The effectiveness of fibrin sealants in head and neck surgery: a systematic review protocol.

OBJECTIVE: This review will investigate the effectiveness of fibrin sealants in adult patients who underwent head and neck surgery. INTRODUCTION: Controlling bleeding is important in head and neck surgery. Complications involving nearby vital structures increase the risk of morbidity and mortality. Surgical tissue adhesives are used in addition to other traditional hemostatic methods to reduce surgical site bleeding. Fibrin sealants have shown some success compared with other tissue adhesives, but individual studies have been inconclusive. INCLUSION CRITERIA: We will include studies comparing fibrin sealants with placebo or usual care in patients 18 years or older who have undergone soft tissue surgery of the head and neck with drain placement. Primary outcomes include wound complications and time to surgical drain removal. Secondary outcomes include length of hospital stay, drain volume output, surgical management of postoperative hematoma, rate of blood transfusions, and adverse reactions. METHODS: We will search electronic databases (PubMed, Embase, Cochrane Database of Controlled Trials) for studies published from 1975 onwards. Titles, abstracts, and full-text papers will be assessed against the inclusion criteria by 2 independent reviewers. Study screening and selection will be performed, and critical appraisal conducted using the standardized JBI appraisal tools. Data will be extracted by 2 independent reviewers. Meta-analysis will be conducted for all outcomes where appropriate, with weighted mean differences for continuous data. Risk ratios will be used for dichotomous data. Certainty will be reported using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. REVIEW REGISTRATION: PROSPERO CRD42023412820.

Protocol of Breast Cancer Prevention Model with Addition of Breast Ultrasound to Routine Gynecological Visits as a Chance for an Early Diagnosis and Treatment in 25 to 49-Year-Old Polish Females.

The low attendance rate for cancer screening tests in Poland is a major healthcare concern that requires specific analysis and the development of implementation recommendations for prevention, and both actions are likely to benefit culturally similar countries. Four female cancers account for approximately 20% of all cancer cases-breast cancer, cervical cancer, endometrial cancer, and ovarian cancer-suggesting that gynecologists have a significant preventative role. Of the four, breast cancer and cervical cancer are among the 10 most common malignant neoplasms globally, regardless of gender, occur only in women and are known to have effective screening measures. Our research aims to create a screening model that combines cervical cancer and breast cancer to maximize health outcomes for women at risk of both cancers. In the study protocol, we have created a model that maximizes benefits for patients with minimal additional costs to the health care system. To achieve the set goal, instead of regular clinical breast exams as recommended by the gynecological societies, we proposed an ultrasound examination, during which palpation may also be performed (in the absence of elastography). We present a scheme for such a protocol that takes into consideration all types of prevention in both cancers, and that emphasizes breast ultrasound as the most frequently missing element. Our study includes a discussion of the strengths and weaknesses of our strategy, and the crucial need for infrastructure and education for the successful implementation of the program. We conclude that our model merits consideration and discussion among health-care decision makers, as the screening changes we propose have significant potential benefits for the female population.

An update on the current epidemiological status of metastatic neoplasms to the thyroid.

Secondary tumours to the thyroid gland are uncommon with an overall prevalence of 5.9% in autopsy studies. In recent clinical series, secondary thyroid cancer is seen in only 1.9% of malignant thyroids. There is no gender predominance both overall (female to male 1.07:1) and when stratified by common histological subtypes (renal cell carcinoma, lung adenocarcinoma and colorectal adenocarcinoma). The median age of patients diagnosed with metastatic thyroid tumours in major studies ranges from 54 to 68 years. Metastases are more frequent in patients with pre-existing or concurrent thyroid pathology. In autopsy studies, the most common primary sites are breast carcinoma and lung carcinoma. Renal cell carcinoma, lung carcinoma and breast carcinoma predominate in clinical series. Upper aerodigestive tract primaries often directly infiltrate the thyroid gland. The underlying frequency of a histological subtype, geographic prevalence and aggressiveness of primary cancer likely contributes to the incidence of metastasis in the thyroid gland. This is seen in case series from Asia where gastric and oesophageal primary cancers predominate. Secondary thyroid cancer can present metachronously (60%), synchronously (34%), or as the first presentation of the underlying cancer (6%). Late metastases and first clinical presentations of disease often originate from renal cell carcinomas while synchronous cases tend to originate from the lungs. Other common primary sites for first presentation of secondary thyroid cancer include the lung and oesophagus. Although rare, secondary thyroid cancer should be considered as a differential particularly in patients with previous malignancy, such as from the kidney, lung, or breast.

