Acupuncture as Complementary Treatment for Acute Tinnitus: A Randomized Controlled Pilot Study.

BACKGROUND: Up to now, tinnitus has been an almost non-treatable symptom affecting more than 18% of the population in industrialized countries. So far, there are only a few studies evaluating the effectiveness of acupuncture in tinnitus treatment, none of which include acute tinnitus (<3 months). The aim of this pilot study was to explore the feasibility of recruitment and adherence to acupuncture conducted according to the principles of traditional Chinese medicine in patients with acute idiopathic tinnitus and to assess effect sizes on subjective and objective outcomes within a randomized controlled design. PATIENTS AND METHODS: After randomization patients of the control group received usual care (n = 23), and patients of the intervention group (n = 25) received 4 additional acupuncture treatments in a 4- to 6-week period. Tinnitus severity was assessed by means of a visual analogue scale as well as standardized and validated tinnitus questionnaires (Tinnitus Functional Index and 12-item Mini Tinnitus Questionnaire) at baseline and 6 weeks after. These subjective parameters were completed by tone audiometry. Comparisons of the groups were carried out using the Wilcoxon-Mann-Whitney test. RESULTS: Both groups were comparable without significant differences in baseline values. All outcomes, except for the overall well-being, showed better improvements in the intervention group with clinically significant differences from baseline to end point. However, among the outcomes only the subjective change in tinnitus severity showed a significant group difference. No serious side effects were observed. CONCLUSION: The design of our pilot study was feasible in terms of recruitment, although patient adherence to treatment remained challenging. However, considering the small intergroup differences, procedures regarding the numbers of acupuncture sessions and the total period of the acupuncture treatment should be reconsidered. The results of this pilot study provide a good basis for future confirmatory trials.

Comparison of acupuncture on specific and non-specific points for the treatment of painful temporomandibular disorders: A randomised controlled trial.

BACKGROUND AND OBJECTIVE: The aim of this single-centre, two-arm, parallel-group, double-blinded, randomised controlled trial was to investigate the disputed specific effectiveness of acupuncture by comparing acupuncture on specific and non-specific points among patients with non-chronic, painful TMDs. METHODS: Following predefined eligibility criteria, 49 consecutive patients of both sexes were recruited to the study. All subjects were diagnosed with a non-chronic (Graded Chronic Pain Scale grade <3) painful TMD, as assessed using the Diagnostic Criteria for Temporomandibular Disorders (DC/TMD). Patients were randomly assigned to group A (acupuncture on specific points) or group B (acupuncture on non-specific points) after the initial examination (T0). Both acupuncture treatment sessions were conducted by a trained dentist once a week for four weeks. The examination was repeated five weeks (T5) after T0 by one calibrated examiner who was unaware of the study groups. Characteristic pain intensity (CPI) was evaluated as the main outcome criterion and compared between times and treatment groups by means of non-parametric tests (significance level set at P = .05). Secondary outcomes comprised the maximum corrected active mouth-opening without pain (MAO); patients' expectations regarding acupuncture treatment and pain development; depressivity; and oral health-related quality of life (OHRQoL). RESULTS: A total of 41 patients (38 female) successfully completed the study (mean age: 40.17 ± 16.61). The two groups did not differ significantly at any time in terms of age and CPI. However, CPI was significantly (P < .05) lower at T5 than at T0 for both groups (29.66 and 30.35% lower in group A and group B, respectively). An increase in MAO was observed at T5 for both groups but was significant for group B only (P = .016). All patients had positive expectations of acupuncture therapy, and the two groups did not differ significantly at T5 with regard to the extent to which their expectations had been fulfilled by the treatment (P = .717). Comparison of T0 and T5 showed a statistically significant reduction of depressivity for group A (P = .0205), but no significant change for group B (P = .329). At T5, OHRQoL had improved significantly for both groups (group A, P = .018; group B, P < .001) compared with at T0. CONCLUSIONS: Acupuncture on both specific and non-specific points reduces the non-dysfunctional pain of TMD patients. The effect of acupuncture on painful TMD cannot be attributed to the specific point selection.

Long-term add-on therapy (compassionate use) with oral artesunate in patients with metastatic breast cancer after participating in a phase I study (ARTIC M33/2).

