A replication-competent adenovirus-vectored influenza vaccine induces durable systemic and mucosal immunity

BACKGROUNDTo understand the features of a replicating vaccine that might drive potent and durable immune responses to transgene-encoded antigens, we tested a replication-competent adenovirus type 4 encoding influenza virus H5 HA (Ad4-H5-Vtn) administered as an oral capsule or via tonsillar swab or nasal spray.METHODSViral shedding from the nose, mouth, and rectum was measured by PCR and culturing. H5-specific IgG and IgA antibodies were measured by bead array binding assays. Serum antibodies were measured by a pseudovirus entry inhibition, microneutralization, and HA inhibition assays.RESULTSAd4-H5-Vtn DNA was shed from most upper respiratory tract–immunized (URT-immunized) volunteers for 2 to 4 weeks, but cultured from only 60% of participants, with a median duration of 1 day. Ad4-H5-Vtn vaccination induced increases in H5-specific CD4⁺ and CD8⁺ T cells in the peripheral blood as well as increases in IgG and IgA in nasal, cervical, and rectal secretions. URT immunizations induced high levels of serum neutralizing antibodies (NAbs) against H5 that remained stable out to week 26. The duration of viral shedding correlated with the magnitude of the NAb response at week 26. Adverse events (AEs) were mild, and peak NAb titers were associated with overall AE frequency and duration. Serum NAb titers could be boosted to very high levels 2 to 5 years after Ad4-H5-Vtn vaccination with recombinant H5 or inactivated split H5N1 vaccine.CONCLUSIONReplicating Ad4 delivered to the URT caused prolonged exposure to antigen, drove durable systemic and mucosal immunity, and proved to be a promising platform for the induction of immunity against viral surface glycoprotein targets.TRIAL REGISTRATIONClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01443936","term_id":"NCT01443936"}}NCT01443936 and {"type":"clinical-trial","attrs":{"text":"NCT01806909","term_id":"NCT01806909"}}NCT01806909.FUNDINGIntramural and Extramural Research Programs of the NIAID, NIH (U19 AI109946) and the Centers of Excellence for Influenza Research and Surveillance (CEIRS), NIAID, NIH (contract HHSN272201400008C).     

Evidence for ovarian “inhibin”: Suppression of the secondary rise in serum follicle stimulating hormone levels in proestrous rats by injection of porcine follicular fluid

The present studies were carried out to see if porcine follicular fluid could inhibit increases in serum follicle stimulating hormone (FSH) levels when injected into the rat. For these studies the pentobarbital-treated proestrous rat was chosen as the major test animal model. If an artificial surge of luteinizing hormone (LH) is administered to these rats, it can induce a synchronized secondary rise in FSH secretion rate. Normal saline-treated rats were also used as test animals. They exhibit preovulatory endogenous "surges" of LH and FSH, and also a secondary FSH rise.Porcine follicular fluid was harvested from medium-sized and large (3- to 10-mm diameter) follicles and treated with charcoal to remove endogenous steroids. Charcoal-treated porcine serum served as a control solution. The fluid was injected intraperitoneally in two 0.5-ml doses into pentobarbital-treated proestrous rats immediately and 3 hr after LH injection. Follicular fluid, but not the serum, suppressed the secondary, LH-induced FSH rise (P < 0.01) in a dose-dependent manner, without altering the effects of LH upon serum ovarian steroid levels or follicular rupture. It was effective down to a total dose of 200 mul. Porcine follicular fluid also blocked the secondary FSH surge in normal proestrous rats exhibiting endogenous LH/FSH primary surges. Thus, it would appear that porcine follicular fluid contains a non-steroidal substance(s) that can block the secretion of FSH that is secondary to a natural or artificial LH surge.     

