Intracerebroventricular infusion of interleukin 1 rapidly decreases peripheral cellular immune responses.

Low doses (50-200 pg or 3.1-12.4 fmol) of interleukin 1 (IL-1) infused into the brain of rats produced rapid suppression of various cellular immune responses in peripheral lymphocytes of rats. Fifteen minutes after infusion of purified IL-1 beta into the lateral ventricle, natural killer cell activity, response to phytohemagglutinin stimulation, and interleukin 2 production were markedly suppressed in lymphocytes isolated from blood and spleen. These effects were due to infusion of IL-1 into brain since they did not occur when IL-1 was infused into the cisterna magna (essentially posterior to brain) or was injected intraperitoneally. Effects of IL-1 in brain could be blocked by simultaneous infusion of alpha-melanocyte-stimulating hormone, which is known to block the biological actions of IL-1. To stimulate release of endogenous IL-1 in brain, lipopolysaccharide was infused; this produced similar effects as IL-1, and these effects also were blocked by alpha-melanocyte-stimulating hormone. At longer intervals after infusion of IL-1 and lipopolysaccharide (3, 6, and 24 hr), immune responses returned to baseline or remained suppressed; i.e., "rebound" immunopotentiation did not occur. Finally, IL-1 infusion suppressed cellular immune responses in adrenalectomized animals, thereby showing that the effects of central IL-1 on peripheral cellular immune responses were, at least in part, independent of the stimulatory effect of IL-1 on secretion of adrenal hormones. These results indicate a link from brain to peripheral immune responses by means of action of a cytokine acting in the brain.     

Continuous absence of metaphase-defined cytogenetic abnormalities,especially of chromosome 13 and hypodiploidy,ensures long-term survival in multiple myeloma treated with Total Therapy I: interpretation in the context of global gene expression

Metaphase cytogenetic abnormalities (CAs), especially of chromosome 13 (CA 13), confer a grave prognosis in multiple myeloma even with tandem autotransplantations as applied in Total Therapy I, which enrolled 231 patients between 1989 and 1994. With a median follow-up of almost 9 years, the prognostic implications of all individual CAs, detected prior to treatment and at relapse, were investigated. Among all CAs and standard prognostic factors examined prior to therapy, only hypodiploidy and CA 13 (hypo-13 CA), alone or in combination, were associated with shortest event-free survival and overall survival (OS). The shortest postrelapse OS was observed with hypo-13 CA, which was newly detected in 18 of all 28 patients presenting with this abnormality at relapse. Superior prognosis was associated with the absence of any CA at both diagnosis and relapse (10-year OS, 40%). The lack of independent prognostic implications of other CAs points to a uniquely aggressive behavior of hypo-13 CA (present in 16% of patients at diagnosis). With the use of microarray data in 146 patients enrolled in Total Therapy II, overexpression of cell cycle genes distinguished CA from no CA, especially in cases of del(13) detected by interphase fluorescence in situ hybridization (FISH). FISH 13, resulting in a haploinsufficiency of RB1 and other genes mapping to chromosome 13, as well as activation of IGF1R, appears to have an amplifying effect on cell cycle gene expression, thus providing a molecular explanation for the dire outcome of patients with CA 13 compared with those with other CAs.     

The effects of surgicel and bone wax hemostatic agents on bone healing: An experimental study

Background:

The biological effects of hemostatic agends on the physiological healing process need to be tested. The aim of this study was to assess the effects of oxidized cellulose (surgicel) and bone wax on bone healing in goats’ feet.

Materials and Methods:

Three congruent circular bone defects were created on the lateral aspects of the right and left metacarpal bones of ten goats. One defect was left unfilled and acted as a control; the remaining two defects were filled with bone wax and surgicel respectively. The 10 animals were divided into two groups of 5 animals each, to be sacrificed at the 3^rd and 5^th week postoperatively. Histological analysis assessing quality of bone formed and micro-computed tomography (MCT) measuring the quantities of bone volume (BV) and bone density (BD) were performed. The results of MCT analysis pertaining to BV and BD were statistically analyzed using two-way analysis of variance (ANOVA) and posthoc least significant difference tests.

