Influence of innate immune activation on endocrine and metabolic pathways in infancy.

Prematurity is the leading cause of neonatal morbidity and mortality worldwide. Premature infants often require extended hospital stays, with increased risk of developing infection compared with term infants. A picture is emerging of wide-ranging deleterious consequences resulting from innate immune system activation in the newborn infant. Those who survive infection have been exposed to a stimulus that can impose long-lasting alterations into later life. In this review, we discuss sepsis-driven alterations in integrated neuroendocrine and metabolic pathways and highlight current knowledge gaps in respect of neonatal sepsis. We review established biomarkers for sepsis and extend the discussion to examine emerging findings from human and animal models of neonatal sepsis that propose novel biomarkers for early identification of sepsis. Future research in this area is required to establish a greater understanding of the distinct neonatal signature of early and late-stage infection, to improve diagnosis, curtail inappropriate antibiotic use, and promote precision medicine through a biomarker-guided empirical and adjunctive treatment approach for neonatal sepsis. There is an unmet clinical need to decrease sepsis-induced morbidity in neonates, to limit and prevent adverse consequences in later life and decrease mortality.

Re-evaluating the role of Doppler ultrasonography in patients presenting with scrotal pain.

AIM: To describe our experience of all patients presenting to a tertiary referral centre over a 5-year time period with acute scrotum and to investigate the role of Doppler ultrasonography (DUS) for investigating this group of patients. METHOD: A retrospective analysis was performed on all patients presenting to the emergency department (ED) of a level 1 trauma centre with acute scrotum from 2009 to 2014 inclusive. Inclusion criteria included all patients who underwent an investigatory DUS and/or emergency scrotal exploration. Recorded patient demographics included age, presenting symptoms, duration of symptoms and relevant examination findings. RESULT: Three-hundred and twelve patients were included with a mean age of 15 years (range 1 day-40 years). In total, 106 patients underwent immediate scrotal exploration, and testicular torsion (TT) was found in 30 % (n = 32/106). Two-hundred and twenty-two patients were initially investigated with DUS and 16 (7.2 %) proceeded to scrotal exploration. Of this sub-group, 2/16 presented with a history <24 h and exploration was negative for TT. In comparison, 14/16 presented with a history >24 h, and DUS findings were consistent with TT. No patients with a normal DUS represented to the ED after discharge. CONCLUSION: DUS may prevent unnecessary scrotal exploration in patients presenting with acute scrotal pain and is useful for diagnosing TT in patients presenting with symptoms >24 h.

Penile cancer--Guideline adherence produces optimum results.

OBJECTIVE: To audit the management and outcome of penile cancer in a tertiary university teaching hospital, comparing our results to international best practice and published guidelines. METHODS: The Hospital Inpatient Enquiry database of the Mercy University Hospital was interrogated for penile cancer patients treated between 2001 and 2012. Data relating to presentation, local treatment, histology, lymph-node management, outcome and survival was recorded. Data were analysed using the Log Rank test, with significance defined as P ≤ 0.05. RESULTS: Twenty-five patients were identified with a median age of 61 years. The majority of cases at presentation were ≥ T2 (54%) and intermediate to high grade (76%). The median follow-up of patients was 3.75 years (range 9 months-10 years). Overall survival was 76% (n = 19), these patients are all disease free to date. Disease-specific survival was 85% at 10 years. Penile cancer related mortality was 8% (n = 2), 4 patients (16%) died of non-penile cancer related causes. Twenty-two patients (88%) had surgery and 3 patients (12%) had radiotherapy. Based on EAU guidelines inguinal lymph node dissection (ILND) was performed in 64% (n = 16) of cases with 44% (n = 7) of these patients requiring concurrent bilateral pelvic lymph node dissection. Fifty percent (n = 8) of ILNDs showed metastatic disease. Ten year disease-specific survival for node negative versus node positive disease is 100% versus 57%. Thirty-two percent (n = 8) of patients received chemotherapy. CONCLUSIONS: Penile cancer is a rare oncological condition that often requires bilateral inguinal ± pelvic lymph node dissection and should be managed according to published guidelines, in specialist centres in order to maximize outcomes.

Matched pair analysis of laparoscopic versus open radical nephrectomy for the treatment of T3 renal cell carcinoma.

