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.

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.

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.

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.

Computer-aided quantification of retinal neovascularization.

Rodent models of retinal angiogenesis play a pivotal role in angiogenesis research. These models are a window to developmental angiogenesis, to pathological retinopathy, and are also in vivo tools for anti-angiogenic drug screening in cancer and ophthalmic research. The mouse model of oxygen-induced retinopathy (OIR) has emerged as one of the leading in vivo models for these purposes. Many of the animal studies that laid the foundation for the recent breakthrough of anti-angiogenic treatments into clinical practice were performed in the OIR model. However, readouts from the OIR model have been time-consuming and can vary depending on user experience. Here, we present a computer-aided quantification method that is characterized by (i) significantly improved efficiency, (ii) high correlation with the established hand-measurement protocols, and (iii) high intra- and inter-individual reproducibility of results. This method greatly facilitates quantification of retinal angiogenesis while at the same time increasing lab-to-lab reproducibility of one of the most widely used in vivo models in angiogenesis research.

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.

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.

Macrophage- and RIP3-dependent inflammasome activation exacerbates retinal detachment-induced photoreceptor cell death.

Detachment of photoreceptors from the retinal pigment epithelium is seen in various retinal disorders, resulting in photoreceptor death and subsequent vision loss. Cell death results in the release of endogenous molecules that activate molecular platforms containing caspase-1, termed inflammasomes. Inflammasome activation in retinal diseases has been reported in some cases to be protective and in others to be detrimental, causing neuronal cell death. Moreover, the cellular source of inflammasomes in retinal disorders is not clear. Here, we demonstrate that patients with photoreceptor injury by retinal detachment (RD) have increased levels of cleaved IL-1ß, an end product of inflammasome activation. In an animal model of RD, photoreceptor cell death led to activation of endogenous inflammasomes, and this activation was diminished by Rip3 deletion. The major source of Il1b expression was found to be infiltrating macrophages in the subretinal space, rather than dying photoreceptors. Inflammasome inhibition attenuated photoreceptor death after RD. Our data implicate the infiltrating macrophages as a source of damaging inflammasomes after photoreceptor detachment in a RIP3-dependent manner and suggest a novel therapeutic target for treatment of retinal diseases.

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.

Generalized anxiety disorder: neurobiological and pharmacotherapeutic perspectives.

The concept of generalized anxiety has evolved over many years, from initial descriptions of "anxiety neurosis" to recognition of generalized anxiety disorder (GAD) as a clinical entity included in the 3rd edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-III) in 1980. Since 1980, the definition of GAD has undergone further change, with modifications in the salience of autonomic and panic like symptoms, duration, and allowance of comorbidity. The importance of these historical considerations lies in the fact that most of our current knowledge about GAD rests on outdated definitions, including most of the literature pertaining to treatment. Indeed, we cannot be sure that the DSM-III definition of GAD bears resemblance to the current concept, and these differences may have profound implications for findings from research. The following two-part report comprises i) a review of the basic neurobiology of GAD, with reference to serotonergic, noradrenergic, neuroendocrine, autonomic imaging, and other systems; and ii) an overview of the current status of pharmacotherapy for GAD.

A preliminary study of lamotrigine for the treatment of posttraumatic stress disorder.

BACKGROUND: The anticonvulsant, lamotrigine, may be useful for symptom management in PTSD. METHODS: Subjects enrolled in a 12-week double-blind evaluation of lamotrigine and placebo. Patients were randomized 2:1 to either lamotrigine or placebo. Lamotrigine was initiated at 25 mg/day and slowly titrated every 1 to 2 weeks over 8 weeks to a maximum dosage of 500 mg/day if tolerated. RESULTS: Fifteen subjects entered treatment, fourteen of whom returned for subsequent visits. Of 10 patients who received lamotrigine, 5 (50%) responded according to the DGRP, compared to 1 of 4 (25%) who received placebo. Lamotrigine patients showed improvement on reexperiencing and avoidance/numbing symptoms compared to placebo patients. Treatments were generally well tolerated. CONCLUSIONS: Lamotrigine may be effective as a primary psychopharmacologic treatment in both combat and civilian PTSD and could also be considered as an adjunct to antidepressant therapy used in the treatment of PTSD. These promising results warrant further large sample double-blind, placebo-controlled trials.

