Blood clearance and organ distribution of intravenously administered polymethacrylic nanoparticles in mice

Polymethacrylic nanospheres (mean diameter 0.25-0.30 microns), prepared by aqueous emulsion copolymerization, were developed as a new site-specific drug delivery system. The nanoparticles were labeled either with indium-111 or iodine-125, and after a single iv injection of labeled particles into mice, their blood clearance and organ distribution were analyzed. A rapid clearance of 111In-labeled nanoparticles from the blood circulation to the mononuclear phagocyte system (MPS) was visualized using external scintigraphic imaging. From 10 to 60 min, radioactivity measurements in blood and organs (liver, spleen, kidneys, lungs, heart) showed that the 125I-labeled nanospheres were rapidly removed from the bloodstream (distribution half-life approximately 3-5 min) and mainly deposited in the liver (60% of the administered dose, 10 min after administration). Up to 1 h, radioactivity in heart and lungs remained insignificant, while in the kidneys, radioactivity levels increased from 8 to 11%.     

Trends in the incidence rates of tonsil and base of tongue cancer in England, 1985�C2006

INTRODUCTION

The aim of this study was to investigate whether incidence rates of tonsil and base of tongue cancer in England are increasing using data from the UK cancer registry.

SUBJECTS AND METHODS

Cancer registrations for oral cavity and oropharynx cancer from 1985–2006 in England were obtained from the National Cancer Information Service. Population estimates were obtained from the Office for National Statistics. Age-adjusted incidence rates and age-specific incidence rates were calculated. The sexes were considered separately as incidence rates are known to differ significantly between men and women. Linear regression was performed to establish whether there was a relationship between incidence rates and time.

RESULTS

There has been an increase in all oral cavity and oropharyngeal cancer in the study period. Linear regression analysis suggests that approximately 90% of the variance in age-adjusted incidence rates for men and women for tonsil, base of tongue and other oral cavity cancer is explained by the passage of time. For other oropharyngeal cancer, the variance is 62% and 46% in men and women, respectively. The estimated annual percentage change from 1985 to 2006 in age-adjusted incidence rates for tonsil and base of tongue cancer is 5.7% and 6.7% for men, and 4.3% and 6.5% for women, respectively.

CONCLUSIONS

This study confirms a wide-spread clinical impression that there has been an increase in age-adjusted incidence rates, between 1985 and 2006, in all oral cavity cancer in England. The age range 40–69 years has seen the biggest increases in age-specific incidence rates for tonsil and base of tongue cancer. This reflects the findings of similar studies in other countries.     

Endogenous BDNF regulates induction of intrinsic neuronal growth programs in injured sensory neurons

Identification of the molecule(s) that globally induce a robust regenerative state in sensory neurons following peripheral nerve injury remains elusive. A potential candidate is brain-derived neurotrophic factor (BDNF), the sole neurotrophin upregulated in sensory neurons after peripheral nerve injury. Here we tested the hypothesis that BDNF plays a critical role in the regenerative response of mature rat sensory neurons following peripheral nerve lesion. Neutralization of endogenous BDNF was performed by infusing BDNF antibodies intrathecally via a mini-osmotic pump for 3 days at the level of the fifth lumbar dorsal root ganglion, immediately following unilateral spinal nerve injury. This resulted in decreased expression of the injury/regeneration-associated genes growth-associated protein-43 and Tα1 tubulin in the injured sensory neurons as compared to injury plus control IgG infused or injury alone animals. Similar results were observed following inhibition of BDNF expression by intrathecal delivery of small interfering RNAs (siRNA) targeting BDNF starting 3 days prior to injury. The reduced injury/regeneration-associated gene expression correlated with a significantly reduced intrinsic capacity of these neurons to extend neurites when assayed in vitro. In contrast, delayed infusion of BDNF antibody for 3 days beginning 1 week post-lesion had no discernible influence on the elevated expression of these regeneration-associated markers. These results support an important role for endogenous BDNF in induction of the cell body response in injured sensory neurons and their intrinsic ability to extend neurites, but BDNF does not appear to be necessary for maintaining the response once it is induced.     

Early Glucose Abnormalities in Cystic Fibrosis Are Preceded by Poor Weight Gain

OBJECTIVE

Progressive β-cell loss causes catabolism in cystic fibrosis. Existing diagnostic criteria for diabetes were based on microvascular complications rather than on cystic fibrosis–specific outcomes. We aimed to relate glycemic status in cystic fibrosis to weight and lung function changes.

RESEARCH DESIGN AND METHODS

We determined peak blood glucose (BG_max) during oral glucose tolerance tests (OGTTs) with samples every 30 min for 33 consecutive children (aged 10.2–18 years). Twenty-five also agreed to undergo continuous glucose monitoring (CGM) (Medtronic). Outcome measures were change in weight standard deviation score (wtSDS), percent forced expiratory volume in 1 s (%FEV1), and percent forced vital capacity (%FVC) in the year preceding the OGTT.

