Induction of immunoglobulin synthesis by interleukin 2 is T4+/T8- cell dependent. A role for interleukin 2 in the pokeweed mitogen-driven system

The role of interleukin 2 (IL2) in the induction of human B cell differentiation in vitro was studied. IL2 was unable to induce immunoglobulin (Ig) production in non-T cells either in the presence or absence of pokeweed mitogen (PWM). However, IL2 alone could induce Ig production in non-T cells when irradiated T cells were present. Similar to the PWM-driven system helper activity was delivered by T4+ but not T8+ cells. Apparently, IL2 acts on T4+ cells and induces these cells to deliver the actual helper signal(s) for Ig production by B cells. Whereas in the PWM-driven system only T8+ cells suppress Ig synthesis, IL2-driven Ig synthesis was suppressed by both T4+ and T8+ cells added to a mixture of non-T cells and irradiated T4+ cells. This suppressor activity could be abrogated by irradiation. PWM was shown to induce IL2 production in both T4+ and T8+ cells. Moreover, PWM-induced Ig synthesis, like IL2-induced Ig synthesis, could be totally abrogated by a monoclonal antibody against the human IL2 receptor (anti-Tac). These findings, coupled to the innate Ig-inducing capacity of IL2, indicate a role for IL2 in the PWM-driven system. The mechanism of suppression in both the PWM- and the IL2-driven systems was not shortage of IL2 in the culture due to consumption or inhibition of production of IL2. Moreover, the T8+ cells produced IL2, despite their failure to help Ig synthesis. Helper T cell activity can thus be divided into two distinct activities: IL2 production and the ability to deliver the actual helper signal such as helper factors for B cell differentiation. This insight allows a better evaluation of the immunoregulatory activities of T cell subsets in health and disease.     

Microalbuminuria is related to marked end organ damage in previously untreated,elderly hypertensive patients

We wondered whether, in an elderly hypertensive population in a primary prevention setting, free from diabetes mellitus and clinical atherosclerosis, differences between end organ damage and microalbuminuria (MA) could be found using a lower level of urinary albumin excretion than that of classically defined MA. From a population survey of 173 previously untreated hypertensive patients (4x blood pressure systolic > or = 160 and < or = 220 mmHg, and/or diastolic > or = 95 and < or = 115 mmHg), mean age 67 +/- 4 years, were screened for MA (defined as albumin excretion between 20 and 300 mg/24 h). End organ damage was determined by B-mode ultrasound scanning of carotid and femoral arteries and echocardiography. Out of 173 hypertensives, 14 showed MA (8%). These hypertensives had a significantly higher intima media thickness (IMT; 1.01 +/- 0.21 vs 0.88 +/- 0.6 mm, p < 0.05) and increased left ventricular mass index (118 +/- 31 vs 103 +/- 22 g/m2, p < 0.05) than hypertensives without MA. Linear regression analysis showed that MA, age, male gender and diastolic blood pressure were independently related to IMT, while systolic blood pressure, male gender and body mass index were independently related to left ventricular mass. Even using lower levels of urinary albumin excretion rate, patients with MA had significantly higher IMT and increased left ventricular mass. Moreover, MA was independently related to IMT in these elderly hypertensives. These results suggest that the threshold value for MA should be reconsidered in hypertension.     

Striatal pleiotrophin overexpression provides functional and morphological neuroprotection in the 6-hydroxydopamine model

Neurotrophic factors are integrally involved in the development of the nigrostriatal system and in combination with gene therapy, possess great therapeutic potential for Parkinson's disease (PD). Pleiotrophin (PTN) is involved in the development, maintenance, and repair of the nigrostriatal dopamine (DA) system. The present study examined the ability of striatal PTN overexpression, delivered via psueudotyped recombinant adeno-associated virus type 2/1 (rAAV2/1), to provide neuroprotection and functional restoration from 6-hydroxydopamine (6-OHDA). Striatal PTN overexpression led to significant neuroprotection of tyrosine hydroxylase immunoreactive (THir) neurons in the substantia nigra pars compacta (SNpc) and THir neurite density in the striatum, with long-term PTN overexpression producing recovery from 6-OHDA-induced deficits in contralateral forelimb use. Transduced striatal PTN levels were increased threefold compared to adult striatal PTN expression and approximated peak endogenous developmental levels (P1). rAAV2/1 vector exclusively transduced neurons within the striatum and SNpc with approximately half the total striatal volume routinely transduced using our injection parameters. Our results indicate that striatal PTN overexpression can provide neuroprotection for the 6-OHDA lesioned nigrostriatal system based upon morphological and functional measures and that striatal PTN levels similar in magnitude to those expressed in the striatum during development are sufficient to provide neuroprotection from Parkinsonian insult.     

