Gut metabolite S-equol ameliorates hyperexcitability in entorhinal cortex neurons following Theiler murine encephalomyelitis virus-induced acute seizures.

OBJECTIVE: A growing body of evidence indicates a potential role for the gut-brain axis as a novel therapeutic target in treating seizures. The present study sought to characterize the gut microbiome in Theiler murine encephalomyelitis virus (TMEV)-induced seizures, and to evaluate the effect of microbial metabolite S-equol on neuronal physiology as well as TMEV-induced neuronal hyperexcitability ex vivo. METHODS: We infected C57BL/6J mice with TMEV and monitored the development of acute behavioral seizures 0-7 days postinfection (dpi). Fecal samples were collected at 5-7 dpi and processed for 16S sequencing, and bioinformatics were performed with QIIME2. Finally, we conducted whole-cell patch-clamp recordings in cortical neurons to investigate the effect of exogenous S-equol on cell intrinsic properties and neuronal hyperexcitability. RESULTS: We demonstrated that gut microbiota diversity is significantly altered in TMEV-infected mice at 5-7 dpi, exhibiting separation in beta diversity in TMEV-infected mice dependent on seizure phenotype, and lower abundance of genus Allobaculum in TMEV-infected mice regardless of seizure phenotype. In contrast, we identified specific loss of S-equol-producing genus Adlercreutzia as a microbial hallmark of seizure phenotype following TMEV infection. Electrophysiological recordings indicated that exogenous S-equol alters cortical neuronal physiology. We found that entorhinal cortex neurons are hyperexcitable in TMEV-infected mice, and exogenous application of microbial-derived S-equol ameliorated this TMEV-induced hyperexcitability. SIGNIFICANCE: Our study presents the first evidence of microbial-derived metabolite S-equol as a potential mechanism for alteration of TMEV-induced neuronal excitability. These findings provide new insight for the novel role of S-equol and the gut-brain axis in epilepsy treatment.

Beliefs regarding COVID-19 vaccines among Canadian workers in the intellectual disability sector prior to vaccine implementation.

BACKGROUND: Workers supporting adults with intellectual disabilities (ID) experience significant stress in their essential role during COVID-19 due to the high risk of their clients contracting COVID-19 and having adverse outcomes. The purpose of the current study was to describe the attitudes of workers towards COVID-19 vaccination prior to vaccination rollout, with a view to informing strategies to promote vaccine uptake within this high-risk sector. METHODS: An online survey was sent via email to workers supporting adults with ID in Ontario, Canada, between January 21 and February 3, 2021 by agency leadership and union representatives. RESULTS: Three thousand and three hundred and seventy-one workers, representing approximately 11.2% of Ontario workers supporting adults with ID completed an online survey. Most reported that they were very likely (62%) or likely (20%) to get a COVID-19 vaccine (vaccination intent) although 18% reported they were less likely to do so (vaccination nonintent). Workers with vaccination nonintent were younger and were more likely to endorse the beliefs that (1) it will not benefit them or those around them, (2) it was not part of their job, (3) rapid development confers uncertainties and risks, and (4) they were scared of potential vaccine side effects. CONCLUSIONS: There is need to address common misconceptions among workers supporting adults with ID to help activate them as vaccine advocates in the communities they serve. Partnered efforts between workers, unions and agency leadership with public health experts to address concerns are required.

Genetic contributors to variation in alcohol consumption vary by race/ethnicity in a large multi-ethnic genome-wide association study.

