Benzo[a]pyrene at an environmentally relevant dose is slowly absorbed by, and extensively metabolized in, tracheal epithelium

While tobacco smoke has been conclusively identified as a lung carcinogen, there is much debate over which smoke constituent(s) are primarily responsible for its carcinogenicity. Previous studies in our laboratory suggested that highly lipophilic carcinogens are slowly absorbed in the thicker epithelium of the conducting airways, potentially allowing for substantial local metabolism. The bioactivation of polycyclic aromatic hydrocarbons in airway epithelium may, hence, be important in tobacco smoke-induced carcinogenesis. In the present study, the hypothesis of slow absorption and substantial local metabolic activation of highly lipophilic carcinogen in airway epithelium was tested in dogs. A single dose of tritiated benzo[a]pyrene (BaP) dissolved in a saline/phospholipid suspension was instilled in the trachea, just anterior to the carina. At intervals of a few minutes up to 30 min over a 3-h period, blood samples were drawn from the azygous vein, which drains the area around the point of instillation, and from the systemic circulation. Tissue samples were taken at the end of the experiment. The concentration of BaP with depth into the tracheal mucosa was determined with autoradiography. BaP was slowly absorbed into the trachea with a half-time of approximately 73 min, which is consistent with diffusion-limited passage through the epithelium and lead to local doses in the tracheal epithelium that were more than a 1000-fold those of other tissues. The long retention of BaP in the epithelium provided the local metabolizing enzymes with high substrate levels over a long period, resulting in extensive metabolism. At 3 h after the exposure, 23% of the BaP-equivalent activity remained in the tracheal mucosa. Of this fraction, 13% was parent compound, 28% was organic extractable, 31% was water-soluble, and 28-7% of the instilled dose was bound to tracheal tissues. These results explain the tendency of highly lipophilic carcinogens, such as BaP, to induce tumors at the site of entry and, furthermore, indicate that the highly lipophilic components of tobacco smoke and polluted air may be the most important contributors to lung tumors of the conducting airways.      

Incidence of diabetic retinopathy in a Hong Kong Chinese population

Background: The aim was to examine the progression and regression of diabetic retinopathy within a four‐year period in a Chinese population with type 2 diabetes mellitus in a community optometry clinic in Hong Kong. Methods: During the period May 2005 to November 2009, 5,160 patients with type 2 diabetes mellitus who had attended at least two diabetic retinopathy screening sessions at a community optometry clinic were included as subjects in this study. All had retinal photographs taken of both eyes, which were of sufficiently good quality for grading. For the purpose of this study, diabetic retinopathy grading was based on the results of the worst eye. The main outcomes were the within four‐year incidence of diabetic retinopathy and the incidence of progression and regression of diabetic retinopathy. Results: Of the 5,160 subjects in this study, 3,647 had no diabetic retinopathy, while 1,513 had diabetic retinopathy at the baseline visit. Of those 3,647 subjects with no diabetic retinopathy, the within four‐year cumulative incidence of any diabetic retinopathy, mild or moderate non‐proliferative diabetic retinopathy and sight‐threatening diabetic retinopathy was 15.16 per cent, 14.45 per cent, 0.69 per cent and 0.03 per cent, respectively. Of those 1,513 subjects with diabetic retinopathy at baseline, the within four‐year progression incidence of diabetic retinopathy was 6.61 per cent and the regression incidence of diabetic retinopathy was 45.54 per cent. Conclusion: The high regression incidence of diabetic retinopathy suggests that it might not be necessary for all patients with diabetes to be screened annually. Other methods to determine the screening frequency for an individual patient should be explored.     

Urinary albumin excretion and transcapillary escape rate of albumin in malignancies

