World Workshop on Oral Medicine VI: a systematic review of medication‐induced salivary gland dysfunction

The aim of this paper was to perform a systematic review of the pathogenesis of medication‐induced salivary gland dysfunction (MISGD). Review of the identified papers was based on the standards regarding the methodology for systematic reviews set forth by the World Workshop on Oral Medicine IV and the PRISMA statement. Eligible papers were assessed for both the degree and strength of relevance to the pathogenesis of MISGD as well as on the appropriateness of the study design and sample size. A total of 99 papers were retained for the final analysis. MISGD in human studies was generally reported as xerostomia (the sensation of oral dryness) without measurements of salivary secretion rate. Medications may act on the central nervous system (CNS) and/or at the neuroglandular junction on muscarinic, α‐and β‐adrenergic receptors and certain peptidergic receptors. The types of medications that were most commonly implicated for inducing salivary gland dysfunction were those acting on the nervous, cardiovascular, genitourinary, musculoskeletal, respiratory, and alimentary systems. Although many medications may affect the salivary flow rate and composition, most of the studies considered only xerostomia. Thus, further human studies are necessary to improve our understanding of the association between MISGD and the underlying pathophysiology.     

Profile of neonates admitted in pediatric ICU and validation of Score for Neonatal Acute Physiology (SNAP)

A retrospective study was conducted in the Pediatric Intensive Care Unit (PICU) of a tertiary care hospital in northern India to profile neonatal admissions and to assess the validity of the Score for Neonatal Acute Physiology (SNAP) in predicting the outcome in terms of mortality and length of hospital stay (LOS). Neonatal sepsis (51%) and birth asphyxia (11.2%) were the commonest indications for admission. Thirty-seven (38.1%) of the neonates died. The mean SNAP score in babies who died was 18.8 +/- 9.8 and 10.1 +/- 6.4 in survivors (P<0.001). There was no correlation between SNAP score and mean length of stay in hospital (P=0.5). We conclude that SNAP correlates well with mortality in neonates admitted to the PICU.     

The effect of refractive surgery on blur thresholds

Purpose:The aim of this study was to measure blur thresholds before and after refractive surgery.Methods:In this prospective cohort study conducted in a tertiary eye hospital in South India. Blur thresholds were measured for 30 young adult myopic patients 1 month prior to and after refractive surgery. Patients were asked to report three stages of blur, namely Detectable Blur (DB), Bothersome Blur (BB), and Non-resolvable Blur (NB). Blur was created by adding plus lenses (in steps of 0.12D) over their optimal subjective refraction. The blur judgments were made both monocularly and binocularly when looking through a 3 mm artificial pupil at one line above the best-corrected visual acuity.Results:A total of 30 participants were included in this study (mean age = 25.5 ± 3.8 (20–36) years; 77% female). The mean binocular preoperative blur of this group was: DB = 0.39 ± 0.26D, BB = 0.74 ± 0.28D and NB = 1.04 ± 0.42D. The corresponding mean binocular blur one-month post-operatively was DB = 0.46 ± 0.28D, BB = 0.83 ± 0.35D, and NB = 1.21 ± 0.44D. Although there was a marginal increase in the blur thresholds postoperatively, the difference was not statistically significant (DB: P = 0.320; BB: P = 0.229; NB: P = 0.054).Conclusion:All three blur thresholds showed an insignificant minimal increase at 1 month post-operatively suggesting that patients adapt to the induced blur following refractive surgery. A longer follow up would reveal how the adaptation to blur would change with time.     

Mini-Exon Genotyping of Leishmania Species in Khuzestan Province,Southwest Iran

Background

Leishmaniasis is a protozoan disease cause by Leishmania genus. Anthroponotic and zoonotic cutaneous leishmaniasis are endemic in Iran. The aim of this study was to identify the causative agent of cutaneous leishmaniasis by mini-exon gene in five regions of Khuzestan Province, southwest of Iran.