PURPOSE: The perioperative and oncological outcomes of laparoscopic radical nephrectomy (LRN) for T1-T2 renal cell carcinoma (RCC) are well established. We aim to determine whether LRN is a comparable alternative to open radical nephrectomy (ORN) in the treatment of T3 RCC using a matched pair analysis study design. METHODS: A review of a prospectively collected database at the Western General Hospital, Edinburgh, between 2000 and 2011 was conducted. Patient pairs were matched based on age at operation, gender, histological subgroup, maximal tumour diameter, TNM stage and grade. Patient demographics, operative and post-operative outcomes were compared. Overall, cancer-specific and progression-free survival [overall survival, cancer-specific survival (CSS) and progression-free survival (PFS)] were estimated using the Kaplan-Meier method. RESULTS: From 252 patients with T3 disease, 25 pairs were matched. Patients were of median age 66.2 years, 64 % male. Tumours were all clear cell RCC, were stage pT3a (32 %) or pT3b and had maximal tumour diameters of 8.7 cm for LRN and 10.0 cm for ORN. Estimated blood loss (100 ml LRN; 650 ml ORN, p < 0.001) and length of post-operative hospital stay (4 days LRN: 9 days ORN, p < 0.001) were lower in the LRN group. Operation time and post-operative complication rates were comparable. CSS and PFS were comparable with a mean CSS of 91.3 months for LRN and 88.7 months for ORN. CONCLUSION: This study reports the longest median follow-up in a T3 LRN cohort. In matched patients, LRN has been shown to have a superior perioperative profile to ORN for the treatment of pT3a/b RCC, with no adverse effect on midterm oncological outcomes.

"Dazed and diffused": making sense of diffusion abnormalities in neurologic pathologies.

To review diffusion abnormalities seen in diffusion-weighted MRI in neurological pathologies. We examine the clinical significance of the abnormalities in a broad spectrum of neurological diseases and highlight our current understanding of their causes. Diffusion abnormalities seen on diffusion-weighted MRI can play an important role in the diagnosis and follow-up of a broad spectrum of neurological diseases. A thorough understanding of the appearance and significance of these abnormalities is critical in patient management.

MAGPI hypospadias repair: factors that determine outcome.

BACKGROUND: This is a review of our experience with the meatal advancement and glanuloplasty incorporated (MAGPI) hypospadias repair, and we point to some of the factors that determine outcome. METHODS: We identified all patients who underwent MAGPI repair by a single surgeon over an 8-year period. We performed a retrospective chart review followed by telephone interview to assess parent satisfaction and also functional and cosmetic outcome. Decision to undergo this type of repair was intra-operative, depending on position and mobility of the meatus and the quality of peri-urethral tissue. RESULTS: We identified 48 patients, with a median age of 19 months (8 months-13 years). Position of meatus was glanular (40) or coronal (eight cases). Chordee required correction in 40 % (12/30). Urethral stenting was required in one case. There was no case of fistula, meatal regression, stenosis, or second procedure. A single case of mucosal prolapse was encountered. The majority (47/48) were performed as a day-case. Forty parents agreed to telephone interview. Cosmetic outcome was deemed satisfactory in 95 % (38/40). With regard to unsatisfactory cosmetic outcome, one had a megameatus and the other was aged 13 years and developed a mucosal prolapse. CONCLUSION: In selected cases, the MAGPI hypospadias repair provide excellent functional and cosmetic outcomes with minimal complications, and it can safely be performed as a day-case procedure.

Incomplete urethral duplication in an adult male.

INTRODUCTION: Urethral duplication is a rare congenital anomaly with less than 200 cases reported. It predominantly occurs in males and is nearly always diagnosed in childhood or adolescence. It is defined as a complete second passage from the bladder to the dorsum of the penis or as an accessory pathway that ends blindly on the dorsal or ventral surface. METHODS: We present the case of a 54-year-old patient with incomplete urethral duplication. DISCUSSION: Urethral duplication commonly occurs in the sagittal plane with one urethral channel lying dorsal to the other. Symptoms vary from completely asymptomatic to urinary incontinence which can lead to a mucopurulent discharge from a low grade urinary tract infection. Other symptoms include double stream (most common complaint) and intermittent urinary discharge.