BACKGROUND: The antimalarial artesunate (ART), a semisynthetic derivative of artemisinin from the Chinese herb artemisia annua has remarkable anticancer properties in vitro and in vivo. Its excellent safety profile known from short-term therapy in malaria was confirmed in an open phase I trial (ARTIC M33/2) for dose-finding as add-on therapy for four weeks. PURPOSE: Patients with metastatic breast cancer, who had not experienced any clinically relevant adverse events (AE) during participation in ARTIC M33/2, were offered to continue ART as compassionate use (CU). Regular monitoring was continued in order to ensure adequate individual safety and tolerability and to collect information about long-term treatment with ART. Clinically relevant AEs or second progression of disease during ART were reasons for discontinuation of the add-on therapy. STUDY DESIGN: Compassionate use was offered open-label to participants of ARTIC M33/2. METHODS: Patients continued to take 100, 150 or 200 mg oral ART daily as add-on therapy to their guideline-based oncological therapy. Clinical and laboratory monitoring included audiological and neurological examination, ECG, NTproBNP and reticulocyte determination. Cumulative treatment days and cumulative ART doses encompass both the phase I study as well as the continued add-on treatment period (CU). RESULTS: Following the 4 ±â€¯1 weeks of the phase I trial, thirteen patients continued the add-on therapy as CU, resulting in a total of 3825 treatment days. In individual patients up to 1115 cumulative treatment days (37 months) and cumulative ART doses up to 167.3 g were reached. A total of 25 AEs grade ≥ 2 at least possibly related to ART long-term add-on therapy were documented, two, six and 17 in dose groups 100, 150 and 200 mg/d ART respectively. Six of these AEs were classified as grade 3, two in patients taking 150 and four in patients on 200 mg/d, none of them being probably or certainly related to ART. CONCLUSIONS: In thirteen patients with metastatic breast cancer up to 200 mg/d long-term oral ART (2.3-4.1 mg/kg BW/d) in up to 1115 cumulative treatment days (37 months) did not result in any major safety concerns.

Are human ATP-binding cassette transporter C11 and earwax associated with the incidence of cholesteatoma?

Cholesteatoma is an ear disease based on a locally destructive noncancerous conglomerate of epidermis and keratin debris. Abnormal growth of stratified keratinized squamous epithelium in the temporal bone causes destruction of the outer and middle ear, potentially leading to hearing impairment, facial palsy, vertigo, lateral sinus thrombosis, and intracranial complications. Although cholesteatoma is effectively treated by surgical resection (mastoidectomy), the lack of effective and nonsurgical therapies potentially results in fatal consequences, establishing the need for a comprehensive investigation of cholesteatoma pathogenesis. Although its etiology is still being debated, interestingly, we found that the trend associated with the 538G allele frequency of the adenosine triphosphate-binding cassette transporter C11 (ABCC11) gene, the determinant of wet-type earwax, and ethnic groups was similar to that between the incidence of cholesteatoma and ethnic groups (countries). The incidences of cholesteatoma in Europe (Denmark, Finland, and Scotland) are higher than in East Asia (Japan), and the frequencies of the ABCC11 538G allele in African, American, and European (Finland and Scotland) populations are higher than those in East Asian populations (Japan). Additionally, a single-nucleotide polymorphism in the ABCC11 gene (rs17822931, 538G > A; Gly180Arg) is closely related to earwax morphotypes. While earwax is often beneficial to ear health, it is sometimes harmful in cases where it causes hearing impairment. Based on independent findings of associations between ABCC11 and the physiological environment of the auditory canal, we hypothesize a possible link between ABCC11, earwax, and the incidence of cholesteatoma.

Randomized study exploring the combination of radiotherapy with two types of acupuncture treatment (ROSETTA): study protocol for a randomized controlled trial.