ECT stimulus intensity: are present ECT devices too limited?

OBJECTIVE: The maximum output charge for ECT devices is limited to 576 millicoulombs in the United States, although there are no data ensuring that this limit will allow consistently effective treatments. The authors examined whether this limit has a negative impact on therapeutic response and, therefore, whether a higher stimulus charge should be available. METHOD: They retrospectively reviewed the records of 471 patients who received a clinical index course of ECT at Duke University between 1991 and 1998. These patients received conservative stimulus dosing of 2.25 times seizure threshold for unilateral ECT and 1.5 times seizure threshold for bilateral ECT. RESULTS: Seventy-two (15%) of the 471 patients required the maximum stimulus intensity during their index ECT course. Of these, 24 (5% of the total) had either a short EEG seizure (less than 25 seconds) or had no seizure at the maximum level. Strategies to augment therapeutic response with caffeine, ketamine, or hyperventilation were used in 14 of the 24 patients, and data on therapeutic response were available for 22 of the 24. Only seven (32%) of these 22 patients were considered ECT responders, compared with 242 (66%) of the remaining 364 patients for whom data on response to ECT were available. Older age and pre-ECT course EEG slowing were predictors of requiring the maximum stimulus level. CONCLUSIONS: The maximum available stimulus output was therapeutically insufficient for 5% of the patients studied even when available means to augment response were instituted. This percentage would likely be even larger with the use of a less conservative dosing protocol for unilateral ECT. Increases in maximum stimulus output for ECT devices should be considered as a means to ensure adequate treatment response.

Influence of site of stimulation on measurement of ventricular vulnerability in the normal and ischemic feline heart.

Site of stimulation is an important variable in the inducibility of ventricular tachycardia in both non-human animal infarction models and in humans; that is, proximity of the stimulating electrode to the site of reentry facilitates the induction of sustained arrhythmia. Whether site of stimulation is decisive in measurement of vulnerability to ventricular fibrillation (VF) during acute coronary occlusion has not been fully evaluated. We measured VF thresholds in 9 chloralose-anesthetized cats at 2 right ventricular and 3 left ventricular sites (2 endocardial, 3 intramural) before and after abrupt occlusion of the anterior descending coronary artery. VF thresholds were measured using a single stimulus of increasing intensity delivered during ventricular drive. Although VF thresholds were lower at endocardial sites, there were no significant differences in VF threshold among any of the sites tested at control. After occlusion, VF thresholds fell to a similar extent at all 5 sites tested. The percent reduction in VF threshold at any site was not influenced by the sequence of testing. VF may be precipitated from multiple sites and, unlike ventricular tachycardia, does not represent an isolated focus of arrhythmogenicity.

Comparison of the biological effects of tamoxifen and a new antioestrogen (LY 117018) on the immature rat uterus.

The uterotrophic and antiuterotrophic activities of tamoxifen and 6-hydroxy-2-(p-hydroxyphenyl)-benzo(b)thien-3-yl p- less than 2-(1-pyrrolidinyl) ethoxyphenyl ketone (LY 117018) in the immature rat uterus have been evaluated. The antioestrogens were administered alone, concurrently or sequentially with or without oestradiol. LY 117018 administered alone was less uterotrophic (oestrogenic) than tamoxifen. At high doses, when administered concurrently with oestradiol, LY 117018 was more antiuterotrophic (antioestrogenic) than tamoxifen. When uterine growth was maximally stimulated by prior treatment with oestradiol, tamoxifen and LY 117018 were equally effective in reducing uterine weight. However, when uterine growth was induced with a dose of oestradiol producing an oestrogenic effect equivalent to that of tamoxifen (but less that produced by LY 117018) LY 117018 was more effective than tamoxifen in reversing the uterotrophic effect of oestradiol. In animals pretreated with LY 117018 a further increase in uterine weight occurred on treatment with tamoxifen. The increase in uterine weight after tamoxifen was progressively reversed by increasing doses of LY 117018. The hypothesis that tamoxifen and LY 117018 may act by different mechanisms, based on the apparent failure of LY 117018 to antagonize the uterotrophic action of tamoxifen, is not supported by these studies.

