Striving to Limit the Impact: Parenting an Adult Child Who Has Multiple Sclerosis-A Grounded Theory Study.

BACKGROUND: Multiple sclerosis (MS) is a chronic, progressive autoimmune inflammatory disorder. Its impact is felt not only by individuals but also by their families; however, little is known about the effect on their parents. This study of a cohort from the United Kingdom aimed to develop a conceptual understanding of the parental role and how it changes over time when an adult son or daughter has MS via firsthand accounts. METHODS: Twelve parents of adults with MS were recruited from a UK hospital providing outpatient services to people with MS and a branch of a national MS charity. A social constructivist grounded theory approach informed audio-recorded semistructured interviews and subsequent data analysis. RESULTS: In this sample, parents of adults with MS strove to limit the impact of MS on their son or daughter by undertaking practical caring activities and providing emotional support. The developed theoretical model illustrates how, in their efforts to meet this aim, parents experienced competing demands between prioritizing their child's needs and managing the effects on their life, between managing the emotional experience and protecting their child from the burden of their experience, and between an intensified instinct/desire to help while maintaining their child's independence. CONCLUSIONS: Findings indicate that parents may be uniquely affected by their adult son or daughter having MS, advocating for their inclusion in research and clinical interventions addressing family adjustment to MS. Further research is needed to ascertain the generalizability of these findings in comparable samples and to determine the impact of sociodemographic and cultural variables on the observed phenomena.

Identification and Structure-Guided Development of Pyrimidinone Based USP7 Inhibitors.

Ubiquitin specific protease 7 (USP7, HAUSP) has become an attractive target in drug discovery due to the role it plays in modulating Mdm2 levels and consequently p53. Increasing interest in USP7 is emerging due to its potential involvement in oncogenic pathways as well as possible roles in both metabolic and immune disorders in addition to viral infections. Potent, novel, and selective inhibitors of USP7 have been developed using both rational and structure-guided design enabled by high-resolution cocrystallography. Initial hits were identified via fragment-based screening, scaffold-hopping, and hybridization exercises. Two distinct subseries are described along with associated structure-activity relationship trends, as are initial efforts aimed at developing compounds suitable for in vivo experiments. Overall, these discoveries will enable further research into the wider biological role of USP7.

Novel triazolo-pyrrolopyridines as inhibitors of Janus kinase 1.

The identification of a novel fused triazolo-pyrrolopyridine scaffold, optimized derivatives of which display nanomolar inhibition of Janus kinase 1, is described. Prototypical example 3 demonstrated lower cell potency shift, better permeability in cells and higher oral exposure in rat than the corresponding, previously reported, imidazo-pyrrolopyridine analogue 2. Examples 6, 7 and 18 were subsequently identified from an optimization campaign and demonstrated modest selectivity over JAK2, moderate to good oral bioavailability in rat with overall pharmacokinetic profiles comparable to that reported for an approved pan-JAK inhibitor (tofacitinib).

Identification of C-2 hydroxyethyl imidazopyrrolopyridines as potent JAK1 inhibitors with favorable physicochemical properties and high selectivity over JAK2.

Herein we report on the structure-based discovery of a C-2 hydroxyethyl moiety which provided consistently high levels of selectivity for JAK1 over JAK2 to the imidazopyrrolopyridine series of JAK1 inhibitors. X-ray structures of a C-2 hydroxyethyl analogue in complex with both JAK1 and JAK2 revealed differential ligand/protein interactions between the two isoforms and offered an explanation for the observed selectivity. Analysis of historical data from related molecules was used to develop a set of physicochemical compound design parameters to impart desirable properties such as acceptable membrane permeability, potent whole blood activity, and a high degree of metabolic stability. This work culminated in the identification of a highly JAK1 selective compound (31) exhibiting favorable oral bioavailability across a range of preclinical species and robust efficacy in a rat CIA model.

Discovery and optimization of C-2 methyl imidazopyrrolopyridines as potent and orally bioavailable JAK1 inhibitors with selectivity over JAK2.

Herein we report the discovery of the C-2 methyl substituted imidazopyrrolopyridine series and its optimization to provide potent and orally bioavailable JAK1 inhibitors with selectivity over JAK2. The C-2 methyl substituted inhibitor 4 exhibited not only improved JAK1 potency relative to unsubstituted compound 3 but also notable JAK1 vs JAK2 selectivity (20-fold and >33-fold in biochemical and cell-based assays, respectively). Features of the X-ray structures of 4 in complex with both JAK1 and JAK2 are delineated. Efforts to improve the in vitro and in vivo ADME properties of 4 while maintaining JAK1 selectivity are described, culminating in the discovery of a highly optimized and balanced inhibitor (20). Details of the biological characterization of 20 are disclosed including JAK1 vs JAK2 selectivity levels, preclinical in vivo PK profiles, performance in an in vivo JAK1-mediated PK/PD model, and attributes of an X-ray structure in complex with JAK1.