Transcapillary escape rate of albumin was determined in 22 patients with different malignancies. In addition, urinary albumin excretion rate was measured in 24-h urine samples using a sensitive immunoassay. Increased urinary albumin excretion was defined as ≥20 μg/min according to conventional standards. Renal glomerular filtration and tubular function was estimated by⁵¹Cr-EDTA plasma clearance and urinary beta 2-microglobulin, respectively. Median urinary albumin excretion rate was 15.0 μg/min (range 6–510 μg/min) and the frequency of increased urinary albumin excretion was 41%. This agrees with other studies showing increased albuminuria in several types of malignant diseases. Patients with advanced disease (tumour, node, metastasis (TNM) stage II–IV) had a significantly higher urinary albumin excretion rate than patients with localized disease (TNM stage I). Serum creatinine, glomerular filtration rate and urinary beta 2-microglobulin were all within normal limits. Median transcapillary escape rate of albumin was 5.5%/h (range 2–8%/h) and this level is comparable with values in healthy subjects. There was no significant difference in transcapillary escape rate between patients with elevated urinary albumin excretion and the normoalbuminuric group. Median value of the absolut outflux of albumin was 10.6 g/h with similar levels in patients with increased urinary albumin excretion and patients with normoalbuminuria. Our results indicate a high prevalence of minor glomerular dysfunction with a slightly elevated urinary albumin excretion in patients with malignancies. The normal endothelial function, as estimated by the transcapillary escape rate of albumin, suggests an overal unaffected capillary permeability and increased urinary albumin loss appears to be an isolated renal phenomenon in cancer patients.     

Prospective development of an individualised predictive model for treatment coverage using offline cone beam computed tomography surrogate measures in post‐prostatectomy radiotherapy

The aim of this study is to prospectively evaluate and model surrogate explanatory variables (SEVs) of target coverage and rectal dose pertaining to soft tissue anatomy visualised on cone beam computed tomography (CBCT) for incorporation into post‐prostatectomy treatment coverage verification protocols. Twenty post‐prostatectomy patients treated with conformal prostate bed radiotherapy (64–74 Gy) underwent CBCT daily at fractions 1 to 5, and then weekly. Treatment coverage was defined on each CBCT using ‘PTV95’, percentage of the CBCT PTV covered by original treatment fields, and ‘RECTD50’, dose delivered to 50% of CBCT rectal volume by original treatment fields. Three candidate SEVs for treatment coverage were defined for each scan: anterior rectal wall movement, change in bladder length and bladder base movement. Both anterior rectal wall movement and increase in bladder length predicted for the decreased PTV95 (P < 0.001 for each). Anterior movement of the anterior rectal wall predicted for increased RECTD50 (P < 0.001). Predictive models for the PTV95 and RECTD50 that accept the significant SEVs as inputs were developed. We developed simple CBCT‐acquired soft tissue anatomic surrogate measures that signal changes in target coverage and rectal dose during post‐prostatectomy radiotherapy. Conventional bony anatomy patient position verification protocols were inadequate in accounting for soft tissue target and organ variation seen with CBCT.     

Outcomes of 25-gauge pars plana vitrectomy for cytomegalovirus retinitis-related retinal detachment

Purpose:The purpose of this study is to evaluate the anatomical and functional outcomes of 25-gauge (G) pars plana vitrectomy (PPV) in patients with cytomegalovirus retinitis (CMVR)-related rhegmatogenous retinal detachment (RRD).Methods:Single-center retrospective consecutive case series of patients who underwent 25-G PPV for CMVR-related RRD repair with a minimum follow-up of 3 months. Complete anatomic success was defined as the complete attachment of retina including the periphery. Best-corrected visual acuity (BCVA) of ≥20/400 was defined as functional success.Results:Sixteen eyes of 15 patients were included in the study. Eleven patients were human immunodeficiency virus positive, three patients had hematological malignancies, and one patient suffered from dyskeratosis congenita. The mean follow-up was 20.5 ± 17.4 months (range 3–60 months). Complete anatomical success was seen in 15 eyes (93.75%). One eye had a residual inferior detachment with attached macula. Silicone oil was used as tamponade in 15 eyes and C₃F₈ gas in one eye. The mean change in BCVA was statistically significant, preoperative LogMAR BCVA was 2.05 ± 0.94 while the final follow-up postoperative LogMAR BCVA was 1.03 ± 0.61 (P < 0.001). Thirteen eyes (81.25%) had final BCVA ≥20/400.Conclusion:Microincision vitrectomy surgery can achieve excellent retinal reattachment rates in post-CMVR RRDs without significant intraoperative and postoperative complications. The visual outcome varies depending on the status of the optic disc and macula. Majority of the patients maintained functional vision.     

Induction of apoptosis by the ginsenoside Rh2 by internalization of lipid rafts and caveolae and inactivation of Akt

Background and purpose:

Lipid rafts and caveolae are membrane microdomains with important roles in cell survival signalling involving the Akt pathway. Cholesterol is important for the structure and function of these microdomains. The ginsenoside Rh2 exhibits anti-tumour activity. Because Rh2 is structurally similar to cholesterol, we investigated the possibility that Rh2 exerted its anti-tumour effect by modulating rafts and caveolae.

