively (p < 0.05). The number of unemployed fell from 36.6% (273/746) pre-operatively to 21% (212/1011) post-operatively. The improvement in employment status was seen at all durations of follow-up. For those in employment pre-operatively, approximately 90% were still in employment at each subsequent follow-up. For those patients who were unemployed pre-operatively, approximately 40% were in employment at each subsequent follow-up. A significant improvement in the percentage employed was seen in all working age groups (p < 0.05). CONCLUSION: This is the largest study worldwide looking at employment outcomes following bariatric surgery. It demonstrates a significant increase in number of employed patients following bariatric surgery. Interestingly, it also showed that some patients employed pre-operatively become unemployed afterwards.

Preoperative endoscopy may reduce the need for revisional surgery for gastro-oesophageal reflux disease following laparoscopic sleeve gastrectomy.

Laparoscopic sleeve gastrectomy is a safe and effective bariatric operation, but postoperative reflux symptoms can sometimes necessitate revisional surgery. Roux-en-Y gastric bypass is the preferred operation in morbidly obese patients with gastro-oesophageal reflux disease. In 2011, we introduced preoperative endoscopy to assess for hiatus hernia or evidence of oesophagitis in conjunction with an assessment of gastro-oesophageal reflux symptoms for all patients undergoing bariatric surgery with a view to avoid sleeve gastrectomy for these patients. A prospectively maintained database was used to identify patients who underwent sleeve gastrectomy before and after we changed the unit policy. The need for revisional surgery in patients with troublesome gastro-oesophageal reflux disease was examined. Prior to 2011, 130 patients underwent sleeve gastrectomy, and 11 (8.5%) of them required conversion to Roux-en-Y gastric bypass for symptomatic reflux disease. Following the policy change, 284 patients underwent sleeve gastrectomy, and to date, only five (1.8%) have required revisional surgery (p = 0.001). Baseline demographics were comparable between the groups, and average follow-up period was 47 and 33 months, respectively, for each group. Preoperative endoscopy and a detailed clinical history regarding gastro-oesophageal reflux symptoms may improve patient selection for sleeve gastrectomy. Avoiding sleeve gastrectomy in patients with reflux disease and/or hiatus hernia may reduce the incidence of revisional surgery.

Mini Gastric Bypass: first report of 125 consecutive cases from United Kingdom.

Mini Gastric Bypass is a promising bariatric procedure with multiple apparent benefits. Ours is the first unit within the National Health Service of the United Kingdom to be routinely performing this procedure. This retrospective cohort study reports our experience with first 125 procedures. Data were retrospectively analysed from a prospective database. Information was further supplemented by interviewing team members, contacting patients' general practitioners and telephonic follow-up. The mean follow-up was 11.4 months. There were 86 (68.8%) females and the mean age was 45 (range 20-70) years. Mean weight and body mass index was 135.8 (range 85-244) kilograms and 48.1 (range 34.5-73.8) kg m(-2) , respectively. The mean operating time was 92.4 (range 45-150) minutes and the mean post-operative hospital stay was 2.2 (range 2-17) days. There was no leak, one 30-day reoperation and no mortality in this study. Three patients required late reoperations and four patients developed marginal ulcers. At 6 months follow-up (n = 114), 27.5 (range 11.4-47.4) % total body weight loss and 60.1 (range 23.2-117.5) % excess body weight loss was seen. The figures at 12 months follow-up (n = 65) were 36.8 (range 23.7-55.4) % and 79.5 (range 44.9-138.3) %, respectively. This study demonstrates early safety and efficacy of Mini Gastric Bypass in a carefully selected British obese population in a high-volume centre.

Renal Autotransplantation in Lynch Syndrome: A Viable Option in a Patient With Contralateral Metachronous Ureteral Cancer.

The success of human kidney allotransplantation was realized over six decades ago. First described 50 years ago, renal autotransplantation has been utilized sparingly as a salvage procedure for patients at risk of losing renal function, either from a benign or malignant condition. While classically associated with colorectal malignancies, Lynch syndrome also carries a small yet significant risk for the development of ureteral carcinoma. For these patients who develop chronic kidney disease, allotransplantation may not be an option due to the lifelong risk of several malignancies. We report the first known case of renal autotransplantation in a patient with metachronous ureteral cancer due to Lynch syndrome.

