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Background: RASopathies account for nearly 20% of cases of childhood hypertrophic cardiomyopathy (HCM). Sudden cardiac death (SCD) occurs in patients with RASopathy-associated HCM, but the risk factors for SCD have not been systematically evaluated., Aim: To validate the HCM Risk-Kids SCD risk prediction model in children with RASopathy-associated HCM and investigate potential specific SCD predictors in this population., Methods: Validation of HCM Risk-Kids was performed in a retrospective cohort of 169 patients with a RASopathy-associated HCM from 15 international paediatric cardiology centres. Multiple imputation by chained equations was used for missing values related to the HCM Risk-Kids parameters., Results: Eleven patients (6.5%) experienced a SCD or equivalent event at a median age of 12.5 months (IQR 7.7-28.64). The calculated SCD/equivalent event incidence was 0.78 (95% CI 0.43-1.41) per 100 patient years. Six patients (54.54%) with an event were in the low-risk category according to the HCM Risk-Kids model. Harrell's C index was 0.60, with a sensitivity of 9.09%, specificity of 63.92%, positive predictive value of 1.72%, and negative predictive value of 91%; with a poor distinction between the different risk groups. Unexplained syncope (HR 42.17, 95% CI 10.49-169.56, p < 0.001) and non-sustained ventricular tachycardia (HR 5.48, 95% CI 1.58-19.03, p < 0.007) were predictors of SCD on univariate analysis., Conclusion: Unexplained syncope and the presence of NSVT emerge as predictors for SCD in children with RASopathy-associated HCM. The HCM Risk-Kids model may not be appropriate to use in this population, but larger multicentre collaborative studies are required to investigate this further., Competing Interests: Declaration of Competing Interest Wolf CM: consultancy with Day One Biopharmaceuticals, Inc., BioMarin Pharmaceuticals, Adrenomed AG, and Pliant Therapeutics; ownership interest: Preventage Therapeutics. Zenker M: consultancy with Day One Biopharmaceuticals, Inc. and Novo Nordisk., (Copyright © 2023. Published by Elsevier B.V.)

Background: Left ventricular outflow tract obstruction (LVOTO) is present in 1/3 of children with Hypertrophic Cardiomyopathy (HCM). Disopyramide improves symptoms associated with LVOTO and delays surgical intervention in adults, but it is not licensed in children., Aim: To describe a single-centre thirty-year experience of using disopyramide to treat LVOTO-related symptoms in a paediatric HCM cohort., Methods: Clinical data were collected for all patients meeting diagnostic criteria for HCM (<18 years) at the time of initiation, 6 months after, and last follow-up or end of disopyramide treatment. It included demographics, clinical history, 12‑lead electrocardiography, and echocardiography. Comparisons between baseline and 6 month follow up, and end of follow up respectively were performed., Results: Fifty-one patients with HCM were started on disopyramide at a mean age 10.2±5.3 years. At 6 months, of those previously symptomatic, 33(86.8%) reported an improvement of symptoms and 12(31.6%) were asymptomatic. PR interval, corrected QT interval and maximal LVOT gradient had not significantly changed, but fewer participants were noted to have systolic anterior motion of the mitral valve 31 (72.1%) vs. 26 (57.80%). Patients were followed up for a median of 1.9 years (IQR 0.83-4.5). Nine patients (17.6%) reported side effects, and eleven patients (33.3%) with initial improvement in symptoms reported a return or worsening of symptoms requiring a change in medication (n = 4, 12.1%) or left ventricular septal myomectomy (n = 7, 21.2%) during follow up., Conclusion: Disopyramide is a safe and effective treatment for LVOTO-related symptoms in childhood obstructive HCM. Any delay in the need for invasive intervention, particularly during childhood, is of clear clinical benefit., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Recent incorporation of simulation in surgical training necessitates developing validated platforms for training and assessment. A tool should fulfill the fundamental criteria of validation., Objective: To report the ability of a simulation-based robotic training curriculum-Fundamental Skills of Robotic Surgery (FSRS)-to assess and distinguish between different performance levels of operator experience (construct validity)., Materials and Methods: This is a prospective multicenter observational study. Participants were classified as novice (0 robotic cases performed) and experts (>150 robotic cases performed). All participants were required to complete 4 key tasks in a previously validated FSRS curriculum: ball placement, coordinated tool control, fourth arm control, and needle handling and exchange. Using the metrics available in the simulator software, the performances of each group were compared to evaluate construct validation., Results: A convenience cohort of 61 surgeons participated. Novice group (n = 49) consisted of 41 fellows/residents/medical students and 8 trained open/laparoscopic surgeons, whereas expert group consisted of 12 surgeons. The novice group had no previous robotic console experience, whereas the expert group had >150 prior robotic cases experience. An overall significant difference was observed in favor of the expert group in 4 skill sets (p < 0.05). Time to complete all 4 tasks was significantly shorter in the expert group (p < 0.001). The expert group displayed significantly lesser tool collision (p = 0.002) and reduced tissue damage (p < 0.001). In performing most tasks, the expert group's camera (p < 0.001) and clutch usage (p < 0.001) was significantly greater when compared with the novice group., Conclusion: The components of the FSRS curriculum showed construct validity. This validation would help in effectively implementing this curriculum for robot-assisted surgical training., (© 2014 Published by Association of Program Directors in Surgery on behalf of Association of Program Directors in Surgery.)