Experimental approach:

A431 cells (human epidermoid carcinoma cell line) were treated with Rh2 and the effects on cell apoptosis, raft localization and Akt activation measured. We also examined the effects of over-expression of Akt and active-Akt on Rh2-induced cell death.

Key results:

Rh2 induced apoptosis concentration- and time-dependently. Rh2 reduced the levels of rafts and caveolae in the plasma membrane and increased their internalization. Furthermore, Akt activity was decreased and consequently, Akt-dependent phosphorylation of Bad, a pro-survival protein, was decreased whereas the pro-apoptotic proteins, Bim and Bax, were increased upon Rh2 treatment. Unlike microdomain internalization induce by cholesterol depletion, Rh2-mediated internalization of rafts and caveolae was not reversed by cholesterol addition. Also, cholesterol addition did not restore Akt activation or rescue cells from Rh2-induced cell death. Rh2-induced cell death was attenuated in MDA-MB-231 cells over-expressing either wild-type or dominant-active Akt.

Conclusions and implications:

Rh2 induced internalization of rafts and caveolae, leading to Akt inactivation, and ultimately apoptosis. Because elevated levels of membrane rafts and caveolae, and Akt activation have been correlated with cancer development, internalization of these microdomains by Rh2 could potentially be used as an anti-cancer therapy.     

Antiurolithiatic and antioxidant activity of Mimusops elengi on ethylene glycol-induced urolithiasis in rats

Objective:

To evaluate the potential of Mimusops elengi in the treatment of renal calculi.

Materials and Methods:

Petroleum ether, chloroform, and alcohol extracts of Mimusops elengi bark were evaluated for antiurolithiatic and antioxidant activity in male albino Wistar rats. Ethylene glycol (0.75%) in drinking water was fed to all the groups (Groups II–IX) except normal control (Group I) for 28 days to induce urolithiasis for curative (CR) and preventive (PR) regimen. Groups IV, V, and VI served as CR, and groups VII, VIII, and IX as PR were treated with different extracts of M. elengi bark. Groups I, II, and III served as normal control, positive control (hyperurolithiatic), and standard (cystone 750 mg/kg), respectively. Oxalate, calcium, and phosphate were monitored in the urine and kidney. Serum BUN, creatinine, and uric acid were also recorded. In vivo antioxidant parameters such as lipid peroxidation (MDA), glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT) were also monitored.

Results:

All the extracts of M. elengi were safe orally and exhibited no gross behavioral changes in the rats. In hypercalculi animals, the oxalate, calcium, and phosphate excretion grossly increased. However, the increased deposition of stone forming constituents in the kidneys of calculogenic rats were significantly (P < 0.001) lowered by curative and preventive treatment with alcohol extract (AlE) of M. elengi. It was also observed that alcoholic extract of M. elengi produced significant (P < 0.001) decrease in MDA, and increased GSH, SOD, and CAT. These results confirm that AlE of M. elengi possess potent antiurolithiatic activity.

Conclusion:

The results obtained suggest potential usefulness of the AlE of M. elengi bark as an antiurolithiatic agent.     

Comparison between elderly inpatient fallers with and without dementia

INTRODUCTION

This study aimed to examine the various factors associated with inpatient falls among patients with and without dementia in a hospital setting.

METHODS

This was a retrospective one-year study using data collected from Singapore General Hospital''s electronic reporting system for inpatient falls.

RESULTS

In the study period, 298 patients aged ≥ 65 years fell during their hospital stay. The majority of the patients (n = 248) did not have dementia. In our study, fallers with dementia were more likely to use ambulatory aids, be visually impaired and have urinary incontinence. More patients with dementia than those without had a history of previous falls, and were placed on fall precaution with restricted freedom of movement, which at times, included restraints. However, the difference between patients who were put on restraints and those who were allowed to move freely was not statistically significant. The majority of falls in both groups occurred at the bedside. We found that fallers without dementia were more likely to fall during the morning shift, whereas fallers with dementia were more likely to fall during the night shift. Fallers with dementia were more likely to be confused at the time of the fall.

CONCLUSION

In our study, we found that fallers with dementia were more likely to have visual impairment, have urinary incontinence, use walking aids, and to be confused and physically restrained at the time of the fall. The fallers without dementia in our study may have undiagnosed dementia.