Clinicopathological and Molecular Features of Secondary Cancer (Metastasis) to the Thyroid and Advances in Management.

Secondary tumours to the thyroid gland are uncommon and often incidentally discovered on imaging. Symptomatic patients often present with a neck mass. Collision tumours of secondary tumours and primary thyroid neoplasms do occur. Ultrasound-guided fine-needle aspiration, core-needle biopsy, and surgical resection with histological and immunohistochemical analysis are employed to confirm diagnosis as well as for applying molecular studies to identify candidates for targeted therapy. Biopsy at the metastatic site can identify mutations (such as EGFR, K-Ras, VHL) and translocations (such as EML4-ALK fusion) important in planning target therapies. Patients with advanced-stage primary cancers, widespread dissemination, or unknown primary origin often have a poor prognosis. Those with isolated metastasis to the thyroid have better survival outcomes and are more likely to undergo thyroid resection. Systemic therapies, such as chemotherapy and hormonal therapy, are often used as adjuvant treatment post-operatively or in patients with disseminated disease. New targeted therapies, such as tyrosine kinase inhibitors and immune checkpoint inhibitors, have shown success in reported cases. A tailored treatment plan based on primary tumour features, overall cancer burden, and co-morbidities is imperative. To conclude, secondary cancer to the thyroid is uncommon, and awareness of the updates on diagnosis and management is needed.

Infection control measures to prevent outbreaks of COVID-19 in Quebec hemodialysis units: a cross-sectional survey.

BACKGROUND: Limited space and resources are potential obstacles to infection prevention and control (IPAC) measures in in-centre hemodialysis units. We aimed to assess IPAC measures implemented in Quebec's hemodialysis units during the spring of 2020, describe the characteristics of these units and document the cumulative infection rates during the first year of the COVID-19 pandemic. METHODS: For this cross-sectional survey, we invited leaders from 54 hemodialysis units in Quebec to report information on the physical characteristics of the unit and their perceptions of crowdedness, which IPAC measures were implemented from Mar. 1 to June 30, 2020, and adherence to and feasibility of appropriate IPAC measures. Participating units were contacted again in March 2021 to collect information on the number of COVID-19 cases in order to derive the cumulative infection rate of each unit. RESULTS: Data were obtained from 38 of the 54 units contacted (70% response rate), which provided care to 4485 patients at the time of survey completion. Fourteen units (37%) had implemented appropriate IPAC measures by 3 weeks after Mar. 1, and all 38 units had implemented them by 6 weeks after. One-third of units were perceived as crowded. General measures, masks and screening questionnaires were used in more than 80% of units, and various distancing measures in 55%-71%; reduction in dialysis frequency was rare. Data on cumulative infection rates were obtained from 27 units providing care to 4227 patients. The cumulative infection rate varied from 0% to 50% (median 11.3%, interquartile range 5.2%-20.2%) and was higher than the reported cumulative infection rate in the corresponding region in 23 (85%) of the 27 units. INTERPRETATION: Rates of COVID-19 infection among hemodialysis recipients in Quebec were elevated compared to the general population during the first year of the pandemic, and although hemodialysis units throughout the province implemented appropriate IPAC measures rapidly in the spring of 2020, many units were crowded and could not maintain physical distancing. Future hemodialysis units should be designed to minimize airborne and droplet transmission of infection.

SPG302 Reverses Synaptic and Cognitive Deficits Without Altering Amyloid or Tau Pathology in a Transgenic Model of Alzheimer's Disease.

Alzheimer's disease (AD) is conceptualized as a synaptic failure disorder in which loss of glutamatergic synapses is a major driver of cognitive decline. Thus, novel therapeutic strategies aimed at regenerating synapses may represent a promising approach to mitigate cognitive deficits in AD patients. At present, no disease-modifying drugs exist for AD, and approved therapies are palliative at best, lacking in the ability to reverse the synaptic failure. Here, we tested the efficacy of a novel synaptogenic small molecule, SPG302 - a 3rd-generation benzothiazole derivative that increases the density of axospinous glutamatergic synapses - in 3xTg-AD mice. Daily dosing of 3xTg-AD mice with SPG302 at 3 and 30 mg/kg (i.p.) for 4 weeks restored hippocampal synaptic density and improved cognitive function in hippocampal-dependent tasks. Mushroom and stubby spine profiles were increased by SPG302, and associated with enhanced expression of key postsynaptic proteins - including postsynaptic density protein 95 (PSD95), drebrin, and amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) - and increased colocalization of PSD95 with synaptophysin. Notably, SPG302 proved efficacious in this model without modifying Aß and tau pathology. Thus, our study provides preclinical support for the idea that compounds capable of restoring synaptic density offer a viable strategy to reverse cognitive decline in AD.