Palliation of malignant biliary obstruction: a prospective trial examining impact on quality of life

BACKGROUND: Endoscopic decompression is used for palliation of patients with malignant biliary obstruction. Little is known of its effect on quality of life. The aims of this study were to determine clinical characteristics that have the greatest adverse impact on quality of life in patients with malignant biliary obstruction, and to quantify changes in the quality of life of patients with malignant biliary obstruction after successful decompression with a plastic stent. METHODS: Patients with malignant biliary obstruction without liver metastases considered nonsurgical candidates and referred to a tertiary university medical center for palliative endoscopic decompression were sequentially enrolled in this prospective cohort study. The SF-36 Health Survey questionnaire at baseline and 1 month after stent insertion was used to quantify quality of life. Results were correlated to clinical and laboratory parameters. Multivariate analyses were carried out to determine independent predictors of baseline quality of life and improvement after stent insertion. RESULTS: Fifty patients (20 men, 30 women; mean [SD] age 72.6 [10.6] years) with a mean weight of 62.4 (12.9) kg and mean body mass index of 23.4 (4.3) kg/m(2) were enrolled. Two thirds had a distal malignant lesion, 12.5% had mid bile duct obstruction, and the rest either hilar or intrahepatic cholangiocarcinoma. At baseline, 70% complained of pruritus and 98% were jaundiced (mean total bilirubin 15 [7] mg/dL). Mean duration of symptoms before decompression was 23 (25) days. Weight loss, and elevated bilirubin level had the greatest impact on baseline quality of life domains in both univariate and multivariate analysis. After biliary drainage, complete follow-up information was available for 51% of the initial cohort. Among these 26 patients, a 33% improvement in bilirubin level was documented in 84% of patients and was associated with significant improvements in social function (relative risk = 0.11; 95% CI [0.03, 0.19]) and mental health (relative risk = 0.036; 95% CI [0.011, 0.08]). A baseline bilirubin of greater than 14 mg/dL was associated with lack of improvement in social function at 1-month follow-up (p = 0.03). CONCLUSIONS: Weight loss and hyperbilirubinemia are strongly predictive of poor quality of life before endoscopic decompression. Successful biliary drainage after stent insertion is associated with improvements in quality of life, although this is less true among patients with a baseline bilirubin over 13 mg/dL. These results may lead to better selection of patients for palliative biliary decompression and require prospective validation.     

Predicting which patients can undergo upper endoscopy comfortably without conscious sedation

BACKGROUND: Eliminating conscious sedation for diagnostic endoscopy may be advantageous for patient safety and cost containment. The aim of this study was to identify and validate independent predictors of a comfortable, technically adequate, unsedated diagnostic upper endoscopy in Canadian patients. METHODS: Patients were consecutively enrolled in a prospective fashion. Data collected on an initial cohort of 268 patients included demographics, a validated anxiety questionnaire, use of sedatives/analgesics, upper endoscopy experience, pharyngeal sensitivity, technical adequacy, and patient assessment of comfort after the procedure. The main outcome measure was "satisfactory upper endoscopy," a composite of optimal scores for patient comfort and technical adequacy. Univariate and multivariate analyses were performed to identify the optimal predictive model of a satisfactory unsedated diagnostic upper endoscopy. Once identified, 68 additional patients were enrolled in a similar fashion from an independent prospective sample for purposes of outcome validation. Multivariate analysis was then repeated with the total cohort (N = 336). These results were then compared for concordance with those obtained from the initial cohort. RESULTS: Among the initial 268 patients (54.3% women; mean age 51 +/- 17 years), 49% were anxious, 15% regularly used sedatives and analgesics, 28% experienced increased pharyngeal sensitivity, and 41% had previously undergone upper endoscopy. Endoscopy was completed in 94.7% of patients without sedation and was technically adequate in 97%, and 80.1% were willing to repeat the procedure under similar conditions. Satisfactory upper endoscopy was achieved in only 59% of the initial cohort. The only independent and significant predictors of a satisfactory upper endoscopy were advancing age (OR 1.2: 95% CI [1.1, 1.4]) and decreased pharyngeal sensitivity (OR 0.5: 95% CI [0.27, 0.93]). Concordance of results were noted after validation with the second cohort. Satisfactory endoscopy was achieved in only 59.5% of the total cohort (n = 336); only 61% reported a comfortable procedural experience. CONCLUSIONS: The proportion of patients who can comfortably undergo technically adequate unsedated upper endoscopy is modest. Unsedated upper endoscopy is most likely to be successful under these procedural conditions in patients of advancing age with decreased pharyngeal sensitivity. The generalizability of these findings to an American population requires further study and may assist in identifying a subgroup of patients in whom it is cost-effective to perform upper endoscopy comfortably without sedation.     