Results:

Histological analysis at 3 weeks showed granulation tissue with new bone formation in the control defects, active bone formation only at the borders for surgicel filled defects and fibrous encapsulation with foreign body reaction in the bone wax filled defects. At 5 weeks, the control and surgicel filled defects showed greater bone formation; however the control defects had the greatest amount of new bone. Bone wax filled defects showed very little bone formation. The two-way ANOVA for MCT results showed significant differences for BV and BD between the different hemostatic agents during the two examination periods.

Conclusion:

Surgicel has superiority over bone wax in terms of osseous healing. Bone wax significantly hinders osteogenesis and induces inflammation.     

Risk Stratification for the In-Hospital Mortality in Subarachnoid Hemorrhage: The HAIR Score

Background

The intracerebral hemorrhage (ICH) score is a simple grading scale that can be used to stratify risk of 30 day mortality in ICH patients. A similar risk stratification scale for subarachnoid hemorrhage (SAH) is lacking. We sought to develop a risk stratification mortality score for SAH.

Methods

With approval from the Institutional Review Board, we retrospectively reviewed 400 consecutive SAH patients admitted to our institution from August 1, 2006 to March 1, 2011. The SAH score was developed from a multivariable logistic regression model which was validated with bootstrap method. A separate cohort of 302 SAH patients was used for evaluation of the score.

Results

Among 400 patients with SAH, the mean age was 56.9 ± 13.9 years (range, 21.5–96.2). Among the 366 patients with known causes of SAH, 292 (79.8 %) of patients had aneurysmal SAH, 65 (17.8 %) were angiogram negative, and 9 (2 %) were other vascular causes. The overall in-hospital mortality rate was 20 %. In multivariable analysis, the variables independently associated with the in-hospital mortality were Hunt and Hess score (HH) (p < 0.0001), age (p < 0.0001), intraventricular hemorrhage (IVH) (p = 0.049), and re-bleed (p = 0.01). The SAH score (0–8) was made by adding the following points: HH (HH1-3 = 0, HH4 = 1, HH5 = 4), age (<60 = 0, 60–80 = 1, ≥80 = 2), IVH (no = 0, yes = 1), and re-bleed within 24 h (no = 0, yes = 1). Using our model, the in-hospital mortality rates for patients with score of 0, 1, 2, 3, 4, 5, 6, and 7 were 0.9, 4.5, 9.1, 34.5, 52.9, 60, 82.1, and 83.3 % respectively. Validation analysis indicates good predictive performance of this model.

Conclusion

The SAH score allows a practical method of risk stratification of the in-hospital mortality. The in-hospital mortality increases with increasing SAH mortality score. Further investigation is warranted to validate these findings.     

Atrial synchronous left ventricular only pacing with VDD pacemaker system – A cost effective alternative to conventional cardiac resynchronization therapy

Introduction

Atrial synchronous left ventricular (LV) only pacing using two leads and VDD pacemaker could be a cost effective alternative to conventional cardiac resynchronization therapy (CRT).

Methods

We implanted right atrial (RA) and LV leads with VDD pulse generator (LV only pacing) in five carefully screened heart failure patients who could not afford conventional CRT. All had NYHA class III/IV symptoms despite maximal guideline directed medical therapy. The sensed atrioventricular delay was programmed to pre-excite the LV and achieve fusion beat. Response to treatment was assessed at 6 months.

Results

Four patients were males. The mean age was 58 ± 12 years. At follow up, there was improvement in electrocardiographic, and echocardiographic parameters: Mean QRS duration decreased from 174 ± 17 msec to 128 ± 10.9 msec (p = 0.009), LV end-diastolic diameter decreased from 73.2 ± 12 mm to 65.8 ± 9.6 mm (p = 0.026), LV end-systolic diameter decreased from 65 ± 12 mm to 54 ± 10 mm (p = 0.020). There was a trend towards reduction of LV end-systolic and end-diastolic volumes. LV ejection fraction improved from 25 ± 6% to 34 ± 6% (p = 0.013) and left atrial dimension reduced from 44 ± 4 mm to 39 ± 5 mm (p = 0.045). All patients improved clinically.