Identification of imidazo-pyrrolopyridines as novel and potent JAK1 inhibitors.

A therapeutic rationale is proposed for the treatment of inflammatory diseases, such as rheumatoid arthritis (RA), by specific targeting of the JAK1 pathway. Examination of the preferred binding conformation of clinically effective, pan-JAK inhibitor 1 led to identification of a novel, tricyclic hinge binding scaffold 3. Exploration of SAR through a series of cycloamino and cycloalkylamino analogues demonstrated this template to be highly tolerant of substitution, with a predisposition to moderate selectivity for the JAK1 isoform over JAK2. This study culminated in the identification of subnanomolar JAK1 inhibitors such as 22 and 49, having excellent cell potency, good rat pharmacokinetic characteristics, and excellent kinase selectivity. Determination of the binding modes of the series in JAK1 and JAK2 by X-ray crystallography supported the design of analogues to enhance affinity and selectivity.

Liver resection: a regional hospital experience.

BACKGROUND: Liver resection is a significant operation usually limited to large metropolitan hospitals. Liver resections were first performed at the Launceston General Hospital (LGH), a regional centre (bed capacity 280), in May 2000. This is a summary of liver resection at LGH. METHODS: Data of liver resections performed between May 2000 and March 2008 at LGH were collected retro-prospectively and reviewed with attention to patient survival, post-operative complications and mortality. RESULTS: There were 102 consecutive liver resections during the study period. Metastatic colorectal adenocarcinoma was the most frequent pathology (n = 61). Six patients had metastases from primaries other than colorectal cancer. There were 13 resections for primary liver malignancy, 2 from invasion by gallbladder carcinoma, 1 for contiguous invasion by gastric cancer and 19 were for benign conditions. Thirteen patients had post-operative wound infections and six had significant bile leaks. There were five deaths in-hospital (surgical mortality 4.9%). At the end of the study period, 51 cancer patients were still alive (14 with disease recurrences) and 30 have died (23 from recurrent diseases). Patients operated for colorectal cancer metastases achieved a 44% 5-year survival rate (median survival = 46 months). Patients with hepatocellular carcinoma had 3-year survival rate of 15% (median survival = 24 months). CONCLUSION: Resection provides the best hope of cure for patients with primary or secondary hepatic malignancy. With adequate expertise, liver resections can be performed safely in a regional hospital.

Risk factors for type II endoleaks after endovascular repair of abdominal aortic aneurysms.

BACKGROUND: Endovascular repair has been shown to be superior to open repair of abdominal aortic aneurysm in terms of aneurysm-related survival. However, endovascular repair has its own unique complications such as endoleak. Type II endoleaks may be associated with aortic rupture. We attempt to identify patient variables associated with the development of endoleaks and hence facilitate their early identification. METHODS: Endovascular repair was carried out for non-ruptured, infrarenal abdominal aortic aneurysms. Patients underwent preoperative computed tomography and angiography and were followed up with computed tomography and/or ultrasound scan at 1, 3 and 6 months and yearly thereafter. Univariate and multivariate analysis was used to identify any patient factors associated with the risk for developing an endoleak. RESULTS: One hundred and one patients were included in the study (12 female : 89 male). Age 59-93 years. Mean follow up was 20.2 months. Type II endoleaks developed in 26 (25.7%) patients. Fifteen cases resolved during follow up, three of which required secondary intervention. Nine cases persist. No aneurysms ruptured. The presence of patent inferior mesenteric artery (P < 0.001) and sac enlargement (P = 0.001) were associated with development of endoleak as was diabetes in a multivariate model (P = 0.005). History of smoking (P = 0.01) was a protective factor. The presence of four or more lumbar arteries (P = 0.55) was not associated with increased risk. CONCLUSIONS: It is possible to identify individual patient risk factors associated with risk for developing type II endoleaks and it may be possible to modify screening practice as a result. The association between patent inferior mesenteric artery preoperatively and endoleak is further confirmed. Spontaneous sealing of endoleaks is common and rupture is rare. Early intervention is not mandatory.