Relative strain is a novel predictor of aneurysmal degeneration of the thoracic aorta: An ex vivo mechanical study.

OBJECTIVE: Current guidelines for prophylactic replacement of the thoracic aorta, primarily based on size alone, may not be adequate in identifying patients at risk for either progression of disease or aortic catastrophe. We undertook the current study to determine whether the mechanical properties of the aorta might be able to predict aneurysmal dilatation of the aorta using a clinical database and benchtop mechanical testing of human aortic tissue. METHODS: Using over 400 samples from 31 patients, mechanical properties were studied in (a) normal aorta and then (b) between normal and diseased aorta using linear mixed-effects models. A machine learning technique was used to predict aortic growth rate over time using mechanical properties and baseline clinical characteristics. RESULTS: Healthy aortic tissue under in vivo loading conditions, after accounting for aortic segment location, had lower longitudinal elastic modulus compared with circumferential elastic modulus: -166.8 kPa (95% confidence interval [CI]: -210.8 to -122.7, P < .001). Fracture toughness was also lower in the longitudinal vs circumferential direction: -201.2 J/m3 (95% CI: -272.9 to -129.5, P < .001). Finally, relative strain was lower in the longitudinal direction compared with the circumferential direction: -0.01 (95% CI: -0.02 to -0.004, P = .002). Patients with diseased aorta, after accounting for segment location and sample direction, had decreased toughness compared with normal aorta, -431.7 J/m3 (95% CI: -628.6 to -234.8, P < .001), and increased relative strain, 0.09 (95% CI: 0.04 to 0.14, P = .003). CONCLUSIONS: Increasing relative strain was identified as a novel independent predictor of aneurysmal degeneration. Noninvasive measurement of relative strain may aid in the identification and monitoring of patients at risk for aneurysmal degeneration. (JVS-Vascular Science 2021;2:1-12.). CLINICAL RELEVANCE: Aortic aneurysm surveillance and prophylactic surgical recommendations are based on computed tomographic angiogram aortic dimensions and growth rate measurements. However, aortic catastrophes may occur at small sizes, confounding current risk stratification models. Herein, we report that increasing aortic relative strain, that is, greater distensibility, is associated with growth over time, thus potentially identifying patients at risk for dissection/rupture.

Generation of a humanized Aß expressing mouse demonstrating aspects of Alzheimer's disease-like pathology.

The majority of Alzheimer's disease (AD) cases are late-onset and occur sporadically, however most mouse models of the disease harbor pathogenic mutations, rendering them better representations of familial autosomal-dominant forms of the disease. Here, we generated knock-in mice that express wildtype human Aß under control of the mouse App locus. Remarkably, changing 3 amino acids in the mouse Aß sequence to its wild-type human counterpart leads to age-dependent impairments in cognition and synaptic plasticity, brain volumetric changes, inflammatory alterations, the appearance of Periodic Acid-Schiff (PAS) granules and changes in gene expression. In addition, when exon 14 encoding the Aß sequence was flanked by loxP sites we show that Cre-mediated excision of exon 14 ablates hAß expression, rescues cognition and reduces the formation of PAS granules.

Giant hepatic haemangioma rupture in a patient on direct oral anticoagulant therapy.

Rupture of a liver haemangioma is extremely rare, with less than 100 cases reported in the literature. This is the first case known to date reporting a rupture occurring with direct oral anticoagulant therapy. A 76-year-old woman presented with acute abdominal pain and syncope in the context of commencing apixaban 4 weeks prior. Abdominal computed tomography and angiography demonstrated a large heterogenous mass in the left liver lobe with contrast blush suggestive of a bleeding tumour. Urgent transcatheter arterial embolization successfully ceased haemorrhage. Due to persistent compressive symptoms, a left lateral hepatectomy was performed. CD34 immunostaining of the tissue revealed variably sized vessels, which was consistent with a ruptured giant hepatic haemangioma. Our case substantiates the limited available literature regarding ruptured haemangiomas. Combined with previous case reports, this report will significantly contribute to our understanding of the risk factors, diagnosis and surgical indications for ruptured hepatic haemangiomas.