Ureteric angioplasty balloon placement to increase localised dosage of BCG for renal pelvis TCC.

Endoscopic percutaneous resection of a renal pelvis transitional cell carcinoma (TCC) is a viable treatment option in those who would be rendered dialysis dependent following a nephroureterectomy. We report endoscopic percutaneous resection of an upper tract TCC recurrence in a single functioning kidney followed by antegrade renal pelvis BCG instillation with novel placement of inflated angioplasty balloon in the ureter to help localise its effect.

A rapid access diagnostic clinic for prostate cancer: the experience after one year.

BACKGROUND: The National Cancer Control Programme is developing standards for access to diagnostics and treatment of prostate cancer. The Rapid Access Prostate Cancer (RAPC) clinic in St. James's Hospital commenced in May 2009 allowing general practitioners (GPs) more streamlined access for patients. AIMS: To demonstrate that RAPC clinics allow GPs direct access to a designated cancer centre improving the prostate cancer referral process. This ultimately should reduce referral delays. METHODS: A prospective analysis of all patients referred to the RAPC clinic in St. James's Hospital over a 12-month period beginning from May 2009. RESULTS: Over the 12-month period 215 patients were referred to the RAPC clinic. The median age was 63 years (range 45-78). The median waiting time between referral and review at the RAPC clinic was 13 days (range 1-37). The median PSA was 7.7 µg/L (range 2.6-150). In total 199 TRUS biopsies were performed, of which 46% were positive for prostate cancer. We found that 70% of all patients had a PSA ≤ 10 µg/L and of these 32% were positive for prostate cancer. For the remaining 30% of patients who had a PSA > 10 µg/L, we found 63% were positive for prostate cancer. Regarding patients diagnosed with prostate cancer 56% have been referred for radiotherapy, 13% for surgery, 13% for hormonal treatment, 10% for active surveillance and 8% watchful waiting. CONCLUSION: RAPC clinics allow GPs easier access to specialist urological opinion for patients suspected of having prostate cancer.

Lessons learned using Snodgrass hypospadias repair.

BACKGROUND: This is a review of our experience with the Snodgrass technique for distal hypospadias repair and we point to lessons learned in improving results. METHODS: We reviewed all patients who underwent Snodgrass hypospadias repair for distal hypospadias over a four-year period by a single surgeon. Chart review followed by parental telephone interview was used to determine voiding function, cosmesis and complication rate. RESULTS: Thirty children and three adults were identified. Age at surgery ranged from seven months to 39 years. The urinary stream was straight in 94%, and 97% reported a good or satisfactory final cosmetic outcome. One patient (3.3%) developed a urethral fistula and 21% developed meatal stenosis which required general anaesthetic. CONCLUSION: The Snodgrass urethroplasty provides satisfactory cosmetic and functional results. High rates of meatal stenosis initially encountered have improved with modifications to technique which include modified meatoplasty and routine meatal dilatation by the parents.

ECT remission rates in psychotic versus nonpsychotic depressed patients: a report from CORE.

OBJECTIVE: To compare the relative efficacy of electroconvulsive therapy (ECT) in psychotic and nonpsychotic patients with unipolar major depression. METHODS: The outcome of an acute ECT course in 253 patients with nonpsychotic (n = 176) and psychotic (n = 77) unipolar major depression was assessed in the first phase of an ongoing National Institute of Mental Health-supported four-hospital collaborative study of continuation treatments after successful ECT courses. ECT was administered with bilateral electrode placement at 50% above the titrated seizure threshold. The remission criteria were rigorous: a score

Preparation and characterisation of a range of diclofenac salts.

