The Clinical Profile and Natural History of Patients Who Fail Screening for Transcatheter Mitral Valve Replacement: Rationale and Design of the Prospective Multicenter Mitral Valve Screening Survey (MVSS).

Mitral valve disease is insidious and associated with a decreased quality of life and survival over time. Despite surgery being the standard of care, many patients are at prohibitive surgical risk. Furthermore, a substantial proportion of patients with symptomatic mitral valve disease fail stringent screening criteria for transcatheter mitral valve replacement (TMVR). The natural history of patients who fail screening is not well-characterized, and data are limited on the reasons for screen failure in this population. The Mitral Valve Screening Survey (MVSS) seeks to detail the clinical profile and natural history of patients who fail screening for TMVR. The MVSS is a prospective, multicenter registry enrolling up to 1000 consecutive subjects who, after screening for TMVR, are deemed not to be candidates. Subjects will be followed for 30 days after failing screening for TMVR and annually for up to 5 years with clinical evaluations. The primary study endpoint of the MVSS registry is all-cause mortality at 1 year. Additional secondary endpoints include all-cause mortality, hospitalizations, subsequent mitral valve intervention (transcatheter or surgical), reason for screen failure, and quality-of-life assessments at 30 days and annually up to 5 years of follow-up. The MVSS registry is the first prospective multicenter study to characterize the clinical and anatomical profile of patients who fail screening for TMVR while providing longitudinal clarification on the natural history and outcomes of these patients. CLINICAL TRIAL REGISTRATION: Mitral Valve Screening Survey (MVSS), https://clinicaltrials.gov/ct2/show/NCT04736667, NCT04736667.

Protection from blood aerosol contamination when managing epistaxis: A study of the effectiveness of a patient mouth mask.

The danger to healthcare personnel of acquiring a blood-borne infection accidentally transmitted by a patient is well known. Such an infection can have serious and career-altering implications. Epistaxis, which is the most common emergency seen in ENT practice, poses a great risk of contaminated blood being spattered on the face of the attending medical provider. Areas of possible contamination include the mucosa of the nasal passages, oral cavity, and conjunctiva. Various strategies to prevent contamination have been described in the literature, most of which involve the wearing of protective equipment by the healthcare provider. We conducted a prospective, randomized study of 60 epistaxis patients to determine if a simple surgical mask warn by the patient over his or her mouth would protect the treating physician from aerosolized blood contamination. We found evidence of significant blood splashes on the physician in 8 of the 30 cases (26.7%) in which the patient did not wear a mask, compared with only 4 cases (13.3%) when the mouth mask was worn. We therefore conclude that a patient mouth mask is a simple, inexpensive, and effective way to minimize the risk of aerosolized blood contamination during the treatment of epistaxis.

Carcinoid tumour of the middle ear.

A case of middle ear mass in a young female from Ireland is described, who presented with left ear hearing loss and intermittent bloody discharge from the same ear. Examination under microscope revealed occlusive polyp in the left ear and a biopsy had been taken under general anaesthesia. Histopathology report described an adenoma / carcinoid tumour of the middle ear confirmed by positive immunohistochemical staining. CT temporal bones revealed the extension of the disease. The patient underwent left tympanotomy and excision of the tumour. In general, these tumours are regarded as benign but may be mistaken for adenocarcinomas because of their histological heterogenecity.

An unusual cause of recurrent throat pain - calcified stylohyoid ligament.

Calcified stylohyoid ligament is also called an elongated styloid process and the symptom complex that it produces is called Eagle's syndrome. The symptoms of neck pain, sore throat, foreign body sensation in the throat, dysphagia and otalgia may be confused with other head and neck pain and are often worsened by yawning, opening the mouth wide or turning the head laterally. This is the result of involvement of cranial nerves, carotid plexus and cervical plexus. Carotid artery involvement causes wider symptomatology. Sometimes, it presents as a complication of tonsillectomy procedure. Elongated styloid process is conveniently identified on firm digital examination of tonsillar fossa. Diagnosis is made with appropriate radiological examination. Non-surgical treatment options include re-assurance, analgesia, anti-inflammatory medications and surgical option is shortening of the elongated styloid process by transoral or external approach. The condition is hereby described in a 59 years old male.

Effects of castration and hormone replacement on male sexual behavior and pattern of expression in the brain of sex-steroid receptors in BALB/c AnN mice.