Pentostatin antagonizes the antiviral activity of MBX-2168 by inhibiting the biosynthesis of the active compound.

MBX-2168 has a mechanism of action similar to that of acyclovir (ACV) and ganciclovir (GCV), but two unique steps differentiate this drug from ACV/GCV. First, MBX-2168 is, at least partially, phosphorylated by the endogenous cellular kinase TAOK3 to a monophosphate. The second involves the removal of a moiety at the 6-position of MBX-2168-MP by adenosine deaminase like protein-1 (ADAL-1). It has been previously demonstrated that co-incubation with pentostatin (dCF), an ADAL-1 inhibitor, antagonizes the anti-viral activity of MBX-2168. We therefore hypothesize that inhibiting ADAL-1 results in a reduction of active compound produced in virus-infected cells. To test this, we examined the effect dCF has on the conversion of MBX-2168 to a triphosphate in HSV-1 and HCMV-infected cells. Our results demonstrate incubation of MBX-2168 alone or with dCF in HCMV-infected cells resulted in 53.1 ± 0.7 and 39.4 ± 1.5 pmol triphosphate/106 cells at 120 h, respectively. Incubation of MBX-2168 alone or with dCF in Vero cells resulted in 12.8 ± 0.1 and 6.7 ± 0.7 pmol triphosphate/106 cells at 24 h, respectively. HSV-1-infected Vero cells demonstrated no statistical difference in triphosphate accumulation at 24 h (13.1 ± 0.3 pmol triphosphate/106 cells). As expected, incubation with dCF resulted in the accumulation of MBX-2168-MP in both HFF (9.8 ± 0.9 pmol MBX-2168-MP/106 cells at 120 h) and Vero cells (4.7 ± 0.3 pmol MBX-2168-MP/106 cells at 24 h) while no detectable levels of monophosphate were observed in cultures not incubated with dCF. We conclude that dCF antagonizes the anti-viral effect of MBX-2168 by inhibiting the production of triphosphate, the active compound.

Biosynthesis and half-life of MBX-2168-triphosphate in herpes virus-infected cells.

The third generation of methylenecyclopropane nucleoside analogs (MCPNAs) elicit an anti-viral effect against all three sub-classes of herpes viruses without inducing cytotoxicity in vitro. It has been previously established that the mechanism of action of MCPNAs is similar to that of ganciclovir (GCV) or acyclovir (ACV). However, the activation of MBX-2168, a third generation MCPNA, involves additional and unique enzymatic steps and this process has not been examined in virus-infected cells. To that end, herpes virus-infected cells were incubated with MBX-2168, synguanol, GCV, or ACV. Incubation of HCMV-infected cells with five times the EC50 of MBX-2168 (4.0 µM), synguanol (10.5 µM), or GCV (25 µM) resulted in a time-dependent increase in triphosphate accumulation reaching a maximum of 48.1 ± 5.5, 45.5 ± 2.5, and 42.6 ± 3.7 pmol/106 cells at 120 h, respectively. Additionally, half-lives of these compounds were similar in HCMV-infected cells (GCV-TP = 25.5 ± 2.7 h; MBX-2168-TP/synguanol-TP = 23.0 ± 1.4 h). HSV-1-infected cells incubated with five times the EC50 of MBX-2168 (33.5 µM) or ACV (5.0 µM) demonstrated a time-dependent increase in triphosphate levels reaching a maximum of 12.3 ± 1.5 and 11.6 ± 0.7 pmol/106 cells at 24 h, respectively. ACV-TP and MBX-2168-TP also had similar half-lives under these conditions (27.3 ± 4.8 h and 22.2 ± 2.2 h, respectively). We therefore conclude that although MBX-2168 does not follow the classical route of nucleoside analog activation, the metabolic profile of MBX-2168 is similar to other nucleoside analogs such as GCV and ACV that do.

Comparison of HEp-2 and Vero Cell Responses Reveal Unique Proapoptotic Activities of the Herpes Simplex Virus Type 1 α0 Gene Transcript and Product.