Differential sensitivities of pathogens in red cell concentrates to Tri-P(4)-photoinactivation

BACKGROUND AND OBJECTIVES: Photodynamic treatment (PDT) with the cationic porphyrin, mono-phenyl-tri-(N-methyl-4-pyridyl)-porphyrin chloride [Tri-P(4)], has previously been shown to be effective at inactivating vesicle stomatitis virus (VSV) in red cell concentrates (RCC) with limited damage to red blood cells (RBC). The aim of this study was to determine the pathogen-inactivating capacity of PDT with Tri-P(4) for a broader range of pathogens and to establish the associated effect on in vitro RBC quality. MATERIALS AND METHODS: A series of viruses and bacteria was spiked into 60% RCC. Pathogen inactivation was determined after PDT with 25 microm Tri-P(4) and red light up to 360 kJ/m2. Human immunodeficiency virus (HIV)-infected cells were evaluated for cell death induction, and RCC were analysed for the induction of haemolysis and ATP content. RESULTS: For the lipid-enveloped viruses bovine viral diarrhoea virus, HIV and pseudorabies virus, and for the Gram positive bacterium, Staphylococcus aureus, and the Gram-negative bacteria, Pseudomonas aeruginosa and Yersinia enterolitica, inactivation of > or = 5 log10 was measured after 60 min of PDT with Tri-P(4). The required treatment time to achieve this level of inactivation was four times longer than required for VSV. For cell-associated HIV, only 1.7 log10 of inactivation was found, despite clear induction of cell death of HIV-infected cells. The non-enveloped virus, canine parvovirus, was completely resistant to the treatment. PDT of RCC with Tri-P(4) for 60 min, and subsequent storage in AS-3, resulted in 4% haemolysis after 35 days of storage. The ATP content of untreated and treated RBC declined with similar kinetics during storage. CONCLUSION: PDT of RCC with Tri-P(4) for 60 min inactivates a wide range of pathogens, but not cell-associated HIV and a non-enveloped virus, and compromises RBC quality. This reduces the suitability of PDT with Tri-P(4) for red cell sterilization. Therefore, further improvements in the treatment procedures to potentiate pathogen inactivation and to preserve RBC integrity will be required to generate an effective treatment for sterilizing RCC.     

Use of fecal occult blood testing in hospitalized patients: Results of an audit

BACKGROUND:

The fecal occult blood test (FOBT), widely used as a colorectal cancer screening tool, continues to be used in hospitalized patients. However, the utility of this test for hospitalized patients is unclear.

OBJECTIVE:

To assess FOBT use in a large urban regional health authority.

METHODS:

Reports of all FOBTs performed between April 1, 2011 and March 30, 2012 from two academic and four community hospitals in Winnipeg (Manitoba) were extracted. Of 650 hospitalizations with a positive FOBT result and 1254 with a negative FOBT result, random samples of 230 and 97 charts, respectively, were reviewed. Information including demographics, admission diagnos(es), indication(s) for ordering the FOBT and clinical management was extracted.

RESULTS:

Thirty-four percent (650 of 1904) of hospitalizations with an FOBT had a positive FOBT result. Family medicine physicians ordered approximately one-half of the reviewed FOBTs. The most common indication for ordering an FOBT was anemia. Of those with a positive FOBT, 66% did not undergo further gastrointestinal investigations. Of those with a positive FOBT and overt gastrointestinal bleeding and/or melena who underwent endoscopy, 60% had their endoscopy performed before the FOBT result being reported while 38% underwent their endoscopy ≥3 days after the stool sample was collected. There were minimal differences in clinical practices between academic and community hospitals.