Australian Vascular Quality of Life Index (AUSVIQUOL): a pilot study of a disease-specific quality of life measure.

BACKGROUND: To develop and test a quality of life (QOL) index specific for patients with vascular disease and appropriate for patients with abdominal aortic aneurysm (AAA) in the clinical setting. METHODS: The questions and domains of the Australian Vascular Quality of Life Index (AUSVIQUOL) were determined by examination of a prospective database for frequency of symptoms and an in-depth interview of a sample population. The validity of the AUSVIQUOL was tested by comparing it with the Medical Outcomes Short Form Health Survey (SF-36) in a study involving 60 patients who underwent endovascular AAA repair and 48 open AAA repair. A subpopulation of 22 patients representative of the two groups was then reassessed using the SF-36 and the AUSVIQUOL, to compare the reliability of the two indices. RESULTS: Similar domains of the SF-36 and the AUSVIQUOL measured common QOL elements. The correlation between the two indices was moderate; the AUSVIQUOL measured additional disease-specific QOL factors. The AUSVIQUOL showed better reliability than the SF-36 in all domains and statistically better in the physical function domain (P < 0.05). CONCLUSION: The AUSVIQUOL is an appropriate tool for the QOL assessment of patients with AAA in the clinical setting.

Endovascular abdominal aortic aneurysm repair: a 7 year experience at the Launceston General Hospital.

BACKGROUND: To review our 7 year experience of endovascular abdominal aortic aneurysm repair (EVR) and to compare this to open repair (OR) during the same time period. METHODS: One hundred and one EVR and 65 OR patients were studied. Parameters analysed included patient and procedure details, intensive care unit (ICU) and hospital admission time, and morbidity and mortality with particular emphasis on procedure-related problems. RESULTS: Endovascular grafts were deployed with successful abdominal aortic aneurysm (AAA) exclusion in 100 patients. Primary technical success was achieved in 84%, clinical success in 86% and secondary success in 90% of cases. Complications occurred in 63% and 88% of EVR and OR patients, respectively. Early device-related complications occurred in 40 EVR patients (40%); 24 (60%) were corrected immediately by further stenting. Late device-related complications occurred in 15 EVR patients (15%); four (27%) required additional stenting. Most of the complications in the OR group were systemic (89%) resulting in longer ICU and hospital stays (median 48 vs 17 h and 13 vs 4 days for OR and EVR, respectively). Death within 30 days of the procedure occurred in three EVR patients. There was no perioperative mortality in the OR group. CONCLUSION: Endovascular AAA repair can be undertaken successfully in a district general hospital. The majority of local and device-related complications can be corrected immediately, while those persisting beyond the initial procedure usually resolve spontaneously. EVR offers a minimally invasive approach to a problem that in the past has involved major surgery.

A concise total synthesis of (+)-okaramine C.

The first total synthesis of (+)-okaramine C is described. Our previously described selenocyclisation-oxidative deselenation sequence was used to establish a 3a-hydroxy-pyrrolo[2,3-b]indole core, which was modified by selective epimerisation to the common pyrrolo[2,3-b]indole of the okaramines.

Surgical masks: operative field contamination following visor-to-visor contact.

BACKGROUND: Clashing of surgical visor masks frequently occurs when two surgeons bend over an operative field simultaneously; however, it is unknown whether this results in contamination. The purpose of the present study was to determine the potential for operative field contamination following surgical visor-mask clashes. The nature of bacterial contamination was also assessed. METHODS: Thirty sham operative procedures were performed under normal operating conditions for a specified time period. The number of surgical visor mask clashes during each procedure was determined by randomization (0, 1, 2, 3, 4 or 6 clashes). All procedures were performed over a standard blood agar plate array. The degree of bacterial contamination was assessed by counting c.f.u. that developed after 24 h of incubation. Bacterial types were also determined. RESULTS: Surgical visor mask clashes resulted in increased contamination of the operative field; however, this was found to be independent of the number of clashes. 95% of pathogens were coagulase negative Staphylococcus species. Other bacteria included Micrococcus species, Bacillus species, Corynebacterium species, various Gram negative bacilli and Staphylococcus aureus (< 1%). CONCLUSION: Surgical visor mask clashes increase the risk of bacterial contamination of the operative field.

A rapid stereocontrolled synthesis of the 3a-hydroxy-pyrrolo[2,3-b]indole skeleton, a building block for 10b-hydroxy-pyrazino[1',2':1,5]pyrrolo[2,3-b]indole-1,4-diones.