Alcohol consumption is a complex trait determined by both genetic and environmental factors, and is correlated with the risk of alcohol use disorders. Although a small number of genetic loci have been reported to be associated with variation in alcohol consumption, genetic factors are estimated to explain about half of the variance in alcohol consumption, suggesting that additional loci remain to be discovered. We conducted a genome-wide association study (GWAS) of alcohol consumption in the large Genetic Epidemiology Research in Adult Health and Aging (GERA) cohort, in four race/ethnicity groups: non-Hispanic whites, Hispanic/Latinos, East Asians and African Americans. We examined two statistically independent phenotypes reflecting subjects' alcohol consumption during the past year, based on self-reported information: any alcohol intake (drinker/non-drinker status) and the regular quantity of drinks consumed per week (drinks/week) among drinkers. We assessed these two alcohol consumption phenotypes in each race/ethnicity group, and in a combined trans-ethnic meta-analysis comprising a total of 86 627 individuals. We observed the strongest association between the previously reported single nucleotide polymorphism (SNP) rs671 in ALDH2 and alcohol drinker status (odd ratio (OR)=0.40, P=2.28 × 10-72) in East Asians, and also an effect on drinks/week (beta=-0.17, P=5.42 × 10-4) in the same group. We also observed a genome-wide significant association in non-Hispanic whites between the previously reported SNP rs1229984 in ADH1B and both alcohol consumption phenotypes (OR=0.79, P=2.47 × 10-20 for drinker status and beta=-0.19, P=1.91 × 10-35 for drinks/week), which replicated in Hispanic/Latinos (OR=0.72, P=4.35 × 10-7 and beta=-0.21, P=2.58 × 10-6, respectively). Although prior studies reported effects of ADH1B and ALDH2 on lifetime measures, such as risk of alcohol dependence, our study adds further evidence of the effect of the same genes on a cross-sectional measure of average drinking. Our trans-ethnic meta-analysis confirmed recent findings implicating the KLB and GCKR loci in alcohol consumption, with strongest associations observed for rs7686419 (beta=-0.04, P=3.41 × 10-10 for drinks/week and OR=0.96, P=4.08 × 10-5 for drinker status), and rs4665985 (beta=0.04, P=2.26 × 10-8 for drinks/week and OR=1.04, P=5 × 10-4 for drinker status), respectively. Finally, we also obtained confirmatory results extending previous findings implicating AUTS2, SGOL1 and SERPINC1 genes in alcohol consumption traits in non-Hispanic whites.

Topiramate alters the gut microbiome to aid in its anti-seizure effect.

Introduction: There is a growing interest in the role of the gut microbiota in epilepsy, however, it is unclear if anti-seizure medications (ASMs) play a role in the gut-brain axis. To test this, we investigated the impact of the ASM topiramate on the gut microbiome of mice. Methods: C57BL/6J mice were administered topiramate in their drinking water for 5 weeks. 16S ribosomal RNA gene sequencing was performed on fecal samples collected at 5 weeks. Analysis of alpha diversity, beta diversity, and differential abundance were performed. Cecal contents were analyzed for short-chain fatty acids (SCFAs) composition. Pentylenetetrazol (PTZ)-kindling was performed in saline, topiramate, Lactobacillus johnsonii, and topiramate and Lactobacillus johnsonii treated mice. Mice received PTZ injection every other day for a total of twelve injections, seizure activity was video monitored for 30 minutes and scored. Results and discussion: Our study revealed that topiramate ingestion significantly increased Lactobacillus johnsonii in the gut microbiome of naïve mice. Treatment with topiramate and Lactobacillus johnsonii together, but not alone, reduced susceptibility to PTZ-induced seizures. Co-treatment also significantly increased the percent of butyrate and the abundance of butyrate-producing family Lachnospiraceae in the gut, and elevated the GABA/glutamate ratio in the cortex. Our results demonstrate that an ASM can alter the gut microbiome to aid in their anti-seizure effect in vivo and suggest the potential of the probiotic Lactobacillus johnsonii as an adjunct therapy with topiramate in reducing seizure susceptibility.

LY3041658/ interleukin-8 complex structure as targets for IL-8 small molecule inhibitors discovery using a combination of in silico methods.