Little is known about the hormonal regulation of sexual behavior and about the pattern of expression in the brain of sex-steroid receptors in the BALB/c AnN strain of mice (Mus musculus). In this study, 8-week old male BALB/c AnN mice were castrated and the temporal course of decline of sexual behavior was studied, as well as the effects of daily treatment with either testosterone propionate (TP), estradiol benzoate (EB), or dihydrotestosterone propionate (PDHT). Castration resulted in rapid decline of sexual behavior, in both control or vehicle-treated mice. TP maintained full sexual behavior of castrated mice, while PDHT or EB did not have this effect. The expression of ER-alpha dropped nearly 50% after castration, and this pattern remained in TP or PDHT-treated mice, while EB increased the ER-alpha mRNA levels to almost the same values as in intact control mice. The same pattern was found when ER-beta mRNA levels were analyzed. The expression of the PR-A/B gene in the different brain regions in intact mice and after castration, or among the differently treated mice, showed significant differences between normal and castrated mice at all times in all brain regions studied, with the exception of the frontal cortex. Castration reduced the expression of AR by 10-fold, as compared to intact control mice, while TP or PDHT treatment returned its expression to the same levels as in intact control mice, in all brain areas studied. The changes are more prominent in POA-HIP than in HYP and CF. These results demonstrated a rapid decline of sexual behavior in this strain of mice after castration, and show that only TP was able to maintain male sexual behavior, with no correlation with the pattern of expression of sex hormone receptors in specific areas of the mouse brain.

Proinflammatory cytokines in granulomas associated with murine cysticercosis are not the cause of seizures.

Neurocysticercosis is a parasitic infection of the human central nervous system caused by the cestode Taenia solium. The most common clinical manifestations of neurocysticercosis are seizures. Taenia crassiceps cysticercosis in mice has been used as an experimental model for T. solium cysticercosis. Granulomas surrounding murine cysticerci have striking immunopathological resemblance to human neurocysticercosis; early stage granulomas were able to induce seizures in a rodent model. To assess the role of proinflammatory cytokines in early stage granulomas, we isolated RNA from murine cysticercal granulomas and checked for cytokine expression by reverse transcriptase-polymerase chain reaction (RT-PCR) and/or ribonuclease (RNase) protection assays. Cytokine expression was compared with histological stages. Interleukin (IL)-1alpha, IL-1beta, IL-1 receptor antagonist, and tumor necrosis factor (TNF-alpha) were the major cytokines detected in all granulomas. Signals for IL-12, IL-18, and IL-6 RNA were not consistently detected and, when detected, were barely demonstrable. Expression of migration inhibitory factor (MIF), IL-6, IL-1alpha, TNF-alpha, and IL-18 was not significantly different between early and late-stage granulomas. Expression of IL-1beta, IL-1 receptor antagonist, and IL-12 p40 were higher in late, compared with early, stages. Thus, we demonstrated a broad range of cytokines in these granulomas. However, we did not document preferential expression of any proinflammatory cytokines in early stage granulomas. Thus, proinflammatory cytokines are not responsible for the seizures in the rodent model of neurocysticercosis.

Protection from murine cysticercosis by immunization with a parasite cysteine protease.

Central nervous system infection by Taenia solium cysts causes neurocysticercosis, a common neurological infection in the Third World. We have previously isolated cysteine proteases from Taenia crassiceps and T. solium. In this study, we immunized BALB/c mice with the purified T. solium cysteine protease and challenged them with Taenia crassiceps. Immunized mice had a 72% reduction in parasite burden compared to mice that received no immunization. Immunized mice developed antigen specific lymphocyte proliferation. These data support further studies of the T. solium cysteine protease as a vaccine candidate.

Cysteine proteinase inhibitors in murine cysticercosis.

We explored the prophylactic efficacies of two novel protease inhibitors in murine cysticercosis. Our results demonstrated a 95% and 80% reduction in parasite burden for mice injected with Z-LLL-FMK and Z-LLY-FMK, respectively. Further studies are merited on the role of cysteine proteinase inhibitors in treatment of cysticercosis.

Characterization of excretory/secretory endopeptidase and metallo-aminopeptidases from Taenia crassiceps metacestodes.

Cysticercosis is caused by Taenia spp. metacestodes, which must survive in the host tissues to complete their life cycle. Their survival depends on their control of host immune responses. Because many parasites use proteases to modulate host responses, we examined culture media from Taenia crassiceps metacestodes for protease activity using peptide substrates. We identified prominent aminopeptidase activity at neutral pH, which was inhibited by chelating agents and partially inhibited by the aminopeptidase inhibitor, bestatin. Endopeptidase substrates were optimally cleaved at slightly acidic pH and endopeptidase activity was inhibited by cysteine protease inhibitors. Gel filtration FPLC and subsequent visualization by silver staining revealed a metallo-aminopeptidase of molecular weight 21 kDa and cysteine proteases of Mr 70 and 64 kDA. Recombinant IL-2 was digested when incubated with parasite culture supernatants, but not with control media. IL-2 degradation was completely inhibited by 1,10 phenanthroline and partially inhibited by bestatin, suggesting that a metallo-aminopeptidase was responsible. Incubation of human IgG with culture supernatants resulted in complete degradation of IgG, which was blocked by cysteine protease inhibitors. These observations demonstrate that Taenia spp. metacestodes secrete a number of proteolytic enzymes, which may target molecules from the host immune system and assist in evasion of the host immune response.

Dynamics of the cytokine messenger RNA expression pattern in the liver of baboons infected with Schistosoma mansoni.