Previous studies have provided evidence suggesting a role for apoptosis in the control of Herpes Simplex Virus 1 (HSV-1) latency. HSV-1 induces and then later blocks apoptosis in infected cells. The immediate early viral gene α0, which synthesizes the ICP0 protein, is necessary and sufficient for HSV-1-induced apoptosis in human epithelial (HEp-2) cells. While previous research showed that ICP0 protein synthesis is not necessary for HSV-1-induced apoptosis in infected HEp-2 cells, circumstantial evidence suggested that it might be needed in infected African green monkey kidney (Vero) cells. In this study, we determined the specific aspects of α0 needed to trigger apoptosis in these two cell types. HEp-2 cells transfected with α0 expressing plasmids that generated either full-length, truncated, or no detectable (multiple stop codons) ICP0 protein died through apoptosis. This indicates that ICP0 protein is not necessary for α0-induced apoptosis and that α0 mRNA alone has apoptotic induction properties in HEp-2 cells. We next investigated the primary structure of α0's mRNA to better define its proapoptotic ability. Since α0 is one of the few HSV-1 genes that are spliced, we transfected cells with a plasmid expressing ICP0 from cDNA copy, pcDNAICP0. The cells transfected with pcDNAICP0 underwent apoptosis at a level equivalent to those transfected with the genomic copy of α0, which indicates that neither splicing events nor introns are required for the apoptotic function of α0 in HEp-2 cells. Next, we studied the ability of α0 to cause apoptosis in Vero cells. Since HSV-1-induced apoptosis in Vero cells requires protein synthesis early in infection, proteins synthesized with immediate early kinetics may facilitate apoptosis. Vero cells were transfected with plasmids producing either full-length ICP0 or ICP0 truncated at codon 212. Full-length ICP0, but not truncated ICP0, induced apoptosis in Vero cells. Together, these results suggest that α0 gene expression triggers apoptosis, but ICP0 protein is needed to facilitate apoptosis in Vero cells. In addition, ICP0's facilitation activity may lie in its carboxyl-terminated domain. Thus, our results demonstrate that α0's mRNA and protein possess proapoptotic properties. The requirement for ICP0 protein during HSV-dependent apoptosis appears to be cell type specific.

Prominin-1 Promotes Biliary Fibrosis Associated With Biliary Atresia.

In patients with biliary atresia (BA), the extent of intrahepatic biliary fibrosis negatively correlates with successful surgical bypass of the congenital cholangiopathy as well as subsequent transplant-free survival. We recently linked the expansion of a population of prominin-1 (Prom1)-expressing hepatic progenitor cells to biliary fibrogenesis. Herein, we hypothesized that Prom1-expressing progenitor cells play a role in BA-associated fibrosis. Rhesus rotavirus (RRV)-mediated experimental BA was induced in newborn mice homozygous for the transgene Prom1cre-ert2-nlacz , which was knocked in to the Prom1 gene locus, thus creating functional Prom1 knockout (KO) mice, and their wildtype (WT) littermates. Clinical data and tissue samples from BA infants from the Childhood Liver Disease Research Consortium were analyzed. Extrahepatic biliary obliteration was present in both WT and KO mice; there was no difference in serum total bilirubin (TBili) levels. The intrahepatic periportal expansion of the PROM1pos cell population, typically observed in RRV-induced BA, was absent in KO mice. RRV-treated KO mice demonstrated significantly fewer cytokeratin-19 (CK19)-positive ductular reactions (P = 0.0004) and significantly less periportal collagen deposition (P = 0.0001) compared with WT. RRV-treated KO mice expressed significantly less integrin-ß6, which encodes a key biliary-specific subunit of a transforming growth factor (TGF) ß activator (P = 0.0004). Infants with successful biliary drainage (Tbili ≤1.5 mg/dL within 3 months postoperatively), which is highly predictive of increased transplant-free survival, expressed significantly less hepatic PROM1, CK19, and COLLAGEN-1α compared with those with TBili >1.5 (P < 0.05). Conclusion: Prom1 plays an important role in biliary fibrogenesis, in part through integrin-mediated TGF pathway activation.

The Ultimate qPCR Experiment: Producing Publication Quality, Reproducible Data the First Time.