Management of posttraumatic stress disorder: diagnostic and therapeutic issues.

Although the hallmark symptoms of posttraumatic stress disorder (PTSD) are clear, this disorder is not always properly diagnosed. Reasons for misdiagnosis include a high rate of comorbidity, patient denial or minimization, overly high diagnostic thresholds set by clinicians, or failure to take a trauma history. There are a number of challenges associated with the treatment of PTSD. Patients with PTSD may not respond to pharmacotherapy in the same manner, and it is unclear whether this is related to gender, trauma type, or other factors. Antidepressants, particularly the selective serotonin reuptake inhibitors, are the most effective form of pharmacotherapy for patients with PTSD. Patients also may respond to therapy with monoamine oxidase inhibitors or tricyclic antidepressants. Psychosocial techniques, such as cognitive-behavioral therapy or stress inoculation training, are effective and may be considered as adjunctive therapy with medication. As awareness of PTSD increases, more patients should receive an accurate diagnosis and appropriate therapy.

Bupropion sustained release: a therapeutic overview.

Sustained-release bupropion (bupropion SR) represents a new form of an already known effective antidepressant drug. Its pharmacokinetics, mechanism of action, metabolism, and efficacy are reviewed. Benefit relative to placebo has been demonstrated in two large multicenter trials, with low doses (100 or 150 mg) having been shown to have therapeutic efficacy. An overview of all placebo-controlled trials of bupropion SR is given, and the differential properties of bupropion and serotonergic drugs are described. The concept of a catecholamine-indolamine spectrum is presented, along with its implications for possible differential therapeutics of selective antidepressants.

Electrophysiologic effects of left ventricular hypertrophy in the intact cat.

Electrophysiologic abnormalities have been described in isolated, hypertrophied left ventricular tissue removed from animals exposed to a chronic pressure load. However, changes in electrical properties of intact hypertrophied hearts have not been described. To study this question, 15 cats underwent supraventricular aortic banding and five underwent a sham procedure. After ten weeks, the animals were anesthetized and instrumented using paired transmural plunge electrodes and endocardial quadripolar pacing catheters. Measurement of pacing threshold, refractoriness, inducibility of ventricular arrhythmias (using programmed electrical stimulation), and vulnerability to ventricular fibrillation (ventricular fibrillation threshold) were made in both groups. Mean left ventricular mass was significantly greater in the banded compared with sham-operated animals (2.5 +/- 0.9 v 2.1 +/- 0.5 g/kg body weight; P less than .05). Pacing thresholds and refractory periods measured at multiple left and right ventricular sites were similar in both groups, and there was no difference in the extent of site-to-site differences in refractoriness (dispersion). Six banded but no sham animals had inducible ventricular tachycardia or fibrillation using programmed stimulation. Furthermore, left ventricular mass was significantly greater in animals with inducible arrhythmias compared with those noninducible (P less than .05). Ventricular fibrillation thresholds, measured in milliamperes (mA), in the banded animals were significantly lower in the left ventricle (13.5 +/- 1.3 mA) than in the right (21.7 +/- 3.2 mA; P less than .05) and was also lower than the thresholds obtained in either the left or right ventricle of the sham-operated animals (18.3 +/- 1.9 mA and 20.1 +/- 1.1 mA, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

A family study of chronic post-traumatic stress disorder following rape trauma.