BACKGROUND: Adverse effects such as fatigue, pain, erythema, nausea and vomiting are commonly known in patients undergoing irradiation (RT) alone or in combination with chemotherapy (RCHT). Patients suffering from these symptoms are limited in their daily life and their quality of life (QOL) is often reduced. As addressed in several trials, acupuncture can cause amelioration of these specific disorders. Especially for pain symptoms, several groups have shown efficacy of acupuncture. To what extent the difference between traditional acupuncture (verum acupuncture) and false acupuncture (sham acupuncture) is in reducing side effects and improvement of QOL is not clear. METHODS/DESIGN: ROSETTA is a prospective randomized phase II trial (version 1.0) to examine the efficacy of traditional acupuncture in patients with RT-related side effects. In the experimental (verum) arm (n = 37) an experienced acupuncture-trained person will treat dedicated acupuncture points. In the control (sham) arm (n = 37) sham acupuncture will be performed to provide a blinded comparison of results. DISCUSSION: This is the first randomized prospective trial to evaluate the effect of traditional acupuncture on RT-related side effects such as fatigue and QOL. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02674646 . Registered on 8 December 2015.

L-Shaped Septal Extension Spreader Graft for Improvement of Tip Symmetry in Unilateral Cleft Lip Nose Deformities.

INTRODUCTION: The unilateral cleft lip nose is characterized by numerous complex and interdependent deformities. Secondary rhinoplasty techniques aim to correct cleft lip nose deformities by using multiple maneuvers combining septum and nasal spine medialization and alar cartilage, as well as soft tissue mobilization and repositioning. Moreover, cartilage grafting is frequently used to restore adequate tip projection and nasal symmetry. We present a technique of cartilage grafting commonly used in noncleft rhinoplasties that we modified for cases of moderate cleft lip nose deformities. PATIENTS AND METHODS: We present a retrospective case study of 21 patients with moderate unilateral cleft lip nose deformities who underwent secondary septorhinoplasty with an L-shaped septal extension spreader graft combined with alar rim, alar batten graft, and soft tissue repositioning. Exclusion criteria were severe or complex septal deviation avoiding a stable fixation of the graft. Mean follow-up time was 28 months. Surgical outcomes were analyzed by anthropometric measurements of standardized preoperative and postoperative photographs. RESULTS: All parameters improved except for the nostril height. The height between the alar base and the dome defining dome symmetry, as well as the angles between the lower lateral cartilage and the alar base (α) defining the orientation of the alar rim, improved significantly. The mean ratios of cleft/noncleft side of the height between the alar base and the dome and α showed statistically significant improvements from 0.833 (preoperative) to 0.994 (postoperative) (P < 0.0001) and from 0.883 to 1.02 (P = 0.0038), respectively. CONCLUSIONS: The L-shaped septal extension spreader graft combined with alar batten graft and soft tissue repositioning is an option for secondary rhinoplasties in unilateral cleft lip nose deformities minimizing tip rigidity with significant improvement of the dome's height and its symmetry, as well as the alar side angle.

Prospective open uncontrolled phase I study to define a well-tolerated dose of oral artesunate as add-on therapy in patients with metastatic breast cancer (ARTIC M33/2).

PURPOSE: The antimalarial drug artesunate (ART) is a promising candidate for cancer treatment as it displays anticancer effects in various models. While in short-term treatment of malaria, an excellent safety profile has been found for ART, the potential long-term treatment of cancer patients demands a phase I dose-finding clinical trial determining the daily ART dose which would be well tolerated as add-on therapy. METHODS: Patients with metastatic breast cancer were to receive either 100 or 150 or 200 mg oral ART daily as add-on to their guideline-based oncological therapy for a study period of four weeks with frequent clinical and laboratory monitoring until 4-8 weeks thereafter. According to the statistical design, recruitment was scheduled in groups of three patients in order not to miss a more than 33% frequency of dose-limiting adverse events (DL-AE) prior to dose escalation. RESULTS: Twenty-three patients were recruited, and all planned dose levels were applied. During the actual trial period of 4 ± 1 weeks, three patients experienced six DL-AEs altogether (leucopenia, neutropenia, asthenia, anemia) possibly related to ART (not exceeding 33% in any dose level). CONCLUSIONS: Up to 200 mg/d (2.2-3.9 mg/kg/d) oral ART were safe and well tolerated; therefore, 200 mg/d are recommended for phase II/III trials. Safety monitoring should include reticulocytes, NTproBNP, as well as audiological and neurological exploration.

Three-dimensional endoscopic visualization in functional endoscopic sinus surgery.