Since interleukin-8 (IL-8/CXCL8) and its receptor, CXCR1 and CXCR2, were known in the early 1990s, biological pathways related to these proteins were proven to have high clinical value in cancer and inflammatory/autoimmune conditions treatment. Recently, IL-8 has been identified as biomarker for severe COVID-19 patients and COVID-19 prognosis. Boyles et al. (mAbs 12 (2020), pp. 1831880) have published a high-resolution X-ray crystal structure of the LY3041658 Fab in a complex human CXCL8. They described the ability to bind to IL-8 and the blocking of IL-8/its receptors interaction by the LY3041658 monoclonal antibody. Therefore, the study has been designed to identify potential small molecules inhibiting interleukin-8 by targeting LY3041658/IL-8 complex structure using an in silico approach. A structure­based pharmacophore and molecular docking models of the protein active site cavity were generated to identify possible candidates, followed by virtual screening with the ZINC database. ADME analysis of hit compounds was also conducted. Molecular dynamics simulations were then performed to survey the behaviour and stability of the ligand-protein complexes. Furthermore, the MM/PBSA technique has been utilized to evaluate the free binding energy. The final data confirmed that one newly obtained compound, ZINC21882765, may serve as the best potential inhibitor for IL-8.

Geographical heterogeneity of dengue transmission in two villages in southern Vietnam.

This study was performed to test the hypothesis that there are 'hotspots', i.e. geographical heterogeneity, of dengue transmission. Data from two repeat serosurveys in two villages in Vietnam were used to identify incident infections and to relate these to prevalence at baseline and thus assess geographical heterogeneity, i.e. clustering, in dengue transmission. A total of 400 households were surveyed; serological data from 521 children at baseline and from 119 children at follow-up were included in a spatial analysis. Geographical heterogeneity of dengue transmission was explored using a permutation null distribution test. This showed for the first time evidence of clustering of dengue virus transmission at the household level in asymptomatic children. Risk areas could be identified by seroprevalence surveys combined with mapping. Control of dengue virus transmission could be supported by identification and control of hotspots.

Structure-based discovery of interleukin-33 inhibitors: a pharmacophore modelling, molecular docking, and molecular dynamics simulation approach.

Interleukin (IL)-33 is a new cytokine of the IL-1 family that is related to several inflammatory and autoimmune diseases. IL-33 binds to its ST2 receptor and leads to biological responses thereof. Currently, no drugs have been approved for the treatment of IL-33 related diseases. The aim of this study was to search for small molecules that inhibit the protein-protein interaction between IL-33 and ST2. A virtual screening was first performed to identify potential molecules that can bind IL-33. By analysing the interactions between key residues in the complex of IL-33/ST2, two pharmacophore hypotheses were then generated based on the 'mimicry' and 'pair-rule' principles. From a database of 62,074 compounds, 60 molecules satisfying the pharmacophore models were identified and docked to IL-33. Among 35 compounds successfully docked into the protein, 9 potential ligands in complex with IL-33 were selected for further analysis by molecular dynamics simulations. Based on the stability of the complexes and the interactions of each ligand with the key residues of IL-33, two compounds DB00158 and DB00642 were identified as the most potential inhibitors that can be further investigated as promising novel IL-33 inhibitory drugs.

Behavior of simetryn and thiobencarb in the plough zone of rice fields.

The behavior of simetryn and thiobencarb in flooded rice soil was investigated in a 2-year study. The concentrations of simetryn and thiobencarb were in the hundreds of µg kg−1 in the top soil layer (0­5 cm) and became significantly lower in tens of µg kg−1 in the deeper soil layers (5­10 and 10­15 cm). The half-lives of the two herbicides were also shorter (36 and 17 days for simetryn and thiobencarb, respectively) in the top soil layer, as they were most affected by environmental conditions, compared with corresponding values of 82 and 69 days in the 5­10 cm soil layer. Simetryn concentration was stable, while thiobencarb's half-life was 165 days in the 10­15 cm layer. About 35% of the applied mass of simetryn and thiobencarb were found in the rice soil compartment.

Peramivir binding affinity with influenza A neuraminidase and research on its mutations using an induced-fit docking approach.

