Targeted hypoglossal nerve stimulation for the treatment of obstructive sleep apnea: Six-month results.

OBJECTIVES/HYPOTHESIS: This feasibility study was designed to show the preliminary safety and efficacy of targeted hypoglossal neurostimulation (THN), and to identify baseline predictors of successful therapy. STUDY DESIGN: Open-label, prospective, multicenter, single-arm cohort study, conducted at seven centers in the U.S.A. and Europe. METHODS: Forty-six participants with moderate to severe obstructive sleep apnea (OSA), failing or intolerant of continuous positive airway pressure, were implanted. Primary (Apnea-Hypopnea Index [AHI], Oxygen Desaturation Index [ODI]) and secondary (Arousal Index, Epworth Sleepiness Scale Index, Sleep Apnea Quality of Life Index) outcomes were measured at baseline and compared at 6 months. Data were analyzed to identify participant characteristics that would predict success with therapy. RESULTS: Sixty-seven adverse events (AEs) were observed among 36 participants; most of the AEs were related to the implant procedure and resolved without sequelae; one device replacement was necessary. Forty-three participants showed significant (P < .01) decreases in both AHI and ODI at 6 months; 35% (15 of 43) met criteria for AHI responders and 40% (17 of 43) for ODI responders. Significant improvement was observed in all the secondary endpoints. Predictors-of-success selection criteria were identified as baseline AHI < 65/hr, baseline apnea index ≤ 30, baseline body mass index < 35, and <15 events/hr of SpO2 decrease > 10%. Seven participants met these criteria; 86% (6 of 7) were AHI responders and 86% (6 of 7) were ODI responders, indicating that THN therapy can be efficacious in a carefully selected population of OSA patients. CONCLUSIONS: This feasibility study suggests that THN therapy is likely to be safe and effective in selected patients. LEVEL OF EVIDENCE: 2b Laryngoscope, 126:2618-2623, 2016.

Epstein-Barr virus colonization of tonsillar and peripheral blood B-cell subsets in primary infection and persistence.

Epstein-Barr virus (EBV) persists in the immune host by preferentially colonizing the isotype-switched (IgD(-)CD27(+)) memory B-cell pool. In one scenario, this is achieved through virus infection of naive (IgD(+)CD27(-)) B cells and their differentiation into memory via germinal center (GC) transit; in another, EBV avoids GC transit and infects memory B cells directly. We report 2 findings consistent with this latter view. First, we examined circulating non-isotype-switched (IgD(+)CD27(+)) memory cells, a population that much evidence suggests is GC-independent in origin. Whereas isotype-switched memory had the highest viral loads by quantitative polymerase chain reaction, EBV was detectable in the nonswitched memory pool both in infectious mononucleosis (IM) patients undergoing primary infection and in most long-term virus carriers. Second, we examined colonization by EBV of B-cell subsets sorted from a unique collection of IM tonsillar cell suspensions. Here viral loads were concentrated in B cells with the CD38 marker of GC origin but lacking other GC markers CD10 and CD77. These findings, supported by histologic evidence, suggest that EBV infection in IM tonsils involves extrafollicular B cells expressing CD38 as an activation antigen and not as a marker of ectopic GC activity.

Differential surface expression and possible function of 9-O- and 7-O-acetylated GD3 (CD60 b and c) during activation and apoptosis of human tonsillar B and T lymphocytes.

The disialoganglioside GD3 (CD60 a) and its O-acetylated variants have previously been described as surface molecules of human T lymphocytes of the peripheral blood system. Here we report the expression of the 9-O-, and 7-O-acetylated disialoglycans of GD3 (CD60 b and CD60 c respectively) on human tonsillar lymphocytes. CD60 b and c are surface-expressed on activated germinal centre B cells and colocalize in raft-like structures on the cell surface together with the cytoplasmic tyrosine kinase Lyn and Syk. Addition of CD60 b and c mAb together with anti-IgM/IL-4 to in vitro cultivated tonsillar B cells resulted in a costimulatory effect. During spontaneous and staurosporine-induced apoptosis a distinct population of activated annexin V+/CD60 b+/CD60 c- B cells was observed. CD60 b and c are also found on cells of the extrafollicular T cell area. On tonsillar T cells, CD60 b mAb had a costimulatory effect together with PHA while CD60 c mAb alone was sufficient to induce proliferation. In further contrast to B cells, during apoptosis a distinct CD60 b+ T cell subpopulation was not observed. Together, surface-expressed CD60 b and c are differently expressed on tonsillar B and T cells and may be involved in the regulation of activation and apoptosis of lymphocytes in secondary lymphatic tissue.

Tonsillar homing of Epstein-Barr virus-specific CD8+ T cells and the virus-host balance.