Quantitative PCR (qPCR) is one of the most common techniques for quantification of nucleic acid molecules in biological and environmental samples. Although the methodology is perceived to be relatively simple, there are a number of steps and reagents that require optimization and validation to ensure reproducible data that accurately reflect the biological question(s) being posed. This review article describes and illustrates the critical pitfalls and sources of error in qPCR experiments, along with a rigorous, stepwise process to minimize variability, time, and cost in generating reproducible, publication quality data every time. Finally, an approach to make an informed choice between qPCR and digital PCR technologies is described.

Dissecting Effects of Anti-cancer Drugs and Cancer-Associated Fibroblasts by On-Chip Reconstitution of Immunocompetent Tumor Microenvironments.

A major challenge in cancer research is the complexity of the tumor microenvironment, which includes the host immunological setting. Inspired by the emerging technology of organ-on-chip, we achieved 3D co-cultures in microfluidic devices (integrating four cell populations: cancer, immune, endothelial, and fibroblasts) to reconstitute ex vivo a human tumor ecosystem (HER2+ breast cancer). We visualized and quantified the complex dynamics of this tumor-on-chip, in the absence or in the presence of the drug trastuzumab (Herceptin), a targeted antibody therapy directed against the HER2 receptor. We uncovered the capacity of the drug trastuzumab to specifically promote long cancer-immune interactions (>50 min), recapitulating an anti-tumoral ADCC (antibody-dependent cell-mediated cytotoxicity) immune response. Cancer-associated fibroblasts (CAFs) antagonized the effects of trastuzumab. These observations constitute a proof of concept that tumors-on-chip are powerful platforms to study ex vivo immunocompetent tumor microenvironments, to characterize ecosystem-level drug responses, and to dissect the roles of stromal components.

Statins Reduce Thoracic Aortic Aneurysm Growth in Marfan Syndrome Mice via Inhibition of the Ras-Induced ERK (Extracellular Signal-Regulated Kinase) Signaling Pathway.

Background Statins reduce aneurysm growth in mouse models of Marfan syndrome, although the mechanism is unknown. In addition to reducing cholesterol, statins block farnesylation and geranylgeranylation, which participate in membrane-bound G-protein signaling, including Ras. We dissected the prenylation pathway to define the effect of statins on aneurysm reduction. Methods and Results Fbn1C1039G/+ mice were treated with (1) pravastatin (HMG-CoA [3-hydroxy-3-methylglutaryl coenzyme A] reductase inhibitor), (2) manumycin A ( MA ; FPT inhibitor), (3) perillyl alcohol ( GGPT 1 and -2 inhibitor), or (4) vehicle control from age 4 to 8 weeks and euthanized at 12 weeks. Histological characterization was performed. Protein analysis was completed on aortic specimens to measure ERK (extracellular signal-regulated kinase) signaling. In vitro Fbn1C1039G/+ aortic smooth muscle cells were utilized to measure Ras-dependent ERK signaling and MMP (matrix metalloproteinase) activity. Pravastatin and MA significantly reduced aneurysm growth compared with vehicle control (n=8 per group). In contrast, PA did not significantly decrease aneurysm size. Histology illustrated reduced elastin breakdown in MA -treated mice compared with vehicle control (n=5 per group). Although elevated in control Marfan mice, both phosphorylated c-Raf and phosphorylated ERK 1/2 were significantly reduced in MA -treated mice (4-5 per group). In vitro smooth muscle cell studies confirmed phosphorylated cR af and phosphorylated ERK 1/2 signaling was elevated in Fbn1C1039G/+ smooth muscle cells (n=5 per group). Fbn1C1039G/+ smooth muscle cell Ras-dependent ERK signaling and MMP activity were reduced following MA treatment (n=5 per group). Corroborating in vitro findings, MMP activity was also decreased in pravastatin-treated mice. Conclusions Aneurysm reduction in Fbn1C1039G/+ mice following pravastatin and MA treatment was associated with a decrease in Ras-dependent ERK signaling. MMP activity can be reduced by diminishing Ras signaling.

Herpes simplex virus virucidal activity of MST-312 and epigallocatechin gallate.