The accuracy of adult limb radiograph interpretation by emergency nurse practitioners: A prospective comparative study.

BACKGROUND: One of the extensions to practice for the emergency nurse practitioner role is to appropriately order and interpret radiographs in the emergency department. OBJECTIVE: The aim of the study was to compare the accuracy in interpreting isolated adult limb radiographs between emergency nurse practitioners and emergency physicians. DESIGN: A prospective comparative study was undertaken. SETTING: Emergency department in a large metropolitan hospital. PARTICIPANTS: 200 adult patients with isolated limb injuries were consented. METHODS: Six emergency nurse practitioners and ten emergency physicians participated. One emergency physician and emergency nurse practitioner independently clinically assessed each patient, determined the need for radiograph and separately recorded their interpretation of the radiograph as either definite fracture, no fracture or possible fracture. A single consultant radiologist reviewed each radiograph and their interpretation was seen as the gold standard. The sensitivity and specificity of emergency physicians and emergency nurse practitioners were calculated. To measure the level of agreement between the two-clinician groups, the weighted Kappa statistic was used. RESULTS: The sensitivity for the emergency nurse practitioners was 91% and 88% for the emergency physicians. The specificity for the emergency nurse practitioners was 85% and for the emergency physicians 91%. The weighted Kappa on the presence of a fracture between the emergency nurse practitioners and emergency physicians was 0.83. CONCLUSIONS: This study validates the clinical and diagnostic skills of emergency nurse practitioners assessed in the interpretation of isolated adult limb injury radiographs.

Revisional laparoscopic Roux-en-Y gastric bypass following failed laparoscopic adjustable gastric banding.

BACKGROUND: Obesity is a worldwide epidemic and surgery is the only proven long-term treatment. The two most commonly performed bariatric procedures are laparoscopic adjustable gastric banding (LAGB) and laparoscopic Roux-en-Y gastric bypass (LRYGB). There are advocates of both procedures but LAGB is associated with potentially high failure rates and may require conversion to an alternative procedure. METHODS: This study reports our unit results for failed LAGB converted to LRYGB and compares them to primary LRYGB patients. All patients undergoing revisional LRYGB from July 2006 to December 2011 were included in the study. Comparisons were made to patients undergoing primary LRYGB over the same time period for post-operative weight loss, complications and length of stay. RESULTS: Of the patients, 722 were analysed of which 55 underwent revisional surgery. There was no statistical difference in percentage of excess weight loss at 6 months, 1 year or 2 years following surgery between the primary and revisional surgery cohorts (54.5, 63.7, 65.2 vs 51.6, 59.5, 59.4, p = NS). There was no difference in morbidity, mortality or length of stay between the two groups. Revisional LRYGB was carried out as a single surgery in 43 (78 %) patients. CONCLUSIONS: Revisional LRYGB surgery can be carried out safely and efficiently in experienced bariatric units. Good short- and medium-term weight loss can be achieved with no increase in morbidity, mortality or length of hospital stay. This study adds weight to the argument that LRYGB is the revisional procedure of choice following failed LAGB.

The relationship of distance from the surgical centre on attendance and weight loss after laparoscopic gastric bypass surgery in the United Kingdom.

Obesity remains a significant worldwide health problem and is currently increasing. Surgery remains the only proven long-term intervention and has been shown to be cost-effective. Evidence suggests that regular follow-up following laparoscopic adjustable gastric banding is related to improved outcome, such evidence is lacking for laparoscopic gastric bypass surgery (laparoscopic Roux-en-Y gastric bypass [LRYGB]). This study examines the effect of distance on attendance at post-operative clinics and subsequent weight loss following surgery. A prospectively maintained database was interrogated to analyze patients undergoing LRYGB before August 2010. Patient demographics, percentage excess weight loss (%EWL), compliance with out-patient clinic attendances and the distance the patients lived from the hospital were examined. Perfect clinic attendees were compared with non-attendees and the distances patients lived from the hospital evaluated. There was a significantly greater %EWL at 1 year post-op observed in the perfect attendees group (65.5 vs. 59.5, P = 0.01). Increased %EWL was also evident at 2 years post-op but did not reach statistical significance (66.9 vs. 59.5, P = 0.06). There was a negative correlation observed between post-operative weight loss and distance from the bariatric centre (R = -0.21, P = 0.04). Close follow-up following LRYGB is essential to optimize outcomes. Increased frequency of out-patient clinic visits was associated with improved post-operative weight loss. Increasing distance between the patient's home and the bariatric centre was associated with worse post-operative weight loss.