Foreign body inhalation in children: Decisive factors for carrying out bronchoscopy

Inhalation of Foreign Body is one of the most common causes of accidental death at home in the paediatric age group. There may not be a clear history of foreign body inhalation and the patient may be asymptomatic at initial presentation. This coupled with the failure of radiological investigations on most occasions makes this a vexing clinical situation. These apparently normal children almost invariably have a bad prognosis if the foreign body is ignored. This study aims to define the most important factors influencing the decision to carry out the definitive surgery, i.e., bronchoscopy, which can be diagnostic as well as therapeutic, based on our experience with 50 cases of suspected FB in the tracheobronchial tree from January 2001 to July 2003. Results from the study suggest that radiological investigations have only limited value in deciding the management of a patient with suspected Foreign Body inhalation. This should not influence the decision to carry out a bronchoscopy, which should rather be based on history and clinical examination.     

Aggression and Dominance: The Roles of Power and Culture in Domestic Violence

In the past few decades, it has become increasingly clear to social scientists and policy makers alike that violence within the family is all too common and carries enormous costs to individuals, families, and society as a whole. Numerous controversies exist in the field, particularly with regard to what factors are significant in the etiology and development of violence between intimate partners. This article focuses on relationship power as a critical construct to consider in domestic violence, as it encompasses aspects of social, dyadic, and individual functioning. The literature on the construct of power and its relationship to domestic violence is reviewed and then placed in cultural context, followed by a discussion of future directions for research on and treatment issues in power and violence.     

Effect of adrenalectomy on rat epididymidis

Aim: To investigate the effect of adrenalectomy (ADX) on the epididymidis of Sprague-Dawley rats. Methods: The histological, biochemical (cholesterol protein, zinc, copper, alkaline and acid phosphatase aryl sulphatase, lactic dehydrogenase and leucine amino peptidase) and hormonal (FSH, LH and testosterone) changes of caput and cauda epididymis in ADX rats were observed. Results: Organ wet weight, histological studies and morphometric measurements indicated a cellular degeneration in caput and cauda epididymis of ADX rats. Serum testosterone level was significantly lower in ADX than in sham-operated rats, while the serum FSH and LH were below the detection limit of 1 mIU/mL. The enzymatic activity was higher in ADX than in sham-operated rats. Epididymal zinc level increased whereas copper level decreased in ADX rats compared to the sham-operated. Conclusion: Adrenalectomy leads to degeneration of caput and cauda epididymidis epithelial cells as a result of decreased supply of testosterone. (Asian J And     

Megakaryocyte colony stimulating activity in allogeneic bone marrow recipients prepared with busulfan and cyclophosphamide

Summary Increased megakaryocyte colony stimulating activity (MK-CSA) has been reported after total body irradiation (TBI) for bone marrow transplant (BMT). We studied the effect of a busulfan (Bu) and cyclophosphamide (Cy) marrow transplant conditioning regimen, without radiation, on MK-CSA production. Initial screening of MK-CSA was done on previously collected and banked sera from 14 BMT patients. MK-CSA was expressed as the ability to stimulate growth of megakaryocyte progenitors (CFU-MK) in standard plasma clot cultures. In the initial samples, MK-CSA peaked at day 7. This preliminary data led to a prospective study of MK-CSA and clinical parameters in seven allogeneic recipients. MK-CSA activity increased from day −7 pre-transplant (2.9 ± 1.7 CFU-MK/10⁵ NATD, mean ± SD) to day O (10.3 ± 4.7 CFU-MK) and peaked by day 9 post-transplant (20.6 ± 6.4 CFU-MK). MK-CSA activity decreased in all seven patients by day 21 at which time five of seven patients studied had recovery of platelet counts to greater than 100 ± 10⁹/l. MK-CSA activity rose rapidly in both groups of sera after the initiation of this non-irradiation. BMT preparative regimen. High MK-CSA levels, early after transplant, may contribute to the rapid platelet recovery in some patients.