Three-dimensional (3D) stereoscopic vision in sinus surgery has been achieved with the microscope so far. The introduction of two-dimensional (2D) endoscopes set a milestone in the visualization of the surgical field and paved the way to functional endoscopic sinus surgery (FESS), although the 2D endoscopes cannot provide a stereoscopic visualization. The latest technology of 3D endoscopes allows stereoscopic vision. We provide a clinical investigation of all commercially available 3D endoscopes in FESS to compare their clinical value and efficacy to routinely used conventional 2D HD endoscopes. In this prospective, randomized, controlled clinical study, 46 patients with polypoid chronic rhinosinusitis underwent FESS with one of the following three endoscopes: 2D 0° high definition (HD), 3D 0° standard definition (SD) and 3D 0° HD. Four surgeons qualitatively assessed endoscopes on stereoscopic depth perception (SDP) of the surgeon, sharpness and brightness of the image, as well as their comfort in use during surgery. Surgeons assessed the brightness of the control (2D HD) significantly better than 3D SD (p = 0.009) and brightness of 3D HD was rated significantly better than 3D SD (p = 0.038). Stereoscopic depth perception (SDP) of 3D SD was assessed highly significantly better than the control (2D HD) (p = 0.021), whereas 3D HD displayed best SDP (p = 0.0001). The comfort in use was rated significantly higher in the 3D HD group compared to the control group (p = 0.025). No significant differences in sharpness could be seen among all endoscopes. 3D HD endoscopy provides an improvement in SDP and brightness of the surgical field. It enhances the intraoperative visualization and is therefore an important and efficient development in endoscopic sinus surgery.

Correction of severe columella and tip retraction in silicone implanted Asian short noses.

BACKGROUND: Silicone Implants and other alloplastic materials are frequently used in rhinoplasty to augment Asian short noses. However, nasal deformities as a result of implant-related infections are increasing in incidence. The resulting tissue scarrings hinder the application of traditional techniques of lengthening short noses. The following paper presents a technique to correct severe postoperative retractions of the tip and columella caused by silicone implants. METHODS: We present a retrospective case study of two Asian patients with recurrent acute infections, secondary to silicone dorsum implants, leading to chronic inflammation of the tip and columella. The treatment consisted of implant removal and the immediate nasal reconstruction by combining uni- or bilateral gingivobuccal flaps along with L-shaped costal cartilage grafting. To evaluate the surgical results, various anthropometric measurements, particularly the nasal length (NL) and nasal tip projection (NTP) of pre- and postoperative profile photographs, were analyzed. RESULTS: Successful nasal lengthening and correction of columellar retraction were achieved. In case I, postoperative NTP and NL increased by 34.7% and 21.1%, respectively. In case II, NL and NTP increased by 23.8% and 10.6%, respectively. However, case II presented necrosis of the distal extremity of one gingivobuccal flap without rib graft resorption, which later healed by secondary intention. CONCLUSION: Pronounced columellar retraction in severe short noses can be successfully managed with a combination of gingivobuccal flaps along with L-shaped costal cartilage grafting. The use of autologous materials decreases the risk of long-term extrusion through the tip. The gingivobuccal flap provides vascularity to the exposed rib cartilage on the columella and prevents its resorption.

Investigation of ototoxicity of artesunate as add-on therapy in patients with metastatic or locally advanced breast cancer: new audiological results from a prospective, open, uncontrolled, monocentric phase I study.

PURPOSE: Artesunate (ART) has been used for a long time in the treatment of Plasmodium falciparum malaria and has been considered safe. The present phase I study aimed to determine the daily dose of ART that is well tolerated as add-on therapy in patients with breast cancer for 4 weeks of therapy. Ototoxicity could be a potential safety concern in settings different from malaria. Therefore, comprehensive audiological assessment was essential. METHODS: The ARTIC M33/2 study was a prospective, open, uncontrolled, monocentric phase I dose-escalation study to evaluate the safety and tolerability of ART in patients with advanced breast cancer. Patients received either 100, 150 or 200 mg oral ART daily for a test phase of 4 weeks as add-on therapy to their ongoing oncological treatment. For the investigation of the safety of ART for hearing, an audiological assessment was performed with each patient before the intake of ART and after 4 weeks of therapy. RESULTS: Twenty-three female patients were included in the study. During the test phase, four patients had adverse events (AEs) of the auditory system possibly related to the intake of ART. However, none of these AEs was classified as severe AE (SAE) and did not require treatment interruption. Four patients had AEs concerning the vestibular system (vertigo) during the test phase, one of which was classified as SAE. However, the SAE was fully reversible after discontinuation of ART. CONCLUSION: None of the audiological results after 4 weeks of therapy with ART showed any dose-limiting auditory toxicity. However, audiological monitoring in further clinical studies with prolonged use of oral ART in doses up to 200 mg daily is warranted. The ARTIC M33/2 study is registered at eudract.ema.europa.eu with the Number 2007-004432-23 and at clinicaltrials.gov with the Number NCT00764036.