Patients with infectious mononucleosis (IM) undergoing primary EBV infection show large expansions of EBV-specific CD8+ T cells in the blood. While latent infection of the B cell pool is quickly controlled, virus shedding from lytically infected cells in the oropharynx remains high for several months. We therefore studied how responses localize to the tonsil, a major target site for EBV, during primary infection and persistence. In acute IM, EBV-specific effectors were poorly represented among CD8+ T cells in tonsil compared with blood, coincident with absence of the CCR7 lymphoid homing marker on these highly activated cells. In patients who had recently recovered from IM, latent epitope reactivities were quicker than lytic reactivities both to acquire CCR7 and to accumulate in the tonsil, with some of these cells now expressing the CD103 integrin, which mediates retention at mucosal sites. By contrast, in long-term virus carriers in whom both lytic and latent infections had been controlled, there was 2- to 5-fold enrichment of lytic epitope reactivities and 10- to 20-fold enrichment of latent epitope reactivities in tonsil compared with blood; up to 20% of tonsillar CD8+ T cells were EBV specific, and many now expressed CD103. We suggest that efficient control of EBV infection requires appropriate CD8+ T cell homing to oropharyngeal sites.

Estriol induced squamous metaplasia on the nasal mucosa in patients with hereditary hemorrhagic telangiectasia.

BACKGROUND: The aim of this study was to evaluate by light and electron microscopy the effect of topical estriol on the nasal mucosa in patients with hereditary hemorrhagic telangiectasia (HHT). METHODS: Twelve patients were instructed to apply twice daily 0.1% estriol as a nose ointment over a period of 12 months. Written consent was obtained from each patient, allowing biopsy specimens of the nasal mucosa to be taken prior to and 3, 6 and 12 months after estriol application. RESULTS: Metaplastic change of the nasal mucosa was observed 6 months after topical estriol application. The former ciliated columnar epithelium changed into a keratinizing squamous epithelium. The effect was reversible after discontinuation of estriol application. CONCLUSIONS: For the first time, we could outline the effect of topical estriol on the nasal mucosa. These histomorphological findings, and the fact that estriol is a low-potency metabolite of estradiol, make estriol a valuable agent in the treatment of HHT patients.

Integration of apoptosis and telomere erosion in virus-specific CD8+ T cells from blood and tonsils during primary infection.

Human-virus-specific CD8+ T cells that are found during primary infection have been studied almost exclusively in the peripheral blood, and it is unclear whether these cells are regulated in the same way as those in secondary lymphoid tissue. We investigated, therefore, the control of apoptosis and telomere erosion of Epstein-Barr virus (EBV)-specific CD8+ T cells found in the blood and tonsils of the same patients during acute infectious mononucleosis (AIM). Although the clonal composition of CD8+ T cells as determined by heteroduplex analysis was similar in both compartments, there was greater CD28 expression in the tonsil population, indicating that they were less differentiated. EBV-specific CD8+ T cells in both tissue types were extremely susceptible to apoptosis related to low Bcl-2 expression and were dependent on exogenous cytokines such as interleukin-2 (IL-2), IL-15, and interferon-alpha/beta (IFN-alpha/beta) for survival. In both compartments, however, these cells maintained their telomere lengths through telomerase induction. Thus, apoptosis-prone EBV-specific CD8+ T cells found during acute infection have to be rescued from death to persist as a memory population. However, signals that induce telomerase ensure that the rescued cells retain their replicative capacity. Significantly, these processes operate identically in cells found in blood and secondary lymphoid tissue.

Plasma surgery and topical estriol: effects on the nasal mucosa and long-term results in patients with Osler's disease.

OBJECTIVE: The study goal was to report on the long-term results and effect of argon plasma coagulation (APC) surgery and topical estriol in patients with Osler's disease who had recurrent epistaxis. Study design In a prospective clinical study, 52 patients underwent APC and estriol application and were followed for 18 months regarding their bleeding frequency and intensity. Patient blood samples were obtained to determine the serum estriol levels. Scanning electron microscopy of the nasal mucosa enabled a better understanding concerning the effect of estriol on the nasal mucosa. RESULTS: Eighteen months after treatment, 96% of the patients stated a significantly reduced bleeding frequency and intensity. Under estriol influence, former berry-like telangiectasia of the nasal mucosa was flatter. The serum estriol levels did not increase significantly in any of the patients. No side effects from the use of topical estriol were observed. CONCLUSION: The combined treatment approach with APC and topical estriol significantly reduces epistaxis in Osler's disease. SIGNIFICANCE: APC and topical estriol have proved to be a promising alternative in the treatment of Osler's disease.

Argon plasma coagulation (APC) surgery in otorhinolaryngology.

The Argon Plasma Coagulation (APC) technique has been used with success in open surgery and endoscopy for hemostasis and thermal devitalisation of pathological tissue. We developed techniques and instruments for the use of this technique in Otorhinolaryngology, because of its excellent hemostatic effects and devitalising properties. APC surgery is based on a monopolar high-frequency (HF) electrical current transmitted through ionized argon gas from the tip of an applicator to the tissue surface in a contact-free mode. Indications for the use of this technique include hyperplasia of the inferior turbinate in nasal obstruction, recurrent epistaxis in hereditary hemorrhagic telangiectasia, leukoplakia of the mucosa, recurrent respiratory papillomatosis (RRP) of the lower airway, in combination with flexible systems. A combined technique of blunt dissection and plasma coagulation has been designed for bloodless removal of the tonsils. This new technique offers a wide variety of advantages. The limited penetration depth makes APC surgery a safe procedure; damage to neighbouring tissue can be avoided. The APC technique is a useful and comparable inexpensive method to achieve devitalisation of tissues and easy to handle hemostasis.