Background: While the size and clinical appearance are known risk factors for malignant transformation of potentially malignant oral the importance of site, grade of dysplasia and exposure to environmental carcinogens remains controversial. We aim to report the clinical determinants of malignant progression in a series of patients with histopathologically graded oral epithelial dysplasia (OED)., Methods: We recruited patients with a histopathological diagnosis of OED to a longitudinal observational study in a tertiary oral dysplasia clinic. Clinical, histopathological and risk factor data were recorded at baseline. One of three clinical endpoints were determined: malignant transformation, progression of dysplasia grade, remission/stable dysplasia grade., Results: Ninety-one patients meeting the criteria gave consent for inclusion to the cohort, with outcomes reported after a median follow up of 48 months. An estimated 22% (SE 6%) of patients underwent malignant transformation within 5 years, with significant predictors being: non-smoking status (χ(2)=15.1, p=0.001), site (χ(2)=15.3, p=0.002), non-homogeneous appearance (χ(2)=8.2, p=0.004), size of lesion >200 mm(2) (χ(2)=4.7, p=0.03) and, of borderline significance, high grade (χ(2)=5.8, p=0.06). Gender, age, number of lesions and alcohol history did not predict for malignant transformation., Conclusions: Although a number of these clinical determinants have previously been associated with higher malignant transformation in OED, the high-risk nature of lesions in non-smokers is of particular note and requires a greater emphasis and recognition amongst clinicians dealing with OED. It suggests that those non-smokers with OED, have an inherited or acquired predisposition and should be treated more aggressively; these should form the focus for further investigation., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Aim: To determine the immediate influence of a validated patient information leaflet (PIL) on patient anxiety and intention to have a screen for oral cancer in primary care attenders., Participants: Patients (n=800) attending their primary health care provider., Setting: Fourteen general practices (eight dental and six medical) in the northwest of England., Design: Randomised controlled trial with two arms: leaflets provided in information group, leaflet was absent in control group., Measures: Single item ratings of (1) intention to have an oral cancer screen, and (2) anxiety towards a screen, (3) perceived risk of oral cancer. Knowledge of oral cancer, self-reported dental service attendance history and demographic variables were also collected., Results: Patients who had read the oral cancer PIL demonstrated an increase in their intention to have a screen (Mann Whitney U test: z=-3.67, P<0.001) and reduced anxiety (Mann Whitney U test: z=-2.07, P<0.05). Subjective risk was not elevated by the extra information. Intention to have a screen was predicted by knowledge level and anxiety (odds ratios: 1.10 and 0.70 respectively, both P's<0.001)., Conclusion: The influence of an information leaflet appeared to have a positive effect on anxiety level and intentions to agree to receive an oral cancer screen.