Pericranial Flap for Inner Lining in Nasal Reconstruction.

INTRODUCTION: The general principle in nasal reconstruction is to reconstruct the 3 layers of skin, cartilage, and mucosa. Reconstructing the inner lining remains a challenge especially when adjacent tissues are not available after tumor resection. The galea and pericranial flaps (PFs) are widely used in anterior skull base reconstructive surgery.We evaluated the use of the PF for the inner nasal lining in an anatomical cadaver study and present its clinical application in patients with benign and malignant tumors of the nose and anterior skull base. METHODS: Four fresh cadavers were injected with red-colored silicone for determining the pattern of vascularization of supraorbital (SOA) and supratrochlear (STA) arteries of each PF. Four surgical cases (2 nasocranial meningiomas, 1 nasal melanoma, and 1 nasal squamous cell carcinoma) received PF for reconstruction of inner lining. RESULTS: The median distances between the superior orbital rim and the division of the deep and superficial branches of STA and SOA were 8 ± 3.3 mm and 8 ± 3.7 mm, respectively. The maximum measured distance was 11 mm. The SOA provided the longest axial vascularization (70.7 ± 13. 9 mm) compared with STA (35 ± 10.4 mm). Median length of PF for subtotal nasal reconstruction including tip and columella were 70 ± 5 mm and 22.5 ± 3.5 mm, respectively.Three cases were successfully reconstructed with PF up to the distal border of the upper lateral cartilage. In 1 patient, distal necrosis of tip and columella occurred. CONCLUSIONS: The blood supply of the PF is mainly based on the SOA arteries. Thus, superficial dissection must end 15 mm above the orbital rim to ensure the survival of the flap. Pericranial flap can be applied for inner lining in combined nasocranial, septal, and nasal defects with extension down to the distal border of the upper lateral cartilage. Vascularization is reliable in flaps up to a length of 70 mm.

SAMHD1's protein expression profile in humans.

The deoxynucleoside triphosphate triphosphohydrolase and 3' → 5' exonuclease SAMHD1 restricts HIV-1 infection in noncycling hematopoietic cells in vitro, and SAMHD1 mutations are associated with AGS. Little is known about the in vivo expression and functional regulation of this cellular factor. Here, we first assessed the SAMHD1 protein expression profile on a microarray of 25 human tissues from >210 donors and in purified primary cell populations. In vivo, SAMHD1 was expressed in the majority of nucleated cells of hematopoietic origin, including tissue-resident macrophages, DCs, pDCs, all developmental stages of thymic T cells, monocytes, NK cells, as well as at lower levels in B cells. Of note, SAMHD1 was abundantly expressed in HIV target cells residing in the anogenital mucosa, providing a basis for its evaluation as a cellular factor that may impact the efficiency of HIV transmission. Next, we examined the effect of the activation status and proinflammatory cytokine treatment of cells on expression and phosphorylation of SAMHD1. Activated, HIV-susceptible CD4(+) T cells carried pSAMHD1(T592), whereas resting CD4(+) T cells and macrophages expressed the unphosphorylated protein with HIV-restrictive activity. Surprisingly, stimulation of these primary cells with IFN-α, IFN-γ, IL-4, IL-6, IL-12, IL-18, IL-27, or TNF-α affected neither SAMHD1 expression levels nor threonine 592 phosphorylation. Only IL-1ß moderately down-regulated SAMHD1 in activated CD4(+) T cells. Taken together, this study establishes the first cross-sectional protein expression profile of SAMHD1 in human tissues and provides insight into its cell cycle-dependent phosphorylation and unresponsiveness to multiple proinflammatory cytokines.

Measurable impact of acupuncture on mucosal swelling of inferior turbinates: a prospective, randomized, controlled study.