Influenza A virus (IAV) has caused epidemic infections worldwide, with many strains resistant to inhibitors of a surface protein, neuraminidase (NA), due to point mutations on its structure. A novel NA inhibitor named peramivir was recently approved, but no exhaustive computational research regarding its binding affinity with wild-type and mutant NA has been conducted. In this study, a thorough investigation of IAV-NA PDB entries of 9 subtypes is described, providing a list of residues constituting the protein-ligand binding sites. The results of induced-fit docking approach point out key residues of wild-type NA participating in hydrogen bonds and/or ionic interactions with peramivir, among which Arg 368 is responsible for a peramivir-NA ionic interaction. Mutations on this residue greatly reduced the binding affinity of peramivir with NA, with 3 mutations R378Q, R378K and R378L (NA6) capable of deteriorating the docking performance of peramivir by over 50%. 200 compounds from 6-scaffolds were docked into these 3 mutant versions, revealing 18 compounds giving the most promising results. Among them, CMC-2012-7-1527-56 (benzoic acid scaffold, IC50 = 32 nM in inhibitory assays with IAV) is deemed the most potential inhibitor of mutant NA resisting both peramivir and zanamivir, and should be further investigated.

Functional, structural and molecular aspects of diastolic heart failure in the diabetic (mRen-2)27 rat.

OBJECTIVE: Diabetic cardiomyopathy is an increasingly recognized cause of cardiac failure despite preserved left ventricular systolic function. Given the over-expression of angiotensin II in human diabetic cardiomyopathy, we hypothesized that combining hyperglycaemia with an enhanced tissue renin-angiotensin system would lead to the development of diastolic dysfunction with adverse remodeling in a rodent model. METHODS: Homozygous (mRen-2)27 rats and non-transgenic Sprague Dawley (SD) rats were randomized to receive streptozotocin (diabetic) or vehicle (non-diabetic) and followed for 6 weeks. Prior to tissue collection, animals underwent pressure-volume loop acquisition. RESULTS: Diabetic Ren-2 rats developed impairment of both active and passive phases of diastole, accompanied by reductions in SERCA-2a ATPase and phospholamban along with activation of the fetal gene program. Structural features of diabetic cardiomyopathy in the Ren-2 rat included interstitial fibrosis, cardiac myocyte hypertrophy and apoptosis in conjunction with increased activity of transforming growth factor-beta (p<0.01 compared with non-diabetic Ren-2 rats for all parameters). No significant functional or structural derangements were observed in non-transgenic, SD diabetic rats. CONCLUSION: These findings indicate that the combination of enhanced tissue renin-angiotensin system and hyperglycaemia lead to the development of diabetic cardiomyopathy. Fibrosis, and myocyte hypertrophy, a prominent feature of this model, may be a consequence of activation of the pro-sclerotic cytokine, transforming growth factor-beta, by the diabetic state.

Association of angiotensinogen gene T235 variant with progression of immunoglobin A nephropathy in Caucasian patients.

Genetic variability in the renin-angiotensin system may modify renal responses to injury and disease progression. We examined whether the M235T polymorphism of the angiotensinogen (AGT) gene, the insertion/deletion polymorphism of the angiotensin-converting enzyme (ACE) gene, and the A1166--> C polymorphism of the angiotensin II type 1 receptor gene may be associated with disease progression in 168 Caucasian patients with IgA nephropathy. All patients had serial measurements of their creatinine clearance, proteinuria, and blood pressure (mean+/-SD) with a follow-up of 6.1+/-4.7 yr. The genotype frequencies for each gene were consistent with Hardy-Weinberg equilibrium, and were similar to those of 100 Caucasian control subjects. We examined two primary outcomes: (a) the rate of deterioration of Ccr, and (b) the maximal level of proteinuria. We found that patients with the AGT MT (n = 79) and TT (n = 29) genotypes had a faster rate of deterioration of Ccr than those with the MM (n = 60) genotype (i.e., median values, -6.6 and -6.2 vs. -3. 0 ml/min/yr, respectively; P = 0.01 by Kruskal-Wallis test). Similarly, patients with AGT MT and TT genotypes had higher maximal values of proteinuria than those with the MM genotype (i.e., median values, 2.5 and 3.5 vs. 2.0 g/d, respectively; P < 0.02 by Kruskal-Wallis test). Neither the ACE insertion/deletion nor angiotensin II type I A1166--> C gene polymorphism was associated with disease progression or proteinuria in univariate analysis. Multivariant analysis, however, detected an interaction between the AGT and ACE gene polymorphisms with the presence of ACE/DD polymorphism adversely affecting disease progression only in patients with the AGT/MM genotype (P = 0.008). Neither of these gene polymorphisms was associated with systemic hypertension. Our results suggest that polymorphisms at the AGT and ACE gene loci are important markers for predicting progression to chronic renal failure in Caucasian patients with IgA nephropathy.