The aim was to determine the immediate influence of a validated patient information leaflet (PIL) on oral cancer and knowledge in primary care attenders. Participants were patients (n=800) attending their primary health care provider from 14 general practices (eight dental and six medical) in the north west of England. Measures were a previously validated knowledge questionnaire (36 dichotomous items), self-reported dental service attendance history and demographic variables. The results showed that patients who had read the oral cancer PIL demonstrated a significant increase in knowledge regardless of clinical setting (F[1,739]=246.24, P<0.0001). Patients showed improvements in selecting the correct signs and risk factors associated with disease. Immediate knowledge gain from a simple PIL about oral cancer was found and independent of the primary care facility, where the PIL was distributed.

The aims of our series of studies were: (1) to prepare an information leaflet about oral cancer for the general public; (2) to design a questionnaire to assess the level of knowledge about oral cancer; and (3) to evaluate the newly prepared leaflet. A study was conducted for each aim. For study 1, multiple drafts of oral cancer leaflets were distributed for comment and editing. For study 2, a large number of statements (100) about oral cancer were compiled and judged. Redundant items were withdrawn. The final version was administered to criterion groups (students, dentists and the public) to assess reliability and validity. For study 3, a multigroup pre- and post-test randomised design (comprising an experimental and two control groups) was adopted to evaluate knowledge improvement from exposure to the oral cancer leaflet. The participants in each study were as follows: in study 1, questions were judged by the authors, colleagues (n=2) and a non-patient group (n=10); in study 2, undergraduate psychology students (n=41), medical students (n=60), dental students (n=82), members of the public (n=54) and general dental practitioners (n=22) were respondents for the reliability/validity assessment; and in study 3, the dental students and members of the public from the previous study participated. The measure was a true/false 36-item questionnaire with additional demographic questions. In study 1 the Flesch readability index for the leaflet equalled approximately 80, i.e. 'fairly easy'. In study 2 the Kuder-Richardson 20 reliability coefficient of the questionnaire equalled 0.76. Criterion validity was confirmed with general dental practitioners scoring greater knowledge than members of the public (p<0.05). In study 3 participants who had access to the leaflet showed a significant increase in knowledge at post-test in comparison to pre-test. Control group results were supportive of a positive effect from leaflet exposure. In conclusion, the design of a health information leaflet, the assessment of reliability and validity of an associated knowledge questionnaire and evaluation of the influence of such a leaflet should be conducted in a series of planned steps. This approach can be used for other health-related issues which require dissemination of information. Three studies have demonstrated the successful application of this design and evaluation model to the area of oral cancer education.

We have used the classic model of neonatal tolerance to investigate the hypothesis that acquired tolerance depends on the generation of regulatory CD4 cells. Injection of neonatal BALB/c mice with semi-allogeneic CAF1 (BALB/c X A/J) spleen cells induces antigen-specific tolerance (TOL) in 80% of mice. TOL mice accept fully allogeneic A/J skin grafts for >60 days. TOL mice show diminished Th1 CD4 and CD8 cell immunity against A/J in vitro. In contrast, TOL mice show increased levels of anti-A/J Th2 CD4 responses. Thus tolerance is associated with the inhibition of Th1 CD4 and TC1 CD8 responses and the enhancement of Th2 CD4 responses. Because of this relationship, we hypothesized that regulatory Th2 CD4 cells in TOL mice maintain tolerance by blocking activation of A/J-reactive TC1-CD8 cells. Using in vitro BrdU assays to measure CD8 proliferation within unfractionated cell cultures, we showed that CD8 cells from TOL mice proliferate normally to exogenous interleukin-2 (IL-2) but fail to proliferate in response to A/J cells. The addition of exogenous IL-2 does not restore CD8 proliferation to A/J, ruling out simple CD8 cell anergy. However, when CD4 cells are depleted from the cultures, IL-2 could restore the ability of A/J-reactive CD8 cells to proliferate and to secrete IFN-gamma. Thus CD4 cells from TOL mice inhibit IL-2 rescue of "anergic" A/J-reactive CD8 cells. The results demonstrate a novel link between two major mechanisms of tolerance, immunoredirection and anergy.

