Test–retest reliability of a self-administered Alcohol,Smoking and Substance Involvement Screening Test (ASSIST) in primary care patients

The time required to conduct drug and alcohol screening has been a major barrier to its implementation in mainstream healthcare settings. Because patient self-administered tools are potentially more efficient, we translated the Alcohol, Smoking and Substance Involvement Screening Test (ASSIST) into an audio guided computer assisted self interview (ACASI) format. This study reports on the test–retest reliability of the ACASI ASSIST in an adult primary care population. Adult primary care patients completed the ACASI ASSIST, in English or Spanish, twice within a 1–4 week period. Among the 101 participants, there were no significant differences between test administrations in detecting moderate to high risk use for tobacco, alcohol, or any other drug class. Substance risk scores from the two administrations had excellent concordance (90–98%) and high correlation (ICC 0.90–0.97) for tobacco, alcohol, and drugs. The ACASI ASSIST has good test–retest reliability, and warrants additional study to evaluate its validity for detecting unhealthy substance use.     

Aetiological risk factors are associated with distinct imaging findings in patients with chronic pancreatitis: A study of 959 cases from the Scandinavian Baltic Pancreatic Club (SBPC) imaging database

ObjectivesThe relation between aetiology and structural changes of the pancreas in patients with chronic pancreatitis (CP) is not fully understood. Earlier studies are limited by focusing on selected factors in studies of limited sample size. We aimed to use a large dataset to explore associations between aetiology and pancreatic morphology in CP.MethodsSubjects with definite or probable CP according to the M-ANNHEIM diagnostic criteria were included in this multicentre cross-sectional observational study and assessed using a standardized and validated CP imaging system. We performed multivariate logistic regression to analyse if aetiological factors adjusted for covariates were independently associated with morphological pancreatic features.ResultsWe included 959 patients (66% males). Mean (SD) age was 55 (14) years. Pancreatic structural changes were found in 94% of the subjects: 67% had calcifications, 59% main pancreatic duct dilatation, 33% pseudo-cysts and 22% pancreatic atrophy. Alcohol abuse was independently associated with pancreatic calcifications (odds ratio (OR, [95% CI]); 1.61, [1.09, 2.37]) and focal acute pancreatitis (OR; 2.13, [1.27, 3.56]), whereas smoking was independently associated with more severe calcifications (OR; 2.09, [1.34, 3.27]) and involvement of the whole gland (OR; 2.29, [1.61, 3.28]). Disease duration was positively associated with calcifications (OR; (per year) 1.05 [1.02, 1.08]) and pancreatic atrophy (OR; 1.05 [1.02, 1.08]) and negatively associated with focal acute pancreatitis (OR 0.91, [0.87, 0.95] and pseudo cysts (OR; 0.96, [0.93, 0.98]).ConclusionIn this large-scale study, etiological risk factors and disease duration in CP were independently associated with specific structural pancreatic imaging changes.     

Voiding and sexual dysfunction after deep rectal resection and total mesorectal excision