Herpes Simplex Virus (HSV) is the cause of cold sores, blindness and encephalitis and often leads to recurrent infections. Use of current anti-viral therapies can be limited when drug resistant HSV mutants arise. Thus, novel drugs for the treatment of HSV are needed. Previous research in our laboratory has determined that the telomerase inhibitor, MST-312, interferes with multiple steps of the HSV life cycle. The structure of MST-312 contains moieties related to a natural compound found in green tea, epigallocatechin gallate (EGCG). EGCG has been reported to possess direct virucidal activities toward HSV-1. Here, we tested the virucidal activity of MST-312 and compared it to that of EGCG. Specifically, HSV-1 was exposed to various concentrations of MST-312 or EGCG for time periods between 1 and 60 min and then the ability of the treated virions to form plaques on Vero cells was assessed. When treated for 60 min, 40 µM MST-312 and 0.5-1.0 µM EGCG significantly reduced the number of HSV-1 plaque forming units. The temperature at which treatment occurred impacted the ability of the compounds to limit viral replication. Both compounds were effective when treatment occurred at 37 °C and room temperature (RT). However, no inhibition was seen when virions were treated with MST-312 at 4 °C. 1 min treatment with 2 µM EGCG at RT was sufficient to significantly reduce HSV titers. Higher concentrations of MST-312 were required to inactivate HSV-1 virions compared to EGCG. These data indicate that both EGCG and MST-312 possess direct virucidal properties on HSV-1.

Efficacy of Hearing Aids on the Cognitive Status of Patients with Alzheimer's Disease and Hearing Loss: A Multicenter Controlled Randomized Trial.

BACKGROUND/OBJECTIVE: This study evaluated the cognitive benefit of hearing aids (HA) in older patients with Alzheimer's disease (AD) and hearing loss (HL) after a 6- and 12-month period of utilization. METHODS: A multicenter double-blind randomized placebo-controlled trial was conducted in patients aged more than 65 years. A group was equipped with active HA for 6 months (active group) and a second group had placebo HA for 6 months (placebo group) followed by a secondary activation phase for a further 6 months (semi crossover procedure). Both groups were retested after a 12-month period. The primary endpoint was the change from baseline of the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS Cog) after a 6-month period in both groups and after 6 months of secondary HA activation in the placebo group. A smaller cognitive decline should be obtained with HA use; an increase in ADAS Cog score of less than 6 points was defined a success. RESULTS: Fifty-one patients aged 68 to 99 years were included; 38 attended the 6-month visit: 18 in the active group and 20 in the placebo group. At 6 months, 14 (82.4%) successes were noticed in the active group, and 15 (88.2%) in the placebo group (p = 1.0); delta ADAS Cog in the active group was 1.8±5.3 and 1.3±5.3 in the placebo group (p = 0.8). In the placebo group, after the secondary HA activation, no significant improvement was observed. CONCLUSION: No significant effect of HA use was observed after 6 months of follow-up in patients with AD and HL.

Do Hearing Aids Influence Behavioral and Psychological Symptoms of Dementia and Quality of Life in Hearing Impaired Alzheimer's Disease Patients and Their Caregivers?

BACKGROUND: It has been suggested that age-related hearing loss (ARHL) and Alzheimer's disease (AD) are commonly associated. OBJECTIVE: The Alzheimer Disease, Presbycusis and Hearing Aids (ADPHA) clinical trial assessed the influence of hearing aids (HAs) on patients affected by ARHL and AD, as judged by behavioral symptoms and functional abilities, as well as patient and caregiver quality of life (QoL). METHODS: A multicenter double-blind randomized placebo-controlled trial, with a semi-crossover procedure over 12 months, was conducted from 2006 to 2012. For the first 6 months, the active group was treated with active HAs and the placebo group with inactive HAs. For the last 6 months, HAs in the placebo group were activated. Assessment was conducted at baseline, 6 months, and 12 months. We performed intergroup and intragroup comparisons. Behavioral symptoms were assessed by neuropsychiatric inventory (NPI), functional abilities by instrumental activities of daily living, and QoL by Zarit, Alzheimer's disease related quality of life, and simplified Duke scales. RESULTS: Fifty-one patients were included and randomized: 22 in active group (mean NPI 17.6; mean age 83±6.2) and 26 in placebo group (mean NPI 25.8; mean age 82.3±7.2) were fitted with HAs. At 6-month follow-up, all scores worsened without significant difference between the two groups. In placebo group, activation of HAs had no effect on the change of these scores. CONCLUSION: These findings do not provide evidence of improvement in behavioral symptoms, functional status, or QoL of hearing impaired AD patients and their caregivers after 6 months of HA use. However, we cannot exclude that HAs may have a positive effect in patients aged less than 75 years.