Objectives: To critically review the potential hazards associated with the use of powdered, natural rubber latex (NRL) gloves in dental practice and to report some practical difficulties which may be encountered when handling dental materials with powdered NRL gloves., Data Sources: Articles published in the international literature over the last 10 years., Study Selection: A number of recent studies in the medical and surgical literature have confirmed that NRL proteins leach out of latex gloves and bind to surgical glove powders. The most serious, potential hazard associated with the continued use of powdered NRL gloves in dental practice is that of latex sensitization by exposure to aerosolized NRL proteins. Hand dermatitis is now recognized as an occupational hazard in dentistry and has been associated with the continuous wearing of protective gloves. Studies, in the dermatological literature, have suggested that glove powders may exacerbate an irritant dermatitis and enhance the potential for adverse reactions to other components of NRL gloves. The surgical literature has already highlighted the risks of post-operative granuloma formation, due to glove powder contamination of the surgical wound. The possible effects of powder contamination of dental implant sites, on the outcome and success of implants has yet to be established. Recent in vitro studies have investigated the effect of latex glove contamination on the shear-bond strength of porcelain laminate veneers: one study demonstrated that starch powder significantly affected the bond strength, whereas the other showed that latex glove contamination of the porcelain surface did not have any significant effect. Long-term, in vivo studies are now required., Conclusions: Dental practitioners should consider the potential health risks which are associated with the use of powdered NRL in dental practice. Powder contamination may affect the long-term results and success of clinical procedures in dentistry.

A 51-yr-old woman was transferred to the emergency department with nonspecific interscapular pain and a progressive right-sided hemiparesis. Physical examination and laboratory examination revealed moderate right-sided hemiparesis, with no other focal neurologic deficits. A computed axial tomography scan of the brain was negative. Emergency arteriography revealed bilateral highgrade fibromuscular dysplasia involving the origins of the left and right common carotid arteries. The patient was admitted with the presumptive diagnosis of embolic cerebrovascular accident. Subsequently, the patient developed a left-sided sensory deficit, and magnetic resonance imaging of the cervical spine revealed a C5-T2 epidural hemorrhage. The patient underwent emergent surgical evacuation of the clot and recovered without incident. Spinal epidural hematomas are rare and typically present as cord compressions with or without pain rather than as unilateral hemiplegia.

Objectives: The purpose of this study was to analyse the protein content of 17 commonly used rubber dams and to determine if they contained known allergenic proteins., Methods: Proteins were eluted with buffer from 17 brands of commercially available rubber dams. The quantity of eluted protein was measured and expressed in micrograms in every gram of rubber. The molecular weights of the individual proteins eluted were then measured after resolution on sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE) and compared with those of known allergens., Results: The rubber dams were shown to contain significant amounts of protein (950-5850 micrograms). The subsequent analysis of these proteins using SDS-PAGE confirmed that some of these proteins were of the same molecular weight as known allergens., Conclusions: The results of this study confirm that all the rubber dams tested contained significant amounts of protein. The molecular weights of these proteins correspond with those of known allergens, and they could, therefore, be a cause of hypersensitivity reactions to dental rubber dams.