Lymph node metastasis in early esophageal adenocarcinoma.

OBJECTIVE: To accurately document the incidence of lymph node metastases (LNM) in early esophageal adenocarcinoma with regard to the depth of invasion of the mucosa or submucosa. BACKGROUND: Endoscopic therapy is now being proposed as a viable treatment for submucosal esophageal adenocarcinoma. If such treatments are appropriate, then the risk of LNM must be shown to be low in these tumors. METHODS: One hundred nineteen consecutive patients underwent radical esophagectomy alone for treatment of superficial esophageal adenocarcinoma or high-grade dysplasia. The resection specimens were analyzed by an expert gastrointestinal pathologist and the presence of LNM and the depth of tumor invasion were recorded. Depth of invasion was classified as either confined to the mucosa, the first third of the submucosa, the middle third of the submucosa, or the final third of the submucosa. RESULTS: Fifty-four patients had high-grade dysplasia or tumors confined to the mucosa with no evidence of LNM (0/54, 0%), 65 patients had tumor invading the submucosa with 8 patients having LNM (8/65, 12%). Subclassification of submucosal invasion showed that 5 of 22 "first third of the submucosa" tumors had LNM (23%), 1 of 24 "middle third of the submucosa" tumors had LNM (4%), and 2 of 19 "final third of the submucosa" tumors had LNM (11%). CONCLUSION: Invasion of the submucosa is associated with significant risk of LNM. Patients with submucosal invasion are not suitable for endoscopic treatment and surgical resection remains the gold standard treatment for patients with submucosal adenocarcinoma who are fit to undergo the procedure.

Towards an understanding of the nature of resistance to Phytophthora root rot in red raspberry.

A mapping population segregating for root rot resistance was screened under both field and glasshouse conditions over a number of seasons. Few correlations between field and glasshouse scores were significant. Final root rot scores were significantly negatively correlated with measures of root vigour. Two QTL associated with resistance were identified as were overlapping QTL for root vigour assessments. Markers significantly associated with the traits were used to identify BAC clones, which were subsequently sequenced to examine gene content. A number of genes were identified including those associated with stem cell identity, cell proliferation and elongation in the root zone, control of meristematic activity and organisation, cell signalling, stress response, sugar sensing and control of gene expression as well as a range of transcription factors including those known to be associated with defence. For marker-assisted breeding, the SSR marker Rub118b 110 bp allele from Latham was found in resistant germplasm but was not found in any of the susceptible germplasm tested.

Prospective study of bone scintigraphy as a staging investigation for oesophageal carcinoma.

BACKGROUND: About 10 per cent of patients undergoing radical oesophagectomy for transmural (T3) carcinoma with lymph node involvement (N1) develop symptomatic bone metastases within 12 months of surgery. The aim of this study was to evaluate the introduction of targeted preoperative bone scintigraphy. METHODS: Of 790 patients with oesophageal carcinoma staged between December 2000 and December 2004, 189 were eligible for potentially curative treatment. (99m)Tc-labelled hydroxymethylene diphosphonate bone scintigraphy was performed in those with stage T3 N1 disease (identified by computed tomography and endoscopic ultrasonography) who were suitable for radical treatment. RESULTS: A total of 115 patients had bone scintigraphy. The histological diagnosis was adenocarcinoma in 82 patients and squamous cell carcinoma in 33. Bone scintigraphy was normal or showed degenerative changes in 93 patients, and abnormal requiring further investigation in 22. Plain radiography, magnetic resonance imaging and biopsy confirmed the presence of bone metastases in 11 patients (9.6 per cent). CONCLUSION: Bone is frequently the first site of identifiable distant metastatic spread, and bone scintigraphy is recommended to exclude metastatic disease before radical treatment of advanced oesophageal carcinoma.