OBJECTIVE: Voiding and sexual dysfunction after deep rectal resection have been described with various frequencies in the literature. In this study, we prospectively evaluated the baseline preoperative voiding and sexual function in a cohort of patients undergoing deep rectal resection with mesorectal excision to determine any pre-existing abnormalities. Postoperatively, we sought first to determine the frequency of a urinary or sexual dysfunction, secondly whether there is a time-dependent change of a dysfunction and thirdly whether there is a relationship between postoperative urological dysfunction and the patient's age. PATIENTS AND METHODS: Fifty-two patients (36 men and 16 women) with a primary rectal carcinoma were prospectively examined directly before and after the operation, as well after the third and sixth postoperative month. The preoperative urological evaluation consisted of a careful voiding and sexual history, uroflowmetry and a sonographic residual urine determination. A detailed sexual history was obtained via the use of a questionnaire. RESULTS: Urological dysfunction: Preoperatively, 49 of the 52 patients had a completely normal bladder function and three patients had post void residual >100 ml. Postoperatively, 12 of the 49 patients with normal preoperatively urinary function had voiding dysfunction, but only four male patients had residual urine in the third postoperative month. Therefore, in about 90% of the patients, postoperative bladder function became normal and only 10% suffered from vesical denervation after 6 months. We could not determine a relationship between the degree of bladder dysfunction and the patient's age due to a relatively small patient cohort in this study. Sexual dysfunction: Preoperatively, 36 (seven women, 29 men) of the 52 patients were potent and had regular sexual intercourse. Eleven men specified a limited erection, but all had occasional sexual intercourse. One of the potent men experienced no ejaculation. Postoperatively, eight of the 29 men were impotent and two of the 29 men experienced retrograde ejaculation. Therefore, 30% of the preoperatively potent men had sexual dysfunction postoperatively. There was no correlation between the postoperative impotence and the age of the patients at the time of surgery. Although it is likely that the potency may diminish with advanced age, the incidence of impotence was not higher in the older patients of our study. CONCLUSIONS: The results of our study underline the importance of risk estimation for possible postoperative urological dysfunction by means of preoperative urologic evaluation in this patient collective. Of patients with postoperative bladder dysfunction, 90% improved within 6 months after surgery and only 10% continued to have bladder dysfunction beyond 6 months, indicating irreversible nerve damage.     

alphaB-crystallin promotes tumor angiogenesis by increasing vascular survival during tube morphogenesis

Selective targeting of endothelial cells in tumor vessels requires delineation of key molecular events in formation and survival of blood vessels within the tumor microenvironment. To this end, proteins transiently up-regulated during vessel morphogenesis were screened for their potential as targets in antiangiogenic tumor therapy. The molecular chaperone alphaB-crystallin was identified as specifically induced with regard to expression level, modification by serine phosphorylation, and subcellular localization during tubular morphogenesis of endothelial cells. Small interfering RNA-mediated knockdown of alphaB-crystallin expression did not affect endothelial proliferation but led to attenuated tubular morphogenesis, early activation of proapoptotic caspase-3, and increased apoptosis. alphaB-crystallin was expressed in a subset of human tumor vessels but not in normal capillaries. Tumors grown in alphaB-crystallin(-/-) mice were significantly less vascularized than wild-type tumors and displayed increased areas of apoptosis/necrosis. Importantly, tumor vessels in alphaB-crystallin(-/-) mice were leaky and showed signs of caspase-3 activation and extensive apoptosis. Ultrastructural analyses showed defective vessels partially devoid of endothelial lining. These data strongly implicate alphaB-crystallin as an important regulator of tubular morphogenesis and survival of endothelial cell during tumor angiogenesis. Hereby we identify the small heat shock protein family as a novel class of angiogenic modulators.     

Human angiogenic cell precursors restore function in the infarcted rat heart: a comparison of cell delivery routes

BACKGROUND: We recently isolated angiogenic cell precursors (ACPs) from human blood, which can induce angiogenesis in vitro. AIMS: In the present study, we used a nude rat model of ischaemic cardiomyopathy to compare the efficacy of intramyocardial and intracoronary ACP implantation, and to evaluate effects on cardiac function, scar size and angiogenesis. METHODS AND RESULTS: Adult nude rats underwent coronary artery ligation. Six days later, ACPs (characterized in vitro prior to implantation) or culture media were injected directly into the ischaemic myocardial region or into the coronary artery via the aorta. Cardiac function was measured by echocardiography prior to and at 2 and 4 weeks after implantation. Scar morphology, cell engraftment, and myocardial angiogenesis were evaluated at 4 weeks. Two and four weeks after implantation, cardiac function declined in both of the control groups but improved in both the intramyocardial and intracoronary ACP groups. Significant reductions in myocardial scar area were only observed in the intramyocardial ACP group, while increases in blood vessel density, which were observed in all ACP recipients, were greatest in the intracoronary ACP group. CONCLUSIONS: Human ACPs, delivered via intramyocardial or intracoronary injection, engrafted into damaged cardiac tissue and improved cardiac function within 4 weeks through effects on scar morphology and blood vessel formation.     