Conclusion

RA-LV pacing using VDD pacemaker is a safe and effective technique of CRT. This may be a cost effective alternative to conventional CRT for patients in developing countries.     

Prevalence of chronic hepatitis B virus infection before and after implementation of a hepatitis B vaccination program among children in Nepal

Background

In Nepal, an estimated 2–4% of the population has chronic hepatitis B virus (HBV) infection. To combat this problem, from 2002 to 2004, a national three dose hepatitis B vaccination program was implemented to decrease infection rates among children. The program does not currently include a birth dose to prevent perinatal HBV transmission. In 2012, to assess the impact of the program, we conducted a serosurvey among children born before and after vaccine introduction.

Methods

In 2012, a cross-sectional nationally representative stratified cluster survey was conducted to estimate hepatitis B surface antigen (HBsAg) prevalence among children born from 2006 to 2007 (post-vaccine cohort) and among children born from 2000 to 2002 (pre-vaccine cohort). Demographic data, as well as written and oral vaccination history were collected. All children were tested for HBsAg; mothers of HBsAg positive children were also tested. Furthermore, we evaluated the field sensitivity and specificity of the SD Bioline HBsAg rapid diagnostic test by comparing results with an enzyme immunoassay.

Results

Among 2181 post-vaccination cohort children with vaccination data by either card or recall, 86% (95% confidence interval [CI] 77–95%) received ≥3 hepatitis B vaccine doses. Of 1200 children born in the pre-vaccination cohort, 0.28% (95% CI 0.09–0.85%) were positive for HBsAg; of 2187 children born in the post-vaccination cohort, 0.13% (95% CI 0.04–0.39%) were positive for HBsAg (p = 0.39). Of the six children who tested positive for HBsAg, two had mothers who were positive for HBsAg. Finally, we found the SD Bioline HBsAg rapid diagnostic test to have a sensitivity of 100% and a specificity of 100%.

Conclusions

This is the first nationally representative hepatitis B serosurvey conducted in Nepal. Overall, a low burden of chronic HBV infection was found in children born in both the pre and post-vaccination cohorts. Current vaccination strategies should be continued.     

Drift,Evolution, and Divergence in Biologics and Biosimilars Manufacturing

Biological medicines (biologics) are produced in living cells and purified in complex, multi-step processes. Compared with chemically synthesized small-molecule drugs, biologics are more sensitive to changes in manufacturing conditions. Process and product consistency should be founded on rigorous design and control of manufacturing processes, but consistency is ultimately ensured through robust quality systems. Even a minor change in any component of a quality system could lead to product drift, evolution, and divergence, which may impact the quality, safety, efficacy, and/or interchangeability of biologics. Unintended or unexplained deviations in manufacturing processes can lead to excursions in product attributes (i.e., drift). Well-managed quality systems can help detect and mitigate drift. Occasionally, quality attributes could shift outside of established acceptable ranges as the result of a known manufacturing change (defined here as evolution). Such changes should be studied extensively for effects on product safety and efficacy. With the advent of biosimilars, similar biologics will be produced by multiple manufacturers with different quality systems. Different patterns of product drift and evolution could contribute, over time, to clinically meaningful differences among biologics, including among originator products across regions and among originator products and biosimilar products, a process defined here as divergence. Manufacturers and policymakers can minimize the potential impact of divergence by establishing robust pharmacovigilance systems; requiring distinguishable names for all biologics, including both originator products and biosimilars; adhering to high standards for designations of interchangeability; and ensuring that patient medical records accurately reflect the specific biologic dispensed, especially if the biologic could be sourced from multiple manufacturers.