CONCLUSIONS: Sham acupuncture turned out to be more effective than expected. The effect of acupuncture cannot be assessed by optical rhinometry (ORM). OBJECTIVES: In most cases nasal congestion is caused by hypertrophy of the inferior turbinate as a result of allergic and chronic rhinitis. Topical decongestants cause severe side effects. As a consequence, there is an increasing demand for alternative treatment options such as traditional Chinese medicine (TCM). METHODS: A total of 25 patients with nasal congestion due to hypertrophic inferior turbinate were recruited. The mucosal swelling status of the inferior turbinate was assessed by continuous ORM for 20 min. Patients were asked to score the severity of their nasal congestion on a visual analogue scale (VAS) before and 10 and 20 min after acupuncture. Specific verum acupuncture points related to nasal congestion were tested against non-specific control sham acupuncture points. RESULTS: Sham acupuncture improved VAS scores, whereas ORM measured an increase in nasal swelling. The ORM revealed a quicker onset of the effect of verum acupuncture on the nasal blood flow. Also, verum acupuncture reaches its maximum effect in a shorter time period, so that the net reaction time was much shorter. However, ORM could not prove a decongestant effect of verum acupuncture on inferior turbinate.

Spontaneous lytic replication and epitheliotropism define an Epstein-Barr virus strain found in carcinomas.

The Epstein-Barr virus (EBV) is found in a variety of tumors whose incidence greatly varies around the world. A poorly explored hypothesis is that particular EBV strains account for this phenomenon. We report that M81, a virus isolated from a Chinese patient with nasopharyngeal carcinoma (NPC), shows remarkable similarity to other NPC viruses but is divergent from all other known strains. M81 exhibited a reversed tropism relative to common strains with a reduced ability to infect B cells and a high propensity to infect epithelial cells, which is in agreement with its isolation from carcinomas. M81 spontaneously replicated in B cells in vitro and in vivo at unusually high levels, in line with the enhanced viral replication observed in NPC patients. Spontaneous replication and epitheliotropism could be partly ascribed to polymorphisms within viral proteins. We suggest considering M81 and its closely related isolates as an EBV subtype with enhanced pathogenic potential.

SAMHD1 restricts HIV-1 infection in resting CD4(+) T cells.

Unlike activated CD4(+) T cells, resting CD4(+) T cells are highly resistant to productive HIV-1 infection. Early after HIV-1 entry, a major block limits reverse transcription of incoming viral genomes. Here we show that the deoxynucleoside triphosphate triphosphohydrolase SAMHD1 prevents reverse transcription of HIV-1 RNA in resting CD4(+) T cells. SAMHD1 is abundantly expressed in resting CD4(+) T cells circulating in peripheral blood and residing in lymphoid organs. The early restriction to infection in unstimulated CD4(+) T cells is overcome by HIV-1 or HIV-2 virions into which viral Vpx is artificially or naturally packaged, respectively, or by addition of exogenous deoxynucleosides. Vpx-mediated proteasomal degradation of SAMHD1 and elevation of intracellular deoxynucleotide pools precede successful infection by Vpx-carrying HIV. Resting CD4(+) T cells from healthy donors following SAMHD1 silencing or from a patient with Aicardi-Goutières syndrome homozygous for a nonsense mutation in SAMHD1 were permissive for HIV-1 infection. Thus, SAMHD1 imposes an effective restriction to HIV-1 infection in the large pool of noncycling CD4(+) T cells in vivo. Bypassing SAMHD1 was insufficient for the release of viral progeny, implicating other barriers at later stages of HIV replication. Together, these findings may unveil new ways to interfere with the immune evasion and T cell immunopathology of pandemic HIV-1.

Identification of a human Th1-like IFNγ-secreting Treg subtype deriving from effector T cells.

