Metallothionein in the central nervous system: Roles in protection, regeneration and cognition

Metallothionein (MT) is an enigmatic protein, and its physiological role remains a matter of intense study and debate 50 years after its discovery. This is particularly true of its function in the central nervous system (CNS), where the challenge remains to link its known biochemical properties of metal binding and free radical scavenging to the intricate workings of brain. In this compilation of four reports, first delivered at the 11th International Neurotoxicology Association (INA-11) Meeting, June 2007, the authors present the work of their laboratories, each of which gives an important insight into the actions of MT in the brain. What emerges is that MT has the potential to contribute to a variety of processes, including neuroprotection, regeneration, and even cognitive functions. In this article, the properties and CNS expression of MT are briefly reviewed before Dr Hidalgo describes his pioneering work using transgenic models of MT expression to demonstrate how this protein plays a major role in the defence of the CNS against neurodegenerative disorders and other CNS injuries. His group's work leads to two further questions, what are the mechanisms at the cellular level by which MT acts, and does this protein influence higher order issues of architecture and cognition? These topics are addressed in the second and third sections of this review by Dr West, and Dr Levin and Dr Eddins, respectively. Finally, Dr Aschner examines the ability of MT to protect against a specific toxicant, methylmercury, in the CNS.     

Performance of visual inspection with acetic acid and human papillomavirus testing for detection of high‐grade cervical lesions in HIV positive and HIV negative Tanzanian women

The aim of this cross sectional study was to assess type distribution of human papillomavirus (HPV) among HIV positive and HIV negative women who underwent cervical cancer screening, and to examine the ability of visual inspection with acetic acid (VIA), the standard detection method in Tanzania, and HPV‐testing to detect cytologically diagnosed high grade lesions or cancer (HSIL+). Women from different areas in Tanzania were invited by public announcement to cervical cancer screening organized by Ocean Road Cancer Institute (Dar‐es‐Salaam). A total of 3,767 women were enrolled. Women underwent gynecological examination with collection of cervical cells for conventional cytological examination, and swab for HPV‐DNA detection (Hybrid‐Capture2) and genotyping (LiPAv2 test). Subsequently VIA was performed. The participants were also tested for HIV. HPV16, HPV52 and HPV18 were the three most common HR HPV types among women with HSIL+ cytology with prevalences of 42.9, 35.7 and 28.6%, respectively, in HIV positive women which was higher than among HIV negative women (30.2, 21.9 and 16.7%). A total of 4.5% of the women were VIA positive, and VIA showed a low sensitivity compared to HPV‐testing for detection of HSIL+. The sensitivity of VIA varied with staff VIA experience, HIV status and age. Vaccines including HPV16, HPV52 and HPV18 will likely reduce the number of HSIL+ cases independently of HIV status. The frequency of HSIL+ was high among HIV positive women, emphasizing the importance of establishing a screening program which also reaches HIV positive women. Our results highlight the importance of continuous training of staff performing VIA, and also point to the need for other screening methods such as HPV‐testing at low cost.     

Induction of non-painful and painful intestinal sensations by hypertonic saline: a new human experimental model.

BACKGROUND AND AIMS: To develop a pain model for chemical stimulation of the human gut. METHODS: In a double-blind experimental study 10 subjects with a previously performed sigmoidostomy were randomised to receive injections with either isotonic or hypertonic saline in the colonic mucosa. In the hypertonic experimental arm, 0.1 ml of 0.9%, 2%, 4%, and 6% and 0.2 ml of 2% and 4% saline were given. In the placebo arm, six 0.9% saline injections of the same quantities were given. In a separate experiment 0.8 ml 4% saline was infused into the mucosa by a pump over a period of 2min. The pain intensity was rated on a 0-10 visual analogue scale with 5 as the pain threshold. RESULTS: The hypertonic saline injections resulted in local as well as referred non-painful and painful sensations in 9 out of the 10 subjects. The evoked sensations were mostly described as a smarting sensation with an intensity of median 1 (range 0-5.6) for 0.1 ml 2% saline to median 2.9 (range 0-6.2) for 0.2 ml 4% saline. Seven subjects reported referred sensations to the abdominal skin. Continuous infusion of 4% saline resulted in a consistent sensory response in all subjects, with a median intensity of 4.1 (range 2.1-8.1). This sensory intensity was reproducible in 70% in a retest experiment after median 7 weeks. In the placebo arm a total of 70 isotonic saline injections only resulted in inconsistent, short-lasting non-painful sensations in three subjects. CONCLUSION: The model represents a safe method for direct chemical activation of the sensory endings in the human gut. The model may be used for pharmacological screening of analgesics and for basic investigations in patients suffering from gastrointestinal diseases.     