Benign mixed tumor of the lacrimal gland. Clinical diagnosis and surgical management.

The accurate clinical diagnosis of benign mixed tumors of the lacrimal gland is important for the proper therapeutic management. We present an adult case with a benign mixed tumor of the orbital lobe of the lacrimal gland, 8 years after periorbital blunt injury. The tumor lesion was diagnosed later in the persisting traumatic tumefaction region. Clinical examination, ultrasonography and MRI revealed a soft-tissue mass with high density and peripheral enhancement over the superior lateral portion of the right eye with expansion to and invasion of the orbital roof and lateral wall. Lateral orbitotomy was performed to resect the tumor. Histopathology disclosed a pleomorphic adenoma of the orbital lobe of the lacrimal gland. Pleomorphic adenomas of the lacrimal gland are seen rarely. The awareness of the clinical and diagnostic features of benign mixed tumors of the orbital lobe should help to avoid complications arising from an incisional biopsy or incomplete tumor resection.

Topical estrogens combined with argon plasma coagulation in the management of epistaxis in hereditary hemorrhagic telangiectasia.

The aim of this study was to assess the value of topically applied estrogens in patients with hereditary hemorrhagic telangiectasia. Twenty-six patients with this disorder were treated with argon plasma coagulation and randomized into 2 groups: group A, which had postoperative application of estriol ointment (n = 14), and group B, which had postoperative application of dexpanthenol ointment (n = 12). Over a period of 12 months, the frequency and intensity of bleeding, the patient's satisfaction, and the success of the treatment were evaluated with a questionnaire. Before the operation, more than 90% of the patients in both groups complained of daily episodes of epistaxis. Twelve months after treatment, the frequency and intensity of bleeding had significantly decreased in group A as compared to group B. Of the patients in group A, 93% were satisfied with the treatment. Of the patients in group B, only 42% were satisfied with the treatment. In both groups, more than 90% of the patients were willing to undergo the same treatment again. The combined treatment approach with argon plasma coagulation and topical estriol enables us to significantly prolong the hemorrhage-free interval.

Administration of autologous fetal membranes: Effects on the coagulation in pregnant mini-pigs.

OBJECTIVE: A hallmark of the so-called amniotic fluid embolism is the induction of coagulation defects. Entry of meconium-free autologous amniotic fluid into the circulation, however, is innocuous. Little is known about the true causative agent or agents. The purpose of this study was to assess the effects of homogenized autologous fetal membranes (FM) on the coagulation system in the mini-pig model. DESIGN: Laboratory study. SETTING: University institute animal laboratory. SUBJECTS: Six near-term pregnant, Göttingen-bred mini-pigs. INTERVENTIONS: After induction of general anesthesia, FM were col-lected from all animals by cesarean section. Animals received 2 g FM (shredded and suspended in lactated Ringer's solution) via an ear vein. MEASUREMENTS: Blood samples were taken from a central vein before administration (baseline), immediately after administration, every 10 mins until 90 mins after administration, and every 20 mins until 150 mins after administration. The following parameters were measured: platelets, partial thromboplastin time, prothrombin time index, fibrinogen, factors II, V, VII, VIII, IX, X, XI, antithrombin III, and protein C. The values relative to baseline in the FM group were compared with a historical control group by rank order test. A p <.05 was considered significant. MAIN RESULTS: In the FM group (compared with the control group), platelets were lower; partial thromboplastin time was prolonged; fibrinogen was lower; prothrombin time index was lower (ie, prothrombin time was prolonged); protein C and antithrombin III were lower; and activity levels of factors V and VII were lower. The levels of factors II, VIII, IX, X, and XI showed a trend toward lower activity in the FM group, but the differences were not statistically significant. CONCLUSIONS: FM can activate coagulation in mini-pigs. The laboratory parameter changes seen are typical for disseminated intravascular coagulation. However, the full clinical picture of amniotic fluid embolism and disseminated intravascular coagulation could not be elicited despite the high dose of FM used.

Candidiasis diseminada en prematuros: estudio anatomopatológico; clínico y micológico de 4 casos / Diseminated candidiasis in prematures: anatomopathological; clinical and micological study of 4 cases

Se describen 4 casos de infección diseminada por Candida albicans, en prematuros de entre 26 y 33 semanas de gestación, y entre 760 y 2.580 g de peso al nacer, inclusive. Todos presentaron signos clínicos de insuficiencia respiratoria y de septicemia. La necropsia demostró en todos ellos signos anatomopatológicos de hipoxia intensa, y en 3 casos evidencias morfológicas que indican a la mucosa gastrointestinal como puerta de entrada y diseminación micótica. La distribución de los organos comprometidos y la reacción inflamatoria tisular es semejante a la descrita en adultos, con y sin granulocitopenia