A two-step selenocyclisation-oxidative deselenaton sequence was used to establish the 3a-hydroxy-pyrrolo[2,3-b]indole core; these tricycles were used as effective precursors to 10b-hydroxy-pyrazino[1',2':1,5]pyrrolo[2,3-b]indole-1,4-diones.

Elective laparoscopic cholecystectomy: implications of prolonged waiting times for surgery.

BACKGROUND: The aim of the present study was to assess the impact of surgical waiting times on patients scheduled for elective laparoscopic cholecystectomy (LC), with emphasis on morbidity and costs incurred. METHODS: A retrospective review of all patients who underwent cholecystectomy at the Launceston General Hospital between 1 January 1999 and 31 December 2001 was performed. RESULTS: A total of 322 LCs was performed during the study period. Median time on the waiting list was 130 (1-1481) days. While awaiting surgery, 44/322 patients (14%) re-presented to the emergency department with biliary symptoms (89 separate presentations); 21 patients (6%) were admitted (28 admissions), of whom 18 (86%) were on the waiting list for biliary colic symptoms only. Reasons for emergency admission included pancreatitis (1), cholangitis (3), choledocholithiasis (7), cholecystitis (7), and exacerbation of symptoms (10). Median hospital stay was 4 days (1-14 days) (total cost of 124 hospital days, excluding subsequent admission for cholecystectomy, $A128 712 according to average bed day costs), and 11 patients required endoscopic retrograde cholangiopancreatography (13 procedures). Mean (median) time on the surgical waiting list for patients who developed complications was 238 (203) days versus 185 (126) days for patients who had LC without interval complications. A total of 198 cancellations occurred in 124/322 patients (39%) before surgery. CONCLUSIONS: Prolonged waiting times for elective LC are associated with morbidity in 14% of patients at the Launceston General Hospital. This, combined with frequent cancellation of elective surgery, may result in significant costs to the health-care sector.

Development of beta-keto 1,3-dithianes as versatile intermediates for organic synthesis.

beta-Keto 1,3-dithianes can be generated by the double conjugate addition of dithiols to propargylic ketones, esters and aldehydes in excellent yields. As masked 1,3-dicarbonyl systems these substrates can be converted to a range of functionalised oxygen-containing heterocycles that can be used in natural product synthesis.

Dressing size and pain: a prospective trial.

BACKGROUND: Pain is a personal, subjective experience. In the postoperative period, pain may be influenced by patient, pharmacological and environmental factors. In surgery the aim is to reduce pain in this period by educating patients and using adequate analgesia. The aim of the present study was to assess the effect of perceived wound size on pain, as indicated by wound dressing, in the immediate postoperative period. METHODS: Patients undergoing appendicectomy were randomized into a group having a dressing the same size (SSD) as the surgical wound or double the size (DSD) of the wound. Patients' pain perception and analgesic requirements were then recorded and analysed to compare the two groups. RESULTS: Both groups had similar results when comparing pain perception. The median total pain score for the SSD and DSD groups at 12 and 24 h postoperatively revealed no statistically significant difference (P > 0.05). CONCLUSION: The data do not support the hypothesis that postoperative pain may be altered by perceived wound dressing size. Dressing size does not appear to be a variable that could easily be altered to reduce postoperative pain in surgical patients.

Cimetidine prevents suppression of delayed hypersensitivity in an animal model of haemorrhagic shock.

BACKGROUND: Cimetidine reverses immunosuppression following trauma, however, its effect on pure haemorrhagic shock is unknown. METHODS: Mice sensitized by injection of sheep red blood cells (SRBCs), were subjected to cardiac puncture and randomized to a control group-A (n=11) and three shock groups (35% of blood volume extracted): group-S had no treatment (n=16), group-CP received cimetidine 50mg/kg intraperitoneally (n=16), group-CW received oral cimetidine (200mg/kg per day, n=16). After 5 days, animals were challenged by injection of SRBCs into the foot-pad of the right hind paw (same volume of saline was injected into left paw). Foot-pad thickness ratios (FPTRs) were determined at 16 and 40 h, and inflammatory response was assessed histologically. RESULTS: At 16 h, FPTRs were greater in group-CW than group-S (P=0.01). There were no differences at 40 h. More animals in groups-CP and -CW had grade 3/4 inflammation, whilst group-S had the least inflammatory response (NS). CONCLUSIONS: Cimetidine prevents suppression of delayed hypersensitivity in this model.