There is evidence that familial factors serve as determinants of risk for post-traumatic stress disorder (PTSD), especially familial anxiety. This study investigates the relationship between chronic PTSD and family psychiatric morbidity. The sample was drawn from 81 female rape survivors with or without lifetime PTSD, 31 major depressive disorder controls, 20 anxiety disorder controls and 39 healthy controls. First-degree family members were directly interviewed (n = 285) and diagnoses assigned of major depressive, anxiety and alcohol or substance use disorder. Information was also available by family history for 639 relatives. In the directly interviewed sample, no consistently increased morbidity risk was observed for anxiety, PTSD, or alcohol/substance abuse in the rape survivor groups, but there was an increase in depression relative to the anxiety in healthy control groups. When comorbid depression in rape survivor probands was taken into account post hoc, an increased risk for depression was noted in family members of PTSD probands with depression, but not in relatives of PTSD probands without lifetime depression. Among rape survivor probands with non-comorbid PTSD, rates by history of familial anxiety and depression were negligible. In a logistic regression analysis, individual vulnerability to depression served as an independent predictor of chronic PTSD, along with specific trauma-related variables. In the family history group, results were consistent with those obtained from the directly interviewed group. Our findings clearly support the view that PTSD following rape is associated with familial vulnerability to major depression, which may thus serve as a risk factor for developing PTSD. The exact nature of this predisposition calls for further inquiry and there is a need to expand this study to include other PTSD populations. PTSD may on occasion represent a form of depression which is induced and/or modified neurobiologically and phenomenologically by extreme stress. Our findings may be a reflection of the sample composition, the current conceptualization of PTSD, or be related to study limitations.

Mutagenicity of cosmetic products containing Kathon.

A variety of shampoos, conditioners, skin-care lotions, and other cosmetic products contain the biocide Kathon CG, which is a mixture of two heterocyclic isothiazolinones: methylisothiazolinone and methylchloroisothiazolinone. This mixture and the related biocide, Kathon 886, have been shown to be potent sensitizers and bacterial mutagens. Five cosmetic products that list the components of Kathon on their labels and two that do not were screened for mutagenicity with Salmonella typhimurium TA100 without S-9. Five of these products and Kathon 886 were further evaluated in TA100 without and with S-9. Kathon 886, a cosmetic product that contained Kathon, and thin layer chromatography-separated components of Kathon 886 were identified by GC/MS analysis. Three of the five products that listed Kathon were direct acting mutagens with TA100. The remaining two products were considerably more toxic than the other products and could not be evaluated for mutagenicity. The addition of S-9 reduced toxicity but did not eliminate mutagenicity. The mutagenic evaluation of Kathon 886 resulted in a dose response similar to that seen with some cosmetic products but at a 1,000-fold lower concentration, and activity was also reduced by the addition of S-9 mix. S-9 reduced activity both with and without cofactors present. Thin layer chromatography separation of the components and subsequent identification by GC/MS indicated that methylisothiazolinone was nonmutagenic while methylchloroisothiazolinone was mutagenic. Additionally, a dichlorinated compound was identified which was also mutagenic. In light of these findings and the reported skin sensitization by Kathon CG in various cosmetics, we recommend that additional testing be done to assure the safety of products containing Kathon CG.

Predictors of treatment response in patients with posttraumatic stress disorder.

1. This study examines the relation between baseline clinical characteristics in patients with posttraumatic stress disorder (PTSD) and response to treatment with a reversible monoamine oxidase A inhibitor (RIMA), brofaromine. 2. Data from two comparable, double-blind, placebo-controlled studies of brofaromine in patients with PTSD were combined. Bivariate analyses of variables of interest and outcome were performed. 3. Treatment response was significantly associated with lower baseline scores on the full scale Clinician-Administered PTSD Scale (CAPS) and on CAPS subscales B (re-experiencing) and C (avoidance/numbing), as well as to drug treatment with brofaromine. Placebo response was related to a history of past sexual trauma. 4. Brofaromine may have therapeutic benefit in treating PTSD, with lower baseline levels of reexperiencing and avoidance/numbing and overall less severe PTSD most predictive of outcome.