Methods

From 2007 to 2008 in this cross-sectional study, cutaneous samples were collected from patients referred to Health Centers and Hospitals of the Khuzestan Province for cutaneous leishmaniasis diagnosis and cultured in Novy-MacNeal-Nicolle (NNN) and RPMI 1640. The propagated promastigotes were harvested and Leishmania species of cutaneous leishmaniasis were identified by RFLP and DNA sequencing of the PCR generated fragments.

Results

L. major and L. tropica were the causative agents of cutaneous leishmaniasis by predominantly of L. major species. The alignment of the mini-exon sequencing isolates with reported sequencing of L. major and L. tropica revealed 92%-99% identity.

Conclusion

Our study showed that mini-exon PCR-RFLP was useful method to identify the causative species of cutaneous leishmaniasis.     

4α-phorbol 12,13-didecanoate activates cultured mouse dorsal root ganglia neurons independently of TRPV4

Background and Purpose

The Ca²⁺-permeable cation channel TRPV4 is activated by mechanical disturbance of the cell membrane and is implicated in mechanical hyperalgesia. Nerve growth factor (NGF) is increased during inflammation and causes mechanical hyperalgesia. 4α-phorbol 12,13-didecanoate (4αPDD) has been described as a selective TRPV4 agonist. We investigated NGF-induced hyperalgesia in TRPV4 wild-type (+/+) and knockout (–/–) mice, and the increases in [Ca²⁺]_i produced by 4αPDD in cultured mouse dorsal root ganglia neurons following exposure to NGF.

Experimental Approach

Withdrawal thresholds to heat, von Frey hairs and pressure were measured in mice before and after systemic administration of NGF. Changes in intracellular Ca²⁺ concentration were measured by ratiometric imaging with Fura-2 in cultured DRG and trigeminal ganglia (TG) neurons during perfusion of TRPV4 agonists.

Key Results

Administration of NGF caused a significant sensitization to heat and von Frey stimuli in TRPV4 +/+ and –/– mice, but only TRPV4 +/+ mice showed sensitization to noxious pressure. 4αPDD stimulated a dose-dependent increase in [Ca²⁺]_i in neurons from +/+ and –/– mice, with the proportion of responding neurons and magnitude of increase unaffected by the genotype. In contrast, the selective TRPV4 agonist GSK1016790A failed to stimulate an increase in intracellular Ca²⁺ in cultured neurons. Responses to 4αPDD were unaffected by pretreatment with NGF.

Conclusions and Implications

TRPV4 contributes to mechanosensation in vivo, but there is little evidence for functional TRPV4 in cultured DRG and TG neurons. We conclude that 4αPDD activates these neurons independently of TRPV4, so it is not appropriate to refer to 4αPDD as a selective TRPV4 agonist.     

Increased Radioresistance to Lethal Doses of Gamma Rays in Mice and Rats after Exposure to Microwave Radiation Emitted by a GSM Mobile Phone Simulator

The aim of this study was to investigate the effect of pre-irradiation with microwaves on the induction of radioadaptive response. In the 1^st phase of the study, 110 male mice were divided into 8 groups. The animals in these groups were exposed/sham-exposed to microwave, low dose rate gamma or both for 5 days. On day six, the animals were exposed to a lethal dose (LD). In the 2^nd phase, 30 male rats were divided into 2 groups of 15 animals. The 1^st group received microwave exposure. The 2^nd group (controls) received the same LD but there was no treatment before the LD. On day 5, all animals were whole-body irradiated with the LD. Statistically significant differences between the survival rate of the mice only exposed to lethal dose of gamma radiation before irradiation with a lethal dose of gamma radiation with those of the animals pre-exposed to either microwave (p=0.02), low dose rate gamma (p=0.001) or both of these physical adapting doses (p=0.003) were observed. Likewise, a statistically significant difference between survival rates of the rats in control and test groups was observed. Altogether, these experiments showed that exposure to microwave radiation may induce a significant survival adaptive response.     