The receptor tyrosine kinase EphB4 is overexpressed in ovarian cancer, provides survival signals and predicts poor outcome.

EphB4 is a member of the largest family of transmembrane receptor tyrosine kinases and plays critical roles in axonal pathfinding and blood vessel maturation. We wanted to determine the biological role of EphB4 in ovarian cancer. We studied the expression of EphB4 in seven normal ovarian specimens and 85 invasive ovarian carcinomas by immunohistochemistry. EphB4 expression was largely absent in normal ovarian surface epithelium, but was expressed in 86% of ovarian cancers. EphB4 expression was significantly associated with advanced stage of disease and the presence of ascites. Overexpression of EphB4 predicted poor survival in both univariate and multivariate analyses. We also studied the biological significance of EphB4 expression in ovarian tumour cells lines in vitro and in vivo. All five malignant ovarian tumour cell lines tested expressed higher levels of EphB4 compared with the two benign cell lines. Treatment of malignant, but not benign, ovarian tumour cell lines with progesterone, but not oestrogen, led to a 90% reduction in EphB4 levels that was associated with 50% reduction in cell survival. Inhibition of EphB4 expression by specific siRNA or antisense oligonucleotides significantly inhibited tumour cell viability by inducing apoptosis via activation of caspase-8, and also inhibited tumour cell invasion and migration. Furthermore, EphB4 antisense significantly inhibited growth of ovarian tumour xenografts and tumour microvasculature in vivo. Inhibition of EphB4 may hence have prognostic and therapeutic utility in ovarian carcinoma.

Definition of novel GP6 polymorphisms and major difference in haplotype frequencies between populations by a combination of in-depth exon resequencing and genotyping with tag single nucleotide polymorphisms.

BACKGROUND: Common genetic variants of cell surface receptors contribute to differences in functional responses and disease susceptibility. We have previously shown that single nucleotide polymorphisms (SNPs) in platelet glycoprotein VI (GP6) determine the extent of response to agonist. In addition, SNPs in the GP6 gene have been proposed as risk factors for coronary artery disease. METHODS: To completely characterize genetic variation in the GP6 gene we generated a high-resolution SNP map by sequencing the promoter, exons and consensus splice sequences in 94 non-related Caucasoids. In addition, we sequenced DNA encoding the ligand-binding domains of GP6 from non-human primates to determine the level of evolutionary conservation. RESULTS: Eighteen SNPs were identified, six of which encoded amino acid substitutions in the mature form of the protein. The single non-synonymous SNP identified in the exons encoding the ligand-binding domains, encoding for a 103Leu > Val substitution, resulted in reduced ligand binding. Two common protein isoforms were confirmed in Caucasoid with frequencies of 0.82 and 0.15. Variation at the GP6 locus was characterized further by determining SNP frequency in over 2000 individuals from different ethnic backgrounds. CONCLUSIONS: The SNPs were polymorphic in all populations studied although significant differences in allele frequencies were observed. Twelve additional GP6 protein isoforms were identified from the genotyping results and, despite extensive variation in GP6, the sequence of the ligand-binding domains is conserved. Sequences from non-human primates confirmed this observation. These data provide valuable information for the optimal selection of genetic variants for use in future association studies.

Differences in the response of a striped dolphin (Stenella coeruleoalba) and a harbour porpoise (Phocoena phocoena) to an acoustic alarm.

Small cetacean bycatch in gillnet fisheries may be reduced by deterring odontocetes from nets acoustically. However, different odontocete species may respond differently to acoustic signals from alarms. Therefore, in this study a striped dolphin and a harbour porpoise were subjected simultaneously to sounds produced by the XP-10 experimental acoustic alarm. The alarm produced 0.3s tonal signals randomly selected from a set of 16 with fundamental frequencies between 9 and 15kHz, with a constant pulse interval of 4.0s (duty cycle 8%) and a Source Level range of 133-163dB re 1muPa (rms). The effect of the alarm was judged by comparing the animals' respiration rate and position relative to the alarm during test periods with those during baseline periods. As in a previous study on two porpoises with the same alarm, the porpoise in the present study reacted strongly to the alarm by swimming away from it and increasing his respiration rate. The striped dolphin, however, showed no reaction to the active alarm. Based on harbour porpoise audiograms and the specific audiogram of the striped dolphin in the present study, and the low background noise levels during the experiment, both animals must have heard the alarm signals clearly. This study indicates that cetacean species are not equally sensitive to human-made noise disturbance. Therefore, source levels of acoustic alarms should be adapted to the species they are supposed to deter. In addition, alarms should be tested on each odontocete species for which they are intended to reduce bycatch.