Zebrafish provide a sensitive model of persisting neurobehavioral effects of developmental chlorpyrifos exposure: Comparison with nicotine and pilocarpine effects and relationship to dopamine deficits

Chlorpyrifos (CPF) an organophosphate pesticide causes persisting behavioral dysfunction in rat models when exposure is during early development. In earlier work zebrafish were used as a complementary model to study mechanisms of CPF-induced neurotoxicity induced during early development. We found that developmental (first five days after fertilization) chlorpyrifos exposure significantly impaired learning in zebrafish. However, this testing was time and labor intensive. In the current study we tested the hypothesis that persisting effects of developmental chlorpyrifos could be detected with a brief automated assessment of startle response and that this behavioral index could be used to help determine the neurobehavioral mechanisms for persisting CPF effects. The swimming activity of adult zebrafish was assessed by a computerized video-tracking device after a sudden tap to the test arena. Ten consecutive trials (1/min) were run to determine startle response and its habituation. Additionally, habituation recovery trials were run at 8, 32 and 128 min after the end of the initial trial set. CPF-exposed fish showed a significantly (p < 0.025) greater overall startle response during the 10-trial session compared to controls (group sizes: Control N = 40, CPF N = 24). During the initial recovery period (8 min) CPF-exposed fish showed a significantly (p < 0.01) greater startle response compared to controls. To elucidate the contributions of nicotinic and muscarinic acetylcholine receptors to developmental CPF-mediated effects, the effects of developmental nicotine and pilocarpine exposure throughout the first five days after fertilization were determined. Developmental nicotine and pilocarpine exposure significantly increased startle response, though nicotine (group sizes: Control N = 32, 15 mM N = 12, 25 mM N = 20) was much more potent than pilocarpine (group sizes: Control N = 20, 100 µM N = 16, 1000 µM N = 12). Neither was as potent as CPF for developmental exposure increasing startle response in adulthood. Lastly, developmental CPF exposure decreased dopamine and serotonin levels and increased transmitter turnover in developing zebrafish larvae (N = 4 batches of 50 embryos/treatment). Only the decline in dopamine concentrations persisted into adulthood (group sizes: Control N = 14, CPF N = 13). This study shows that a quick automated test of startle can detect persisting neurobehavioral impairments caused by developmental exposure to CPF. This may be helpful in screening for persisting neurobehavioral defects from a variety of toxicants.     

The sestamibi scan as a preoperative screening tool

Sestamibi scan is generally recognized in the literature to play a role in the imaging of parathyroid adenoma. Most institutions quote sensitivities ranging from 80 to 100 per cent. There is still a question as to whether patients need preoperative localization studies. Preoperative localization can potentially result in less invasive surgery, shorter operative times, decreased hospital stays, and decreased need for re-exploration. Our hypothesis is that the sestamibi scan is a sensitive predictor of parathyroid adenomas. The objectives of this study are to determine the sensitivity of sestamibi scan in detecting parathyroid adenoma, and to determine whether either parathyroid hormone (PTH) level or calcium level is an independent predictor of a positive scan. One hundred patients were retrospectively reviewed at Louisiana State University Health Sciences Center-Shreveport and Louisiana State University Health Sciences Center-Monroe from March 1993 through December 2000. All patients had a preoperative sestamibi scan. This scan was performed using the dual-phase technique in which the parathyroid glands are visualized after washout of tracer from the thyroid. The scan was followed by either a unilateral or bilateral neck dissection. There were 82 female patients and 18 male patients who ranged in age from 23 to 78 years. The median weight of glands with a positive scan was 795 mg. The median weight of glands with a negative scan was 480 mg. This difference was statistically significant (P < 0.04). Overall there were 107 adenomas. Of these 93 had positive scans and 14 had negative scans. This results in a sensitivity of 87 per cent. There were 67 glands that weighed at least 500 mg. Of these 67 glands 61 had positive scans and six had negative scans. This resulted in a sensitivity of 91 per cent. There were 40 glands that weighed less than 500 mg. Of these 40 glands 32 had positive scans and eight had negative scans. This resulted in a sensitivity of 80 per cent. Using multiple linear regression analysis calcium level correlated with the weight of the gland (P < 0.01). Calcium level also correlated with the PTH level (P < 0.01). However, neither the PTH level nor the calcium level correlated with a positive sestamibi scan. Sestamibi scan is a sensitive predictor for parathyroid adenoma greater than 500 mg (91% sensitivity). Even in smaller glands (<500 mg) 80 per cent sensitivity was demonstrated. Although the calcium level correlates with the PTH level neither PTH level nor calcium level is predictive of a positive sestamibi scan.