Periovular granulomas are the major lesions in baboons infected with Schistosoma mansoni. Temporal Northern blot analysis of cytokine messenger RNA (mRNA) expression in granulomatous baboon livers demonstrated tissue-specific expression. Interleukin 1 beta (IL-1beta, IL-6, tumor necrosis factor alpha, and migration inhibitory factor (MIF) mRNAs were expressed strongly at week 6 of infection and decayed thereafter, whereas interferon gamma (IFN-gamma), IL-2, IL-10, and IL-12 mRNAs were first expressed at week 12, with IFN-gamma and IL-12 mRNA expression persisting until week 17. IL-4 and IL-5 mRNAs first appeared at week 12, with IL-4 persisting unchanged and IL-5 increasing by week 17. Thus, egg deposition induced strong hepatic expression of proinflammatory and downregulatory cytokines. The cooccurrence of IL-2, IFN-gamma, IL-4, and IL-5 mRNAs at week 12 confirms that baboons, like humans, show a mixed type 1-type 2 cytokine response. When granulomas had become smaller at 17 wk, IFN-gamma, IL-4, and IL-5 were the only cytokine mRNAs that were expressed strongly, implicating them in granuloma modulation. The early expression of MIF mRNA and MIF's role as the main counterregulator of glucocorticoid immunosuppression ties in with our earlier demonstrations of circulating adrenal steroids changing with the progression of schistosomiasis in baboons and of proinflammatory cytokine mRNA expression in the hypothalamic-pituitary-adrenal axis tissues of infected baboons. Together, these data imply neuroendocrinological influences on disease progression in schistosomiasis.

Expression of mRNA for interleukin-1beta, interleukin-6, tumor necrosis factor-alpha and macrophage migration inhibitory factor in HPA-axis tissues in Schistosoma mansoni-infected baboons (Papio cynocephalus).

Cytokines may regulate the function of the hypothalamic-pituitary-adrenal axis during schistosomiasis. This possibility was investigated in baboons experimentally infected with Schistosoma mansoni. Serum levels of corticotrophin-releasing hormone, adrenocorticotrophin, cortisol and dehydroepiandrosterone were confirmed to be decreased in infected baboons as previously shown. To explore if this effect is associated with specific expression of cytokines with endocrine activity, and are also associated with the pathology of the disease, Northern blots for interleukin-1beta, interleukin-6, tumor necrosis factor-alpha and macrophage migration inhibitory factor in hypothalamic-pituitary-adrenal axis tissues were performed. Infection induced interleukin-1beta gene expression in the hypothalamus, while interleukin-6 and migration inhibitory factor mRNAs were induced only in the pituitary and adrenal glands. Tumor necrosis factor-alpha gene expression was induced in the hypothalamus and the pituitary gland. Histopathological analysis of the hypothalamic-pituitary-adrenal axis tissues in infected and control baboons revealed no morphological differences between them. These results suggest that specific cytokines expressed in hypothalamic-pituitary-adrenal axis tissues could regulate hormone secretion during schistosomiasis.

A novel cathepsin B active site motif is shared by helminth bloodfeeders.

This study compared specific protein sequence motifs present within cathepsin B-like cysteine proteases from a number of helminth parasites. We have focused our efforts on cathepsin B-like proteases of Haemonchus contortus, Caenorhabditis elegans, Schistosoma mansoni, Schistosoma japonicum, Ostertagia ostertagi, and Ancylostoma caninum. The goal of this work is to correlate specific features, or proposed roles, of the cathepsin B-like proteases with primary sequence motifs discovered within the proteins. We report here a general motif for the identification of cathepsin B enzymes, and more significantly, a motif within this pattern that is found, with one exception, only in cathepsin B-like proteases of helminth bloodfeeders. We suggest that the "hemoglobinase" motif arose evolutionarily in a minimum of three independent events as a specialized response to increase the efficiency of hemoglobin degradation by these cathepsin B-like enzymes. This motif should be useful in identifying additional helminth hemoglobinases and may provide a specific target for drug design efforts.

Do interleukin-6 and macrophage-migration inhibitory factor play a role during sex-associated susceptibility in murine cysticercosis?

In murine Taenia crassiceps cysticercosis, females sustain larger intensities of infection than males. However, during chronic infection, this difference disappears and males show a feminization process. To further study the role of two cytokines, interleukin-6 (IL-6) and macrophage-migration inhibitory factor (MIF), known to be involved in immunoendocrinological processes during sex-associated susceptibility in cysticercosis, IL-6 and MIF gene knockout (KO) mice were infected, and the number of parasites and serum sex-steroid levels were measured. Results show that IL-6 and MIF KO mice of both genders infected with T. crassiceps cysticerci harbor similar numbers of parasites, with no change in sex-hormone levels. However, in wild-type strains, females have twice as many parasites as males. At the same time, there is a decrease of 80% in testosterone and dihydrotestosterone serum levels, and a 100-fold increase in the levels of estradiol in infected male mice. These results suggest a role for both IL-6 and MIF genes in sex-associated susceptibility in murine T. crassiceps cysticercosis.