Characteristics and function of effector T-cells with regulatory properties (induced Treg, "iTreg") in humans are ill defined. Here we report that a proportion of activated, initially CD4(+)CD25(-)CD127(+) effector T-cells from human peripheral blood can convert into T-cells with regulatory activity while concomitantly secreting IFNγ. Upon short-term culture in vitro these cells expressed a panel of common Treg markers, including FOXP3, CD25, GITR, HLA-DR and CTLA-4 in parallel with the Th1-specific transcription factor T-bet. Despite their own IFNγ secretion they effectively suppressed IFNγ secretion in effector T cells in parallel with inhibition of their proliferation. Highly purified IFNγ(+)iTreg shared many functional properties with nTreg: Their suppressive activity was antigen-independent, contact-mediated and cytokine-independent. Of note, in contrast to nTreg an inhibitor of TGF-ß1 signalling promoted the proliferation of IFNγ(+)iTreg, without abrogating their suppressive function. In addition in vivo in tonsils of patients with chronic tonsillitis an IFNγ-secreting subpopulation of the CD4(+)CD25(-)CD127(+)CD45RA(-) memory T helper cell population was detected, which exhibited regulatory properties as well. Our results support the existence of Th1-like adaptive Tregs in humans that express a robust regulatory phenotype, comparable to nTreg and at the same time share characteristics of Th1 cells. According to our in vitro data IFNγ(+)iTreg can emerge from activated effector T cells and downregulate Th1-mediated immune responses, supporting the hypothesis of effector T cell plasticity as a means for proper initiation and self regulation of inflammatory processes. This report characterizes a new subpopulation of human adaptive regulatory T-cells that derive from effector Th-cells and concomitantly express Th1-specific T-bet and IFNγ with Foxp3.

Factors determining sensitivity and resistance of tumor cells to arsenic trioxide.

Previously, arsenic trioxide showed impressive regression rates of acute promyelocytic leukemia. Here, we investigated molecular determinants of sensitivity and resistance of cell lines of different tumor types towards arsenic trioxide. Arsenic trioxide was the most cytotoxic compound among 8 arsenicals investigated in the NCI cell line panel. We correlated transcriptome-wide microarray-based mRNA expression to the IC(50) values for arsenic trioxide by bioinformatic approaches (COMPARE and hierarchical cluster analyses, Ingenuity signaling pathway analysis). Among the identified pathways were signaling routes for p53, integrin-linked kinase, and actin cytoskeleton. Genes from these pathways significantly predicted cellular response to arsenic trioxide. Then, we analyzed whether classical drug resistance factors may also play a role for arsenic trioxide. Cell lines transfected with cDNAs for catalase, thioredoxin, or the anti-apoptotic bcl-2 gene were more resistant to arsenic trioxide than mock vector transfected cells. Multidrug-resistant cells overexpressing the MDR1, MRP1 or BCRP genes were not cross-resistant to arsenic trioxide. Our approach revealed that response of tumor cells towards arsenic trioxide is multi-factorial.

Pharmacogenomic determination of genes associated with sensitivity or resistance of tumor cells to curcumin and curcumin derivatives.

Curcuma longa L. has long been used as a medicinal plant in traditional Chinese medicine against abdominal disorders. Its active constituent curcumin has anti-inflammatory, chemopreventive and cytotoxic properties. In the present investigation, we have analyzed the cytotoxic activity of curcumin and four derivatives. Among these compounds, ethoxycurcumintrithiadiazolaminomethylcarbonate was the most cytotoxic one. The curcumin-type compounds were not cross-resistant to standard anticancer drugs and were not involved in ATP-binding cassette transporter-mediated multidrug resistance. A combined approach of messenger RNA-based microarray profiling, COMPARE analyses and signaling pathway analyses identified genes as determinants of sensitivity and resistance to curcumin and specific signaling routes involved in cellular response to curcumin. These genes may be useful as biomarkers to develop individualized treatment options in the future. From a nutritional point of view, it is a thriving perspective to further investigate whether C. longa may be used as a spice to improve cancer therapy.

Phytomedicine in otorhinolaryngology and pulmonology: clinical trials with herbal remedies.

Phytomedicine has become an important alternative treatment option for patients in the Western world, as they seek to be treated in a holistic and natural way after an unsatisfactory response to conventional drugs. Ever since herbal remedies have been introduced in the Western world, clinicians have raised concerns over their efficacy and possible side-effects. A PubMed (Medline) search was performed covering the last five years (01/07-04/12) and including 55 prospective clinical randomized control trials in the medical specialities Otorhinolaryngology and Pulmonology. In this review, we present evidence-based clinical data with herbal remedies and try to enlighten the question of efficacy and reliability of phytomedicine.