Physicochemical properties of diclofenac salts prepared using eight different counterions and including five novel salts, obtained with the bases 2-amino-2-methyl-1,3-propanediol, 2-amino-2-methylpropanol, tert-butylamine, benzylamine and deanol, were compared. Four of the bases used to prepare these salts were related in their chemical structure, differing only in the number of hydroxy groups. Characterisation techniques included X-ray diffraction, differential scanning calorimetry, thermogravimetric analysis, thermomicroscopy, Karl Fischer titration, FT-IR spectroscopy and elemental analysis. In the case of salts prepared from 2-amino-2-methylpropanol and benzylamine, two polymorphic forms of each salt were identified. For the 2-amino-2-methyl-1,3-propanediol salt, a pseudopolymorphic form was identified. The aqueous solubilities of the salts studied ranged from 3.95 mM (tris(hydroxymethyl)aminomethane salt) to 446 mM (deanol salt), corresponding to a 113-fold difference in solubility. The solubility of diclofenac deanol was higher than the solubilities for diclofenac salts reported earlier. Correlation was found between the inverse of the salt melting point and the logarithm of salt solubility. A log-log relationship was observed between salt solubility and hydrogen ion concentration in the salt solution. Relationships between the properties of the salt-forming agents and those of the resulting diclofenac salts were explored. Reasonable correlation was found between the free base melting point and the salt melting point.

Comparison of the physicochemical properties of the N-(2-hydroxyethyl) pyrrolidine, diethylamine and sodium salt forms of diclofenac.

Non steroidal anti-inflammatory agents (NSAIDs) such as diclofenac have very low aqueous solubilities and consequently salt formation may be used to enhance solubility and dissolution rate. In this study, we examined the physicochemical properties of three diclofenac salts, diclofenac sodium (DNa), diclofenac N-(2-hydroxyethyl)pyrrolidine (DHEP) and diclofenac diethylamine (DDEA), and their different solid state forms to determine the influence of salt form on solubility, dissolution rate and membrane transport. The equilibrium solubility of DDEA at 25 degrees C was determined as 33 mM, lower than the solubilities of DHEP (273 mM) and DNa (66 mM) previously reported (Ledwidge and Corrigan, 1998). In addition to the dihydrate form of DHEP previously characterised, monohydrate forms of DHEP and DDEA were identified. Intrinsic dissolution rate studies were used to determine the solubility ratios of the hydrated and anhydrous forms. The monohydrate form of DHEP was found to be 1.8 times less soluble than the anhydrate, whereas DDEA anhydrate was approximately 1.7 times as soluble as the monohydrate form. On investigation of the pH-solubility profile (25 degrees C) of DDEA, appreciable supersaturation (76 mM) relative to the theoretical profile, was detected at the pH(max). This contrasts with values of >800 and 67 mM for DHEP and DNa, respectively. The transport of salt solutions through a porous membrane (Visking) was investigated. A linear relationship between concentration (mM) and rate of transport (mmol/h) was established for DNa and DHEP solutions. The mass transfer coefficient determined for DHEP was lower than that for the other two salts. Nevertheless, the maximum transport rate obtained for DHEP is almost six times higher than that obtained for DDEA.

Distributive spirals: negotiation impasses and the moderating role of disputant self-efficacy.

Negotiations do not always end in agreements. Yet, we know little about impasses and how they affect negotiators. In three studies, we compare how negotiators experience impasses and agreements, paying particular attention to the moderating role of disputant self-efficacy. Specifically, we propose and find that negotiators who impasse find themselves caught in a distributive spiral-they interpret their performance as unsuccessful, experience negative emotions, and develop negative perceptions of their counterpart and the process. In terms of their future behavioral intentions, they are less willing to work together in the future, plan to share less information, plan to behave less cooperatively, and they lose faith in negotiation as an effective means of managing conflicts. As predicted, negotiators with relatively high levels of self-efficacy were insulated from some of these negative outcomes.

Typological predictions in developmental phonology.

Two common and seemingly independent error patterns, namely consonant harmony and gliding, are examined for their typological characteristics based on cross-sectional and longitudinal evidence from young children's developing phonologies. Data are drawn from the published literature and from the developmental phonology archives at Indiana University. An asymmetry is observed such that the occurrence of harmony is found to imply the occurrence of gliding, but not vice versa. While this finding would be unexpected within contemporary derivational theories, it can be shown to follow within optimality theory from a fixed universal ranking relationship among certain constraints. Optimality theory is also argued to offer a viable developmental account with clinical implications that can serve as a further test of the theory.

The costs of managing advanced colorectal cancer: a broad perspective.