The influence of acoustic emissions for underwater data transmission on the behaviour of harbour porpoises (Phocoena phocoena) in a floating pen.

To prevent grounding of ships and collisions between ships in shallow coastal waters, an underwater data collection and communication network is currently under development: Acoustic Communication network for Monitoring of underwater Environment in coastal areas (ACME). Marine mammals might be affected by ACME sounds since they use sounds of similar frequencies (around 12 kHz) for communication, orientation, and prey location. If marine mammals tend to avoid the vicinity of the transmitters, they may be kept away from ecologically important areas by ACME sounds. One marine mammal species that may be affected in the North Sea is the harbour porpoise. Therefore, as part of an environmental impact assessment program, two captive harbour porpoises were subjected to four sounds, three of which may be used in the underwater acoustic data communication network. The effect of each sound was judged by comparing the animals' positions and respiration rates during a test period with those during a baseline period. Each of the four sounds could be made a deterrent by increasing the amplitude of the sound. The porpoises reacted by swimming away from the sounds and by slightly, but significantly, increasing their respiration rate. From the sound pressure level distribution in the pen, and the distribution of the animals during test sessions, discomfort sound level thresholds were determined for each sound. In combination with information on sound propagation in the areas where the communication system may be deployed, the extent of the 'discomfort zone' can be estimated for several source levels (SLs). The discomfort zone is defined as the area around a sound source that harbour porpoises are expected to avoid. Based on these results, SLs can be selected that have an acceptable effect on harbour porpoises in particular areas. The discomfort zone of a communication sound depends on the selected sound, the selected SL, and the propagation characteristics of the area in which the sound system is operational. In shallow, winding coastal water courses, with sandbanks, etc., the type of habitat in which the ACME sounds will be produced, propagation loss cannot be accurately estimated by using a simple propagation model, but should be measured on site. The SL of the communication system should be adapted to each area (taking into account bounding conditions created by narrow channels, sound propagation variability due to environmental factors, and the importance of an area to the affected species). The discomfort zone should not prevent harbour porpoises from spending sufficient time in ecologically important areas (for instance feeding areas), or routes towards these areas.

Equine vaccine for West Nile virus.

To meet the urgent need of controlling West Nile virus (WNV) infection in the equine population, we have developed a killed WNV vaccine. A dose titration study in horses was first conducted to evaluate serum neutralization antibody responses against WNV in these animals. Horses were vaccinated intramuscularly twice with the test vaccine at low, medium and high dose, three weeks apart. Serum samples were collected periodically and were measured for serum neutralizing antibody using a plaque reduction neutralization test. Significant increases in serum neutralizing antibody were detected in all three dosage groups 14 days post the second vaccination. Twelve months after the second vaccination, horses vaccinated with the medium dose of WNV vaccine and non-vaccinated control horses were experimentally challenged with WNV. Nine out of 11 (81.8%) controls developed viraemia after challenge while only one out of 19 (5.3%) vaccinates had transient viraemia, representing a 94% preventable fraction. In a separate study, the safety of the killed WNV vaccine was demonstrated under field conditions. A total of 648 horses, including 32 pregnant mares, were enrolled in the study. During the two weeks post vaccination period, no local or systemic adverse reactions were observed following 96% of the vaccinations administered while mild, transient injection site reactions were noted in a small number of horses. These results indicate that the killed WNV vaccine developed by Fort Dodge Animal Health is safe and efficacious.

The identification of alpha-ketoamides as potent inhibitors of hepatitis C virus NS3-4A proteinase.