Small intestinal mucosal inflammation observed in celiac disease is associated with the local release of growth factors and various cytokines. In a previous study, we investigated the effect of various cytokines on triacylglycerol and apoB secretion by CaCo-2 cells and observed that TNF-alpha, IL-1 beta, and particularly IL-6, decreased apolipoprotein (apo) B and triacylglycerol secretion. In this study, we explored possible mechanisms to explain the inhibitory effect of IL-6 on apoB secretion. IL-6, 10 ng/mL, added to the basolateral medium of CaCo-2 cells grown on semi-permeable filters, decreased apoB secretion by 42%. Adding a blocking monoclonal antibody (mAb 528) to the EGF receptor completely prevented this effect. IL-6 decreased the amount of EGF receptor protein and the binding of iodinated EGF to its receptor by 50% and 30%, respectively. Incubation of cells with various ligands to the EGF receptor, such as EGF, TGF-alpha, HB-EGF, and amphiregulin, also decreased apoB secretion. Inhibition of apoB secretion by EGF was prevented by the mAb 528 or an EGF neutralizing antibody. In a dose-dependent manner, the neutralizing antibody to EGF prevented the decrease in secretion of apoB, triacylglycerol mass, and cell-surface binding of labeled EGF caused by IL-6. Similar to the effects of IL-6, EGF decreased the secretion of triacylglycerol mass and the synthesis and secretion on newly synthesized apoB. The results suggest that, in CaCo-2 cells, IL-6 causes the release of EGF or an EGF-like molecule. By binding to cell surface EGF receptors, the molecule then causes a decrease in triacylglycerol and apoB secretion.

The oral lesions in patients with tylosis (palmoplantar keratoderma) associated with oesophageal cancer, are evaluated, based on their clinical presentation, histological features and long term follow-up. The terminology of these lesions is discussed, together with a proposed reclassification of some forms of palmoplantar keratoderma.

Objectives: There is no clear evidence to support the recommendation that rings and watches should be removed prior to operative dental procedures. The aim of this study was to measure and identify the bacteria isolated from the skin under rings and watches worn by a group of dental surgeons and to compare the results with a group of non-clinical staff., Methods: Forty volunteers participated in the study; of these 20 were dental surgeons and 20 were non-clinical staff. Four skin sites were sampled for each volunteer; the skin directly under the ring and on the same finger of the other hand and the skin under the watch face and wrist of the control hand. Bacteria on the swabs were dispersed and inoculated onto plates, which were incubated aerobically for 24 h at 37 degrees C., Results: In both groups of volunteers there was a significantly greater number of bacteria isolated from under rings and watches compared with control sites. Few qualitative differences were found between the microflora found on the skin under rings and watches in the two volunteer groups., Conclusions: The bacterial flora isolated from volunteers do not commonly cause oral infections but could pose a threat to the immunocompromised patient, particularly in the event of gloves becoming torn or perforated. Effective hand disinfection is difficult to achieve if ring and watches are not removed; they should therefore be removed prior to hand disinfection and donning of gloves.

Hypoallergenic gloves have been introduced in response to the growing problems of occupationally acquired hand dermatitis. Such labelling can, however, be misleading and some gloves contain measurable allergen levels. Hypoallergenic gloves containing natural rubber latex will not address the problem of individuals suffering from latex allergy and their inappropriate use may provoke a potentially life threatening reaction. Regulatory authorities must ensure that manufacturers provide adequate labelling for gloves, with the appropriate warning about their allergen content. Dental health care workers must become more knowledgeable about gloves and staff should be given appropriate advice about the risks of latex sensitisation.

delta-9-Tetrahydrocannabinol (THC), the major psychoactive component of marihuana, retarded sexual maturation in the pubertal female rat as indicated by a delayed appearance of estrus and ovulation. Twice daily intraperitoneal injections of 10 mg THC/kg body weight from 27 days of age until the first day of full vaginal cornification delayed the onset of estrus and the occurrence of the first ovulation by an average of 4.3 +/- 0.9 (S.E.M.) days in comparison with pair-fed, vehicle-treated animals (p less than 0.001). Ovulation during the first estrus occurred in 92% of the animals in each treatment group without a difference in the average number of ova ovulated. The delayed sexual maturation in animals treated with THC could not be attributed to reduced body weight gain since body weights in THC- and vehicle-treated groups were equivalent when vehicle-treated animals came into estrus. Delayed ovulation in THC-treated animals did not merely reflect the repeated blockade of ovulation from otherwise competent follicles in that the onset of vaginal cornification was delayed to a comparable extent. Rather, the data suggest retarded development of ovarian follicles, possibly as a result of pituitary suppression. It is noteworthy that, although delayed, both vaginal cornification and ovulation occurred in spite of continued THC treatment, suggesting the development of drug tolerance.