Safety and immunogenicity of live attenuated influenza reassortant H5 vaccine (phase I–II clinical trials)

Objective Our studies aimed to evaluate in clinical trials the safety and immunogenicity of an H5 live influenza vaccine candidate obtained using classical reassortment techniques from a low pathogenicity avian influenza (LPAI) A/Duck/Potsdam/1402‐6/86(H5N2) virus and the cold‐adapted (ca) donor strain A/Leningrad/134/17/57(H2N2). Methods During Phase I–II clinical trials, volunteers received intranasally two doses of reassortant influenza vaccine strain A/17/Duck/Potsdam/86/92 (H5N2) 21 days apart. Clinical examination of all vaccinees was conducted 7 days post‐vaccination. Serum antibody responses were measured by hemagglutination‐inhibition and microneutralization and local antibodies were estimated using an enzyme‐linked immunosorbent assay test. Results The vaccine was safe and of low reactogenicity with no febrile reactions. After revaccination 47·1–54·8% of subjects showed ≥fourfold seroconversions of Hamagglutination inhibition (HAI) antibodies to the hemagglutinin (HA) antigen of the A/17/Duck/Potsdam/86/92 (H5N2) virus and 29·4–30·8% were seroconverted to the HA antigen of the reverse genetics reassortant A/Indonesia/05/2005 × PR8 IBCDC‐RG (H5N1). Virus‐neutralizing antibody levels in sera of volunteers were similar to those shown in HAI test. The virus‐specific nasal IgA antibody response after two vaccine doses demonstrated significant increases of ≥fourfold rise SIgA antibodies (65%) geometrical mean titers (16·0) and a rise in SIgA antibodies (2·8) compared with one dose. Conclusion The live attenuated influenza vaccine candidate prepared using the LPAI A(H5N2) strain was well tolerated and elicited serum and local immune responses. There was evident cross‐reactivity to the A(H5N1) strain in the HAI test.     

Thrombopoietin cooperates with FLT3-ligand in the generation of plasmacytoid dendritic cell precursors from human hematopoietic progenitors

Type 1 interferon-producing cells (IPCs), also known as plasmacytoid dendritic cell (DC) precursors, represent the key effectors in antiviral innate immunity and triggers for adaptive immune responses. IPCs play important roles in the pathogenesis of systemic lupus erythematosus (SLE) and in modulating immune responses after hematopoietic stem cell transplantation. Understanding IPC development from hematopoietic progenitor cells (HPCs) may provide critical information in controlling viral infection, autoimmune SLE, and graft-versus-host disease. FLT3-ligand (FLT3-L) represents a key IPC differentiation factor from HPCs. Although hematopoietic cytokines such as interleukin-3 (IL-3), IL-7, stem cell factor (SCF), macrophage-colony-stimulating factor (M-CSF), and granulocyte M-CSF (GM-CSF) promote the expansion of CD34+ HPCs in FLT3-L culture, they strongly inhibit HPC differentiation into IPCs. Here we show that thrombopoietin (TPO) cooperates with FLT3-L, inducing CD34+ HPCs to undergo a 400-fold expansion in cell numbers and to generate more than 6 x 10(6) IPCs per 10(6) CD34+ HPCs within 30 days in culture. IPCs derived from HPCs in FLT3-L/TPO cultures display blood IPC phenotype and have the capacity to produce large amounts of interferon-alpha (IFN-alpha) and to differentiate into mature DCs. This culture system, combined with the use of adult peripheral blood CD34+ HPCs purified from G-CSF-mobilized donors, permits the generation of more than 10(9) IPCs from a single blood donor.