Initial impacts and field validation of host range for Boreioglycaspis melaleucae Moore (Hemiptera: Psyllidae), a biological control agent of the invasive tree Melaleuca quinquenervia (Cav.) Blake (Myrtales: Myrtaceae: Leptospermoideae).

Invasion of south Florida wetlands by the Australian paperbark tree, Melaleuca quinquenervia (Cav.) S.T. Blake (melaleuca), has caused adverse economic and environmental impacts. The tree's biological attributes and favorable ambient biophysical conditions combine to complicate efforts to restore and maintain south Florida ecosystems. Management requires an integrated strategy that deploys multiple biological control agents to forestall reinvasion and to supplement other control methods, thereby lessening recruitment and regeneration after removal of existing trees. This biological control program began during 1997 when an Australian weevil, Oxyops vitiosa (Pascoe), was released. A second Australian insect, the melaleuca psyllid (Boreioglycaspis melaleucae Moore), first introduced during 2002, has also widely established. After inoculation of the psyllid in a field study, only 40% of seedlings survived herbivory treatments compared with 95% survival in controls. The resultant defoliation also reduced growth of the surviving seedlings. A weevil-induced decline at a site comprised mainly of coppicing stumps had slowed after a 70% reduction. Psyllids colonized the site, and 37% of the remaining coppices succumbed within 10 mo. The realized ecological host range of B. melaleucae was restricted to M. quinquenervia; 18 other nontarget plant species predicted to be suboptimal or nonhosts during laboratory host range testing were unaffected when interspersed with psyllid-infested melaleuca trees in a common garden study. Evaluations are ongoing, but B. melaleucae is clearly reducing seedling recruitment and stump regrowth without adversely impacting other plant species. Manifestation of impacts on mature trees will require more time, but initial indications suggest that the psyllid will be an effective supplement to the weevil.

Machine learning-, rule- and pharmacophore-based classification on the inhibition of P-glycoprotein and NorA.

The efflux pumps P-glycoprotein (P-gp) in humans and NorA in Staphylococcus aureus are of great interest for medicinal chemists because of their important roles in multidrug resistance (MDR). The high polyspecificity as well as the unavailability of high-resolution X-ray crystal structures of these transmembrane proteins lead us to combining ligand-based approaches, which in the case of this study were machine learning, perceptual mapping and pharmacophore modelling. For P-gp inhibitory activity, individual models were developed using different machine learning algorithms and subsequently combined into an ensemble model which showed a good discrimination between inhibitors and noninhibitors (acctrain-diverse = 84%; accinternal-test = 92% and accexternal-test = 100%). For ligand promiscuity between P-gp and NorA, perceptual maps and pharmacophore models were generated for the detection of rules and features. Based on these in silico tools, hit compounds for reversing MDR were discovered from the in-house and DrugBank databases through virtual screening in an attempt to restore drug sensitivity in cancer cells and bacteria.

Climate Factors as Important Determinants of Dengue Incidence in Curaçao.

Macro- and microclimates may have variable impact on dengue incidence in different settings. We estimated the short-term impact and delayed effects of climate variables on dengue morbidity in Curaçao. Monthly dengue incidence data from 1999 to 2009 were included to estimate the short-term influences of climate variables by employing wavelet analysis, generalized additive models (GAM) and distributed lag nonlinear models (DLNM) on rainfall, temperature and relative humidity in relation to dengue incidence. Dengue incidence showed a significant irregular 4-year multi-annual cycle associated with climate variables. Based on GAM, temperature showed a U-shape, while humidity and rainfall exhibited a dome-shaped association, suggesting that deviation from mean temperature increases and deviation from mean humidity and rainfall decreases dengue incidence, respectively. Rainfall was associated with an immediate increase in dengue incidence of 4.1% (95% CI: 2.2-8.1%) after a 10-mm increase, with a maximum increase of 6.5% (95% CI: 3.2-10.0%) after 1.5 month lag. A 1 °C decrease of mean temperature was associated with a RR of 17.4% (95% CI: 11.2-27.0%); the effect was inversed for a 1°C increase of mean temperature (RR= 0.457, 95% CI: 0.278-0.752). Climate variables are important determinants of dengue incidence and provide insight into its short-term effects. An increase in mean temperature was associated with lower dengue incidence, whereas lower temperatures were associated with higher dengue incidence.