Cancer care is expensive, consuming between 5 and 10% of health-care resources in industrialized countries. Therefore increasing emphasis is being placed on the value of treatment interventions. Colorectal cancer is the second most common cancer in the Western world and nearly two-thirds of patients will require palliative treatment. Only limited data are available on the cost of palliative chemotherapy for patients with advanced disease. The profile of raltitrexed ('Tomudex', formerly ZD1694) suggests that it may reduce costs associated with the administration of chemotherapy. Recent studies demonstrate that the total monthly cost of raltitrexed is lower or about the same as a variety of commonly used 5-fluorouracil-based regimens and offers potential savings for hospitals in terms of demand on specialist facilities, physician, nursing and pharmacy time, and overnight bed occupancy. The personal cost borne by patients and their carers for travelling and time off work is reduced with raltitrexed compared with the widely used Mayo regimen. However, there may be disincentives within certain national health-care systems to the introduction of a more resource-efficient drug such as raltitrexed. Physicians will need information on both the benefits and costs of drug treatments to be able to make informed decisions on the provision of high quality, cost-effective patient care, and it is likely that health economic assessment will be incorporated into increasing numbers of clinical trials.

Unweighting accelerates tidemark advancement in articular cartilage at the knee joint of rats.

Morphologic development of articular cartilage is influenced by biologic adaptation to functional demands. It has been theorized that intermittent stresses generated by load bearing and motion determine cartilage thickness by controlling advancement of the subchondral mineralization front. The mineralization front is comprised of two interfaces, the tidemark and chondroosseus junction, each of which advances through a different biologic process. This study was designed to evaluate the influence of one month of hind limb unweighting, with and without concurrent restriction of joint motion, on mineral apposition at the tidemark and vascular invasion at the chondroosseus junction in the knee joints of young adult rats. In mobile joints, hind limb unweighting induced a 2-fold increase in the tidemark mineral apposition rate (p = 0.0001) at the primary weight bearing region, resulting in a thinning of the uncalcified cartilage layer and a concurrent thickening of the calcified layer. Cast immobilization negated the effect of unweighting at the tidemark while it activated subchondral vascular encroachment into the calcified cartilage (p = 0.001). These findings suggest that cartilage thinning associated with the elimination of weight bearing is mediated through a different biological mechanism than cartilage loss associated with restriction of joint motion.

Effects of microgravity on bone healing in a rat fibular osteotomy model.

Bone healing was investigated histologically in a rat fibular osteotomy model subjected to microgravity (shuttle flight STS-29) and the tail suspension microgravity simulation model. Exposure to microgravity or tail suspension occurred during the last 5 days of a 10-day healing period. Periosteal osteogenesis and the development of vascular channels in both experimental groups were similar to that observed in a weightbearing control group. Chondrogenesis was more advanced in weightbearing rats than in either flight or tail-suspended rats. Angiogenesis in the osteotomy gap was more advanced in weightbearing and tail-suspended rats than in the flight group. These findings suggest that bone healing may be impaired during space travel. Interpretation of the findings is complicated by observations that flight and suspended rats lost weight during the flight period and that suspended rats consumed less water than control rats. Tail suspension did not produce the same pattern of healing as spaceflight; therefore, long-term studies of bone healing, conducted entirely in the microgravity environment, are needed to distinguish metabolic from mechanical influences and to determine whether effective fracture consolidation will occur in the absence of gravitational forces.

Symmetrical, unsymmetrical and bridged calix[4]arene derivatives as neutral carrier ionophores in poly (vinyl chloride) membrane sodium selective electrodes.

The complexing ability of a range of 19 symmetrical, unsymmetrical and bridged calix[4]arene derivatives having ester, ketone, amide, amine and thioether functionalities were determined by the picrate extraction method. On incorporating these calix[4]arene derivatives as neutral carrier ionophores in sodium-selective poly (vinyl chloride) membrane electrodes the performance was assessed on the basis of the sensitivity and selectivity over the alkali, alkaline earth metals and hydrogen and ammonium ions. The temperature dependence, response times and lifetimes were also determined. Four ionophores in particular gave excellent sensitivity and selectivity and lifetimes of > 200 days. These electrodes were then tested without additional lipophilic additives and one ionophore was incorporated into poly (vinyl chloride) membrane electrodes with plasticizing solvents of varying polarity.