Peptides based upon the non-prime side residues of the NS4A-4B cleavage site of hepatitis C virus (HCV) NS3-4A proteinase containing an alpha-ketoamide moiety in place of the scissile amide bond are potent inhibitors of this enzyme.

Characterization, cloning and immunogenicity of antigens released by transforming cercariae of Schistosoma mansoni.

A schistosome infection is initiated when the parasite penetrates the skin of a susceptible host. Relatively large quantities of protein are released by transforming cercariae compared to later larval stages. This represents the first parasite material to which the host's immune system is exposed, yet little is known about the proteins which are released during the first few hours post-transformation. We have shown that antiserum raised against such molecules was capable of imparting protection against a schistosome challenge infection upon passive transfer to naïve mice. By screening a cercarial cDNA library with this serum, 38 positive clones were identified. Sequence analysis showed these to represent 8 different molecules which included Schistosoma mansoni 21-7 kDa antigen, calcium-binding-protein and the vaccine candidate glutathione S-transferase (Sm28GST). In addition, 5 clones were isolated, 1 of which had significant homology to many cytochrome C proteins, another with leukocyte elastase inhibitors and 3 which represented novel molecules. Four clones were expressed in a prokaryotic high-level expression vector, sera produced against each purified recombinant protein and used subsequently to probe Western blots and parasite sections. The leukocyte elastase inhibitor homologue and 2 unknowns induced significant proliferation by lymph node cells recovered from mice vaccinated with irradiated cercariae. More strikingly, the 2 novel proteins stimulated very high levels of interferon gamma (IFNgamma) secretion both by lymph node cells and those recovered by broncho-alveolar lavage from the lungs of vaccinated mice. Such results will be discussed in the context of vaccine development.

Children and computers: new technology--old concerns.

Computer technology has ushered in a new era of mass media, bringing with it great promise and great concerns about the effect on children's development and well-being. Although we tend to see these issues as being new, similar promises and concerns have accompanied each new wave of media technology throughout the past century: films in the early 1900s, radio in the 1920s, and television in the 1940s. With the introduction of each of these technologies, proponents touted the educational benefits for children, while opponents voiced fears about exposure to inappropriate commercial, sexual, and violent content. This article places current studies on children and computers in a historical context, noting the recurrent themes and patterns in media research during the twentieth century. Initial research concerning each innovation has tended to focus on issues of access and the amount of time children were spending with the new medium. As use of the technology became more prevalent, research shifted to issues related to content and its effects on children. Current research on children's use of computers is again following this pattern. But the increased level of interactivity now possible with computer games and with the communication features of the Internet has heightened both the promise of greatly enriched learning and the concerns related to increased risk of harm. As a result, research on the effects of exposure to various types of content has taken on a new sense of urgency. The authors conclude that to help inform and sustain the creation of more quality content for children, further research is needed on the effects of media on children, and new partnerships must be forged between industry, academia, and advocacy groups.

The design and synthesis of potent inhibitors of hepatitis C virus NS3-4A proteinase.

Hepatitis C virus (HCV) is the cause of the majority of transfusion-associated hepatitis and a significant proportion of community-acquired hepatitis worldwide. Infection by HCV frequently leads to persistent infections that result in a range of clinical conditions including an asymptomatic carrier state, severe chronic active hepatitis, cirrhosis and, in some cases, hepatocellular carcinoma. The HCV genome consists of a single-stranded, positive sense RNA containing an open reading frame of approximately 9060 nucleotides. This is translated into a single polyprotein of approximately 3020 amino acids (C-E1-E2-p7-NS2-NS3-NS4A-NS4B-NS5A-NS5B), which in turn is processed by a series of host and viral proteinases into at least 10 cleavage products. The N-terminal portion of the NS3 protein encodes a serine proteinase that is responsible for the cleavage at the NS3-4A, NS4A-4B, NS4B-5A and NS5A-5B junctions. The 54 amino acid NS4A protein is a cofactor that binds to the NS3 protein and enhances its proteolytic activity. This report describes the expression of a recombinant NS3-4A proteinase fusion protein in Escherichia coli and the in vitro characterization of the enzyme activity using synthetic peptide substrates. It then demonstrates how these results were employed to guide the design of potent inhibitors of this enzyme.