The role of multifunctional drug therapy as an antidote to combat experimental subacute neurotoxicity induced by organophosphate pesticides

Organophosphate pesticides are used in agriculture where they are associated with numerous cases of intentional and accidental misuse. These toxicants are potent inhibitors of cholinesterases leading to a massive build‐up of acetylcholine which induces an array of deleterious effects, including convulsions, oxidative damage and neurobehavioral deficits. Antidotal therapies with atropine and oxime yield a remarkable survival rate, but fail to prevent neuronal damage and behavioral problems. It has been indicated that multifunction drug therapy with potassium channel openers, calcium channel antagonists and antioxidants (either single‐agent therapy or combination therapy) may have the potential to prevent cell death and/or slow down the processes of secondary neuronal damage. The aim of the present study, therefore, was to make a relative assessment of the potential effects of nicorandil (2 mg/kg), clinidipine (10 mg/kg), and grape seed proanthocyanidin (GSPE) extract (200 mg/kg) individually against subacute chlorpyrifos induced toxicity. The test drugs were administered to Wistar rats 2 h after exposure to Chlorpyrifos (CPF). Different behavioral studies and biochemical estimation has been carried in the study. The results showed that chronic administration of CPF significantly impaired learning and memory, along with motor coordination, and produced a marked increase in oxidative stress along with significantly reduced acetylcholine esterase (AChE) activity. Treatment with nicorandil, clinidipine and GSPE was shown to significantly improve memory performance, attenuate oxidative damage and enhance AChE activity in rats. The present study also suggests that a combination of nicorandil, clinidipine, and GSPE has a better neuroprotective effect against subacute CPF induced neurotoxicity than if applied individually. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1017–1026, 2016.     

Ecstasy cannot be assumed to be 3,4-methylenedioxyamphetamine (MDMA)