In this study the macrophage electrophoretic mobility (MEM) test was modified by using tanned sheep erythrocytes in place of guinea pig peritoneal macrophages as the indicator cells of lymphocyte sensitization to antigens. This modification is named the tanned sheep erythrocyte electrophoretic mobility (TEEM) test, and a comparison of the kinetics of the two systems allowed the following conclusions to be made: 1) Treatment of freshly drawn sheep red blood cells with a concentration of 1/40,000 tannic acid produced optimum results in the TEEM test. 2) Lymphocyte-antigen and lymphocyte-number response curves show similarity in the two test systems. 3) A plateau response with slowing factor is achieved at a lower dilution in the TEEM test than in the MEM test. 4) Whilst similarity in the first stage reaction was found in the two systems, in the second stage of the test (at 37 degrees C) tanned sheep red cells gave a plateau response after 45 min instead of the 60 min found in the MEM test. 5) The two slowing factors showed similar gel filtration patterns with molecular weights between 13,000 and 15,000 daltons, and had equivalent activity in both test systems. 6) The disadvantages of the guinea pig macrophage as an indicator cell are discussed. 7) The TEEM test seems simpler to perform than the MEM test and may be widely applicable in clinical immunology for the estimation of lymphocyte sensitization.

The following parameters of the cytopherometric test system have been studied. 1. Temperature is less important for the production of macrophage slowing factor (MSF) by lymphocyte-antigen interaction than it is for the activity of MSF on macrophages. 2. Lymphocyte number titration curves allow discrimination between 'weak' and 'strong' antigen responses. 3. Lymphocyte-antigen reaction reaches a plateau after 30 min incubation, whilst maximum MSF-macrophage reaction requires 60 min. 4. Interaction of MSF with macrophages is sensitive to cycloheximide. 5. Irradiation of peritoneal exudate cells (200 rad) is essential in order to obtain a maximal result in the MEM test. In the 'split MEM test, 200 rad to the indicator peritoneal exudate cells produces a greater result, i.e. it in some way amplifies the macrophage response to MSF. 6. Excess of peritoneal exudate cells, especially when non-irradiated, suppresses the test result. This is not due to consumption of MSF produced. Probably macrophages rather than lymphocytes are responsible for the suppression.

In female neonatal rats, opiate receptor blockade markedly raises serum luteinizing hormone (LH) levels. The LH effect of acute treatment with opiate antagonists is apparently brief in older rats; however, age-related differences in antagonist pharmacokinetics may result in different LH response patterns. The duration of LH response to naloxone (NAL) and naltrexone (NTX) was examined in 5 day-old (d.o.) female rats and compared to the duration of analgesia blockade. The rise in serum LH following opiate receptor blockade in 5 d.o. rats was of similar duration to that previously observed in older animals and much briefer than blockade of analgesia. Furthermore, neonatal rats exhibited a delayed suppression of LH 6 hr following NAL, but not NTX, treatment. Stimulation and later suppression of LH were still observed after five repetitive NAL treatments at 6 hr intervals.

By observing the effect of 0.08 and 0.02 mg/ml linoleic acid (LA on the electrophoretic mobility of fresh red blood cells derived from the parents of a subject with DMD, it has been shown that all of 16 fathers as well as 15 mothers, consistently differ from normal. In normal subjects, whilst 0.08 mg/ml LA causes increased mobility, 0.02 mg/ml causes reduced mobility (P less than 0.001). In both parents this reversal is abolished and 0.02 mg/ml LA gives the same increased electrophoretic mobility of the RBC as does 0.08 mg/ml. This indicates that there is qualitative alteration of the RBC membrane in both, apparently genetically determined. Only when such an abnormal male mates with an abnormal female can DMD occur in a male offspring; other children appear either normal or showing the same abnormality as do the parents, thus continuing the production of DMD parents, the chance mating of whom produces further DMD. The evidence supports the hypothesis that in DMD there is a widespread membrane disturbance. Other relatives have also been explored. It would appear that the common DMD of children is of autosomal recessive origin with strong limitation to the male.