Angiotensin II type 1 receptor gene polymorphism and the response to hyperglycemia in early type 1 diabetes.

Recent studies suggest that there is an association between the A1166-->C polymorphism of the angiotensin II type 1 receptor (AGT1R), glycemic control, and the risk of diabetic nephropathy in subjects with type 1 diabetes. Because hypertension and renal hemodynamic function are also related to the risk of diabetic nephropathy and because hyperglycemia can activate the renin angiotensin system, we sought to determine if there is an association between the AGT1R polymorphism, baseline renal and peripheral hemodynamic function, and pressor response to high glucose in subjects with early uncomplicated type 1 diabetes. There were 39 diabetic subjects genotyped for the AGT1R polymorphism by polymerase chain reaction and segregated into 2 groups: those with and those without the C1166 allele (AA and AC/CC). The average age was 27 +/- 1 years, and the mean duration of diabetes was 3.5 +/- 0.6 years. HbA(1c) values were <10% in all subjects and were similar in the 2 groups (8.2 +/- 0.3 vs. 9.1 +/- 0.4%). After a 7-day controlled diet (150 mmol sodium, 1.5-2.0 g x kg(-1) x day(-1) protein), renal hemodynamic function was assessed by inulin and para-aminohippurate clearance during clamped euglycemic conditions (4-6 mmol/l). Mean values for glomerular filtration rates did not differ between groups during euglycemia. In contrast, mean values for renal plasma flow and renal blood flow were significantly greater in the AC/CC group compared with the AA group. Values for mean arterial pressure were similar in the 2 groups, whereas renal vascular resistance was significantly reduced in the AC/CC group. In 20 subjects (10 from each genotype subgroup), hemodynamic function was assessed on a second occasion during controlled clamped hyperglycemia (9-11 mmol/l) after a similar preparatory period. In response to high glucose, plasma renin activity increased in both genotype groups to the same extent, but a pressor response was noted only in subjects with the C1166 allele. Mean arterial pressure increased significantly in the AC/CC subgroup and remained unchanged in the AA subgroup. We conclude that there is an association between the AGT1R A1166-->C polymorphism and renal hemodynamic function in early type 1 diabetes. But more importantly, the pressor response to hyperglycemia is augmented in those diabetic patients with the C1166 allele and may represent a factor that predisposes them to renal injury during periods of inadequate glucose control.

Three- and four-class classification models for P-glycoprotein inhibitors using counter-propagation neural networks.

P-glycoprotein (P-gp) is an ATP binding cassette (ABC) transporter that helps to protect several certain human organs from xenobiotic exposure. This efflux pump is also responsible for multi-drug resistance (MDR), an issue of the chemotherapy approach in the fight against cancer. Therefore, the discovery of P-gp inhibitors is considered one of the most popular strategies to reverse MDR in tumour cells and to improve therapeutic efficacy of commonly used cytotoxic drugs. Until now, several generations of P-gp inhibitors have been developed but they have largely failed in preclinical and clinical studies due to lack of selectivity, poor solubility and severe pharmacokinetic interactions. In this study, three models (SION, SIO, SIN) to classify specific 'true' P-gp inhibitors as well as three other models (CPBN, CPB1, CPN) to distinguish between P-gp inhibitors, CYP 3A inhibitors and co-inhibitors of these proteins with rather high accuracy values for the test set and the external set were generated based on counter-propagation neural networks (CPG-NN). Such three and four-class classification models helped provide more information about the bioactivities of compounds not only on one target (P-gp), but also on a combination of multiple targets (P-gp, CYP 3A).

Evidence for transcriptional self-regulation of variable surface antigens in Paramecium tetraurelia.