LINKED ARTICLES

This is a rebuttal by the authors (Green et al., pp. 1523–1536 of this issue) to a commentary by Parrott, pp. 1518–1520 of this issue. To view the article by Green et al. visit http://dx.doi.org/10.1111/j.1476-5381.2011.01819.x. To view the commentary by Parrott visit http://dx.doi.org/10.1111/j.1476-5381.2012.01941.xWe thank Prof Parrott (Parrott 2012) for his interest in our review (Green et al., 2012). Our main aim was to discuss the problems that arise in interpreting data obtained when administering 3,4-methylenedioxymethamphetamine (MDMA) to experimental animals in terms of possible clinical consequences and vice versa, not to disparage the evidence that Ecstasy is neurotoxic in humans. We presented evidence that the pharmacokinetics of MDMA in rats and primates are fundamentally different from the pharmacokinetics of the drug in humans. Because the plasma half-life of the drug in rats is 10 times shorter than in humans, the acute adverse events in rats may be minimal compared with those in humans, and this includes body temperature and endocrine changes. Conversely, the rapid metabolism of the drug in rats to form neurotoxic metabolites may result in more severe long-term effects in that species than those that may occur in humans.We had no intention of suggesting that there was no evidence for some recreational Ecstasy users presenting with evidence of 5-HT neurotoxicity, albeit it is clear from the literature that some of this evidence remains open to several interpretations. What we did claim was that pure 3,4-methylenedioxymethamphetamine (MDMA) taken alone was unlikely to cause 5-HT neurotoxicity in man. Here we must emphasize the term MDMA, as it is crucial to our discussion. Parrott, in contrast, uses the term ‘Ecstasy/MDMA’ several times when discussing neurotoxicity (Parrott, 2012). This association of Ecstasy with MDMA is one of the major problems of translation that we addressed. The Ecstasy tablet that most recreational users buy and ingest is not necessarily MDMA. Indeed, in many cases, it clearly is not. The tablet is often adulterated with other compounds, and one investigation identified no less than 14 substances other than MDMA in Ecstasy tablets, which users nevertheless presumably believed contained only MDMA (Vogels et al., 2009). Many of the adulterants identified were also psychoactive and included compounds structurally related to MDMA such as 3,4-methylenedioxyethylamphetamine and 2-methylamino-1-(3,4-methylenedioxyphenyl)butane, which have poorly researched pharmacology and toxicology. In addition, most recreational users of Ecstasy also knowingly ingest other psychoactive compounds such as alcohol and cannabis. Alcohol, for example, alters the pharmacokinetics of MDMA (Hamida et al., 2009). While, as Parrott states, clinical studies have attempted to allow for these confounding factors in any examination of the physical and psychological effects of MDMA in humans, such analysis is always limited not only by the other compounds the evaluators are unaware of, but also drugs perhaps not even considered to be relevant by the user and therefore not disclosed. It is unlikely that coffee and ‘energy drinks’ such as Red Bull are always disclosed, but there is now good preclinical evidence that caffeine, which incidentally has also been found as an adulterant in Ecstasy tablets, enhances both the hyperthermia and neurotoxicity induced in rats by MDMA (Camarasa et al., 2006; Vanattou-Saïfoudine et al., 2010). And this brings us to the crux of the problem and weakness of all the clinical data cited by Parrott (2012). A basic tenet of all good clinical pharmacology is accurate knowledge of the doses administered, frequency of administration and any confounding factors such as other drugs being consumed. None of these data are available with any precision in the clinical studies quoted. Of course one has some indication as to dose (although as Vogels et al., (2009) reported, the dose contained in illicitly obtained tablets is highly variable) and frequency of drug ingestion, but this information is generally obtained from the user whose recall is likely to be limited or who decides to obfuscate. Crucially, the information can never take into account the problem of drug tablet adulteration. The fact that hair or urine samples detect MDMA merely shows the user has consumed the drug, not how much or when or what other drugs were taken concurrently.We never suggested that MDMA exposure was not going to be associated with physical or psychological change. However such changes are not necessarily associated with long-term neurotoxic damage. We have shown that long-term behavioural effects can occur in rats both with and without 5-HT neurotoxicity (Fone et al., 2002; Bull et al., 2003; Rodsiri et al., 2011). It is interesting that Parrott approvingly quotes the Verheyden et al. (2003) study in support of his contention that neurotoxic damage has occurred. Because this study noted that the majority of persons reporting chronic psychiatric problems reported ‘improved mental health’ after quitting the drug, this surely allows us to conclude that the drug had produced subacute changes rather than any that could be associated with long-term neurotoxic damage.A further limitation to any clinical study is that one cannot perform prospective studies with the aim of investigating whether long-term neurotoxic events occur, so weaknesses arise with regard to any psychological abnormalities observed. Are persons with high risk of psychiatric problems more likely to misuse the drug, or does the drug induce changes in high-risk individuals? If high risk also happened to be associated with 5-HT abnormalities in the brains, then any conclusion that MDMA has induced neurotoxicity is spurious.We most certainly did not suggest that MDMA acted as a neurotoxin only under conditions of severe hyperthermia as is stated by Parrot in his sixth paragraph (Parrott, 2012). We have been involved in many studies on the effects of MDMA on body temperature in rats (see Docherty and Green, 2010) including one that demonstrated that neurotoxicity can occur in the absence of hyperthermia (O''Shea et al., 1998) and another that showed that hyperthermia worsens neurotoxic damage (Green et al., 2004). In our review, what we did propose was that because of the very different pharmacokinetics of MDMA in rats and humans, it is probable that humans would suffer serious or fatal adverse events at plasma levels below those likely to be required to induce 5-HT neurotoxicity.We emphasize again that we are not denying the clinical observations reviewed by Parrott, but conclude that the effects seen cannot be ascribed solely to the effects of MDMA, as he seems to be proposing. We also repeat our contention that MDMA in combination with other drugs may induce neurotoxicity and this could be said to be supported by the clinical studies quoted by Parrott.Finally, we can but assume that Parrott concurs with our principal conclusion that ‘the doses currently being used to investigate the possible therapeutic benefits of MDMA are unlikely to produce any severe acute or importantly any long-term neurotoxic damage in the human brain’ as he used such a dose (100 mg or approximately 1.4 mg·kg ⁻¹) in one of his recent studies in human volunteers (Parrott et al., 2011).     