RESULTS

Declining wtSDS and %FVC were associated with higher BG_max (both P = 0.02) and with CGM time >7.8 mmol/l (P = 0.006 and P = 0.02, respectively) but not with BG_{120 min}. A decline in %FEV1 was related to CGM time >7.8 mmol/l (P = 0.02). Using receiver operating characteristic (ROC) analysis to determine optimal glycemic cutoffs, CGM time above 7.8 mmol/l ≥4.5% detected declining wtSDS with 89% sensitivity and 86% specificity (area under the ROC curve 0.89, P = 0.003). BG_max ≥8.2 mmol/l gave 87% sensitivity and 70% specificity (0.76, P = 0.02). BG_{120 min} did not detect declining wtSDS (0.59, P = 0.41). After exclusion of two patients with BG_{120 min} ≥11.1 mmol/l, the decline in wtSDS was worse if BG_max was ≥8.2 mmol/l (−0.3 ± 0.4 vs. 0.0 ± 0.4 for BG_max <8.2 mmol/l, P = 0.04) or if CGM time above 7.8 mmol/l was ≥4.5% (−0.3 ± 0.4 vs. 0.1 ± 0.2 for time <4.5%, P = 0.01).

CONCLUSIONS

BG_max ≥8.2 mmol/l on an OGTT and CGM time above 7.8 mmol/l ≥4.5% are associated with declining wtSDS and lung function in the preceding 12 months.Progressive β-cell loss causes catabolism and weight loss in cystic fibrosis (1,2). Weight is a prognostic indicator (3), and prevention of weight decline is a major clinical objective in children and adolescents with cystic fibrosis. Median life expectancy of patients with cystic fibrosis has risen progressively over recent decades but remains drastically shorter (∼36 years) than that of the general population (4). The presence of cystic fibrosis–related diabetes (CFRD) is associated with an increase in early mortality of up to sixfold (5). CFRD is usually diagnosed by the North American Cystic Fibrosis Foundation criteria (6) or World Health Organization (WHO) criteria for diabetes (7). These criteria were designed to identify patients at risk of microvascular complications in type 2 diabetes (8) and were not designed with cystic fibrosis–specific outcomes in mind. Microvascular complications occur in cystic fibrosis (9); however, catabolic decline in weight and deteriorating lung function may be more relevant outcomes. Poor weight gain is associated with worsening lung function (10,11), and both are associated with early mortality (12,13). Weight and lung function declines have been shown to precede the diagnosis of CFRD by standard criteria (2), but the earliest glycemic abnormality associated with clinical decline has not been determined. Glycemic status can be assessed in detail using an oral glucose tolerance test (OGTT) with 30-min samples and, more recently, continuous interstitial fluid glucose monitoring (CGM). We aimed to determine the relationship between glycemic status and the change in weight standard deviation score (wtSDS) and the change in lung function over the preceding year.     

Exogenous NT-3 and NGF differentially modulate PACAP expression in adult sensory neurons, suggesting distinct roles in injury and inflammation

Expression of pituitary adenylate cyclase-activating polypeptide in sensory neurons varies with injury or inflammation. The neurotrophins NGF and NT-3 are profound regulators of neuronal peptidergic phenotype in intact and injured sensory neurons. This study examined their potential for modulation of PACAP expression in adult rat with intact and injured L4-L6 spinal nerves with or without immediate or delayed intrathecal infusion of NT-3 or NGF. Results indicate that in L5 DRG, few trkC neurons express high levels of PACAP mRNA in the intact state, but many do following injury. The elevated expression in injured neurons is mitigated by NT-3 infusion, suggesting a role for NT-3 in returning the 'injured phenotype' back towards an 'intact phenotype'. NGF dramatically up-regulated PACAP expression in trkA-positive neurons in both intact and injured DRGs, implicating NGF as a positive regulator of PACAP expression in nociceptive neurons. Surprisingly, NT-3 modulates PACAP expression in an antagonistic fashion to NGF in intact neurons, an effect most evident in the trkA neurons not expressing trkC. Both NT-3 and NGF infusion results in decreased detection of PACAP protein in the region of the gracile nuclei, where central axons of the peripherally axotomized large sensory fibers terminate. NGF infusion also greatly increased the amount of PACAP protein detected in the portion of the dorsal horn innervated by small-medium size DRG neurons, while both neurotrophins appear able to prevent the decrease in PACAP expression observed in these afferents with injury. These results provide the first insights into the potential molecules implicated in the complex regulation of PACAP expression in sensory neurons.     

Pineal germinoma: MR imaging

Magnetic resonance (MR) imaging characteristics of pineal germinomas are described in seven patients imaged with MR and computed tomography (CT). In patients with symptoms of an enlarging process in the quadrigeminal plate cistern, MR imaging was as sensitive as CT scanning in detecting the mass. MR imaging did not detect a normal-sized, calcified neoplastic gland. Germinoma, germinoma with embryonal cell carcinoma elements, and pineoblastoma demonstrated different MR signal characteristics. Although direct coronal and sagittal MR images were useful in defining the relationship of the tumor to the posterior third ventricle, Sylvian aqueduct, and vein of Galen, the ease, rapidity, and sensitivity of CT scanning suggest that CT should remain the modality of choice for initial evaluation and screening of the pineal region, especially in the younger pediatric population, in whom detection of calcification may provide the only clue of an abnormality.