CONCLUSIONS:

The present study suggests that FOBT results in hospitalized patients may have little beneficial impact on clinical management. Hospital laboratories may be better served in directing resources to other tests.     

International multi-centre evaluation of a dipstick assay for human leptospirosis

A dipstick assay for the detection of Leptospira-specific immunoglobulin M (IgM) antibodies in human sera was evaluated in 27 laboratories in 23 countries. 873 serum samples from 711 patients including 329 laboratory-confirmed leptospirosis case patients, 239 noncase patients and 69 patients with viral infections causing heamorrhagic fever were tested. Relative to the results of the reference leptospirosis test, the sensitivity of the dipstick assay was 84.5% for serum samples collected during the first 10 days of the disease and 92.1% for serum samples collected 10-30 days after the onset of disease. The specificity was 87.5% and 94.4%, respectively. Similar to viral haemorrhagic fevers, leptospirosis may cause bleeding. A small number of serum samples from patients with haemorrhagic viral infections gave a weak (1 +) stain. All other samples were negative. In conclusion, the dipstick assay is sensitive and specific and reacts well with serum samples from patients infected with a range of leptospiral strains. It is also easy to use and does not require special equipment or refrigeration. Therefore the assay is ideal for use in developing countries and rural settings.     

Abnormal pattern of cell proliferation in the entire colonic mucosa of patients with colon adenoma or cancer

Using autoradiography after 1 h of pulsed labeling with tritiated thymidine in endoscopic biopsy specimens from normal-appearing mucosa, cell proliferation was determined at six predetermined sites of the whole colon in patients with neoplastic disease of the large bowel and was compared with that of subjects without macroscopic colonic pathology. The labeling index (the percentage of cells incorporating [3H]thymidine) was 8.6 +/- 0.5 (mean +/- SEM) in 13 patients with colon carcinoma (p less than 0.001 vs. 16 control patients whose labeling index was 4.9 +/- 0.2) and 9.1 +/- 0.4 in 11 patients with a large adenoma in the colon (p less than 0.001 vs. controls). Twenty-one patients with one or more small adenomas (diameter less than 1 cm) had a moderately increased cell proliferation compared with controls (labeling index 6.2 +/- 0.3, p less than 0.02 vs. controls). In patients with neoplastic disease an enlargement of the proliferative compartment was found, whereas 6 patients with Crohn's colitis had values for labeling index and a distribution of labeled cells along the crypt comparable to that of control subjects. An increased cell proliferation was found along the entire colon under each of the neoplastic conditions studied. These findings indicate that although neoplastic lesions develop in a limited area of the colon, the entire large bowel may be at risk for tumor growth.     

Routine testing of liver function after biliary-enteric anastomosis has no clinical relevance.

BACKGROUND/AIMS: Patients who had a biliary-enteric anastomosis often have elevated liver function tests. The aim of this study was to investigate whether elevated liver function tests are associated with recurrent episodes of cholangitis. METHODOLOGY: Thirty-two patients, who received a biliary-enteric anatomosis for benign biliary disease were evaluated. Follow-up consisted of the patient's history, physical examination, determination of liver function tests, ultrasonography and hepatobiliary scintigraphy using 99mTc-HIDA. RESULTS: Median duration of follow-up was 45 months (range: 1-192) and liver function tests were elevated in 22 patients (69%) at some time during follow-up. Dilated intrahepatic ducts were found in 3 of 30 patients (10%), all of whom had elevated liver function tests at follow-up. Delayed passage from the liver was observed using scintigraphy in 10 (31%) of the patients. Seven patients (22%) experienced one episode of cholangitis and none experienced more than one episode. Multivariate analysis showed that male sex was an independent risk factor for elevated liver function tests (odds ratio: 10.9; P < 0.05). For cholangitis, no risk factors could be identified. CONCLUSIONS: It is concluded that elevated liver function tests are relatively common after a biliary-enteric anastomosis for benign biliary tract disease and are not predictive of the occurrence of cholangitis. We, therefore, recommend omitting routine laboratory screening for elevated liver function tests in the follow-up of a biliary-enteric anastomosis.