Inhibition of matrix metalloproteinase-2 improves endothelial function and prevents hypertension in insulin-resistant rats

BACKGROUND AND PURPOSE

Insulin resistance is often found to be associated with high blood pressure. We propose that in insulin-resistant hypertension, endothelial dysfunction is the consequence of increased activity of vascular MMP-2. As MMP-2 proteolytically cleaves a number of extracellular matrix proteins, we hypothesized that MMP-2 impairs endothelial function by proteolytic degradation of endothelial NOS (eNOS) or its cofactor, heat shock protein 90 (HSP90).

EXPERIMENTAL APPROACH

We tested our hypothesis in bovine coronary artery endothelial cells and fructose-fed hypertensive rats (FHR), a model of acquired systolic hypertension and insulin resistance.

KEY RESULTS

Treatment of FHRs with the MMP inhibitor doxycycline, preserved endothelial function as well as prevented the development of hypertension, suggesting that MMPs impair endothelial function. Furthermore, incubating endothelial cells in vitro with a recombinant MMP-2 decreased NO production in a dose-dependent manner. Using substrate cleavage assays and immunofluorescence microscopy studies, we found that MMP-2 not only cleaves and degrades HSP90, an eNOS cofactor but also co-localizes with both eNOS and HSP90 in endothelial cells, suggesting that MMPs functionally interact with the eNOS system. Treatment of FHRs with doxycycline attenuated the decrease in eNOS and HSP90 expression but did not improve insulin sensitivity.

CONCLUSIONS AND IMPLICATIONS

Our data suggest that increased activity of MMP-2 in FHRs impairs endothelial function and promotes hypertension. Inhibition of MMP-2 could be a potential therapeutic strategy for the management of hypertension.     

Low incidences of human immunodeficiency virus and hepatitis C virus infection and declining risk behaviors in a cohort of injection drug users in Chennai, India

The authors characterized human immunodeficiency virus (HIV) and hepatitis C virus (HCV) incidence and prospective changes in self-reported risk behavior over 2 years among 1,158 injection drug users (IDUs) recruited in Chennai, India, in 2005-2006. At baseline, HIV prevalence was 25.3%, and HCV prevalence was 54.5%. Seropositive persons with prevalent HIV infection were used to estimate baseline HIV incidence by means of the Calypte HIV-1 BED Incidence EIA (Calypte Biomedical Corporation, Portland, Oregon). Longitudinal HIV and HCV incidence were measured among 865 HIV-negative IDUs and 519 HCV antibody-negative IDUs followed semiannually for 2 years. Participants received pre- and posttest risk reduction counseling at each visit. Estimated HIV incidence at baseline was 2.95 per 100 person-years (95% confidence interval (CI): 1.21, 4.69) by BED assay; observed HIV incidence over 1,262 person-years was 0.48 per 100 person-years (95% CI: 0.17, 1.03). HCV incidence over 645 person-years was 1.71 per 100 person-years (95% CI: 0.85, 3.03). Self-reported risk behaviors declined significantly over time, from 100% of participants reporting drug injection at baseline to 11% at 24 months. In this cohort with high HIV and HCV prevalence at enrollment, the authors observed low incidence and declining self-reported risk behavior over time. While no formal intervention was administered, these findings highlight the potential impact of voluntary counseling and testing in a high-risk cohort.