Variable surface antigens are commonly found on free-living and parasitic protozoa, yet the regulation of antigen expression and switching is not fully understood in any system. A cell line of Paramecium tetraurelia stock 51 can express at least 11 different antigens yet only one type is found on the surface at any one time. Previous studies have shown that mutually exclusive expression of Paramecium surface antigens can be overcome if two antigen genes contain the same 5' coding region. In this article we utilize a gene chimera containing portions of A51 and B51 to analyze the effect of a frameshift mutation on transcription and steady-state mRNA levels. We show that a frameshift mutation near the 3' end prevents expression of the protein on the cell surface and reduces the rate of transcription of the corresponding gene. The difference in transcription is not the result of differences in plasmid copy number. We propose that expression of the antigen on the cell surface is part of a self-regulatory pathway that influences transcription of the corresponding gene. A model incorporating the previous and current data is presented.

A comparison of photodynamic therapy using topical methyl aminolevulinate (Metvix) with single cycle cryotherapy in patients with actinic keratosis: a prospective, randomized study.

BACKGROUND: Actinic keratosis (AK) is a very common condition, which has the potential of progressing to squamous cell carcinoma. The present study is a prospective, randomized study comparing the lesion response, cosmetic outcome, patient satisfaction and tolerability of a new treatment modality, photodynamic therapy (PDT), using topical methyl aminolevulinate (Metvix), with the most commonly used standard therapy for AK, cryotherapy. METHODS: A total of 204 patients with clinically diagnosed AK were randomized to either cryotherapy or PDT. The PDT patients were further assigned to an active or placebo group in a random, double-blind manner. Cryotherapy was performed using liquid nitrogen spray in a single freeze-thaw cycle. PDT was performed using 160 mg/g methyl aminolevulinate cream or placebo, a 3-hour application time, red light (570-670 nm) and a total light dose of 75 J/cm(2). PDT was repeated after 7 days. Two sessions of PDT were undertaken, as a previous study had shown a single session had similar efficacy to cryotherapy. Lesion response was assessed clinically after 3 months (complete response or non-complete response). RESULTS: The lesion response rate was 91% in the methyl aminolevulinate PDT group, 68% in the cryotherapy group and 30% in the placebo PDT group. Methyl aminolevulinate PDT was statistically significantly better than both cryotherapy and placebo PDT in terms of response rates and cosmetic outcome. Most patients preferred PDT to other treatments. CONCLUSIONS: PDT with methyl aminolevulinate is an excellent treatment option, particularly for patients with widespread damage or AK lesions in cosmetically sensitive areas.

Reduction mammaplasty in postburn breasts.

Thermal injury to the anterior chest in the adolescent girl can lead to severe disfigurement of the breasts. Just as in certain non-burn female patients, mammary hyperplasia can occur in patients with previous full-thickness burns of their breasts. Most plastic surgeons have been reluctant to perform reduction mammaplasty in these patients for fear of devascularizing the skin graft or the nipple-areola complex. A series of six patients with full-thickness burns of the breasts and subsequent skin graft coverage before reduction mammaplasty is reported. Four patients had bilaterally burned breasts requiring reduction. Two patients had one burned breast reduced, and one required a balancing procedure on the unburned side. Reduction mammaplasty was performed using the inferior-pedicle technique. The mean amount of tissue removed for the left and right breasts was 454 and 395 g, respectively. There was no nipple loss, hematoma, infection, or major loss of skin flaps. Reduction mammaplasty in this group of patients is safe and carries minimal risk if certain key concepts are followed carefully.

Total eyelid reconstruction with free dorsalis pedis flap after deep facial burn.

A case of severe facial and corneal burns with complete loss of upper and lower eyelids is reported together with the acute management and surgical options for total eyelid defects secondary to thermal injury. An acutely burned man with 78 percent total burn surface area presented with complete exposure of the left cornea. Because of the severe thermal injury, no facial tissues were available as donor sources for reconstructing the eyelid. A free dorsalis pedis flap was used to cover the exposed cornea after bilateral conjunctival advancement flaps, with septal cartilage graft for structural support. A conjunctivodacryocystorhinostomy was performed at the time of the coverage. The patient was unable to perform an exact visual acuity test; however, his gross vision was intact.