Clofazimine Inhalation Suspension Demonstrates Promising Toxicokinetics in Canines for Treating Pulmonary Nontuberculous Mycobacteria Infection.

Pulmonary nontuberculous mycobacteria (NTM) infection is recognized as a major global health concern due to its rising prevalence worldwide. As an opportunistic pathogen with increasing antibiotics resistance, prolonged systemic dosing with multiple antibiotics remains the primary treatment paradigm. These prolonged treatments, administered predominantly by oral or parenteral routes, often lead to systemic toxicity. A novel inhaled formulation of clofazimine may finally resolve issues of toxicity, thereby providing for improved NTM therapy. Clofazimine inhalation suspension was evaluated in canines to determine toxicity over 28 days of once-a-day dosing. The good laboratory practice (GLP) repeat dosing study evaluated low, mid, and high dosing (2.72 mg/kg and 2.95 mg/kg; 5.45 mg/kg and 5.91 mg/kg; and 10.87 mg/kg and 10.07 mg/kg, average male versus female dosing) of nebulized clofazimine over 30, 60, and 120 min using a jet nebulizer. Toxicokinetic analyses were performed on study days 29, 56, and 84. All three dose levels showed significant residual drug in lung tissue, demonstrating impressive lung loading and long lung residence. Drug concentrations in the lung remained well above the average NTM MIC at all time points, with measurable clofazimine levels at 28 and 56 days postdosing. In contrast, plasma levels of clofazimine were consistently measurable only through 14 days postdosing, with measurements below the limit of quantitation at 56 days postdosing. Clofazimine inhalation suspension may provide an effective therapy for the treatment of NTM infections through direct delivery of antibiotic to the lungs, overcoming the systemic toxicity seen in oral clofazimine treatment for NTM.

Effects of endocrine-disrupting chemicals on hypothalamic oxytocin and vasopressin systems.

Exposures to endocrine disrupting chemicals (EDCs) perturb hormonal systems. EDCs are particularly problematic when exposure happens in the fetus and infant due to the high sensitivity of developing organisms to hormone actions. Previous work has shown that prenatal polychlorinated biphenyl (PCB) exposure disrupts hypothalamic development, reproductive physiology, mate preference behavior, and social behaviors in a sexually dimorphic manner. Based on evidence that EDCs perturb social behaviors in rodents, we examined effects of PCBs on the neuropeptides oxytocin (OXT) and vasopressin (AVP) that are involved in regulating these behaviors. Rats were exposed prenatally (gestational days 16 and 18) to the weakly estrogenic PCB mixture Aroclor 1221 (0.5 or 1 mg/kg), to estradiol benzoate (EB, a positive control), or to the vehicle (3% dimethyl sulfoxide). In adult (~P90) brains, we counted immunolabeled oxytocin and vasopressin cell numbers in the paraventricular nucleus (PVN) and supraoptic nucleus (SON) of the hypothalamus. EDCs did not change absolute numbers of oxytocin or vasopressin cells in either region, although there were some modest shifts in the rostral-caudal distribution. Second, expression of genes for these nonapeptides (Oxt, Avp), their receptors (Oxtr, Avpr1a), and the estrogen receptor beta (Esr2), was determined by qPCR. In the PVN, there were dose-dependent effects of PCBs in males (Oxt, Oxtr), and effects of EB in females (Avp, Esr2). In the SON, Oxt, and Esr2 were affected by treatments in males. These changes to protein and gene expression caused by prenatal treatments suggest that transcriptional and posttranscriptional mechanisms play roles in mediating how EDCs reprogram hypothalamic development.

A simple method for preconditioning radial forearm flaps in the case of an insufficient ulnar vascular supply: a retrospective clinical analysis.

Due to its versatile applicability, many reconstructive surgeons use the radial forearm flap (RFF) as the first choice for soft tissue replacement. Donor site limitations of the flap arise with an insufficient blood supply along the ulnar artery. This study presents a simple and safe method for RFF preconditioning by recruitment of the deep palmar arch via the ulnar artery. Fourteen patients scheduled for RFF surgery between 2013 and 2018 showed an insufficient vascular supply according to the Allen test, which was confirmed by digital subtraction angiography (DSA). These 14 patients underwent temporary ligature of one or both radial arteries with elastic vessel loops under local anaesthesia and continuous pulse oximetry. A control DSA was performed about 24hours later in 10 of the 14 patients. Recruitment of the blood supply along the enlarged ulnar artery or reanimated collaterals was confirmed in all 10 patients. No local complications such as ischemia of the hand were seen. All flaps could be harvested regularly and were used for different reconstructive purposes. This simple technique may help to overcome vascular limitations of the RFF via the rapid, efficient, and reliable recruitment of the biological vascular reserve. Within the limits of a case series, this procedure appears practicable and safe.

The dichotomy between disease phenotype databases and the implications for understanding complex diseases involving the major histocompatibility complex.

Many genes related to innate and adaptive immunity reside within the major histocompatibility complex (MHC) and have been associated with a multitude of complex, immune-related disorders. Despite years of genetic study, this region has seen few causative determinants discovered for immune-mediated diseases. Reported associations have been curated in various databases including the Genetic Association Database, NCBI database of clinically relevant variants (ClinVar) and the Human Gene Mutation Database and together capture genetic associations and annotated pathogenic loci within the MHC and across the genome for a variety of complex, immune-mediated diseases. A review of these three distinct databases reveals disparate annotations between associated genes and pathogenic loci, alluding to the polygenic, multifactorial nature of immune-mediated diseases and the pleiotropic character of genes within the MHC. The technical limitations and inherent biases imposed by current approaches and technologies in studying the MHC create a strong case for the need to perform targeted deep sequencing of the MHC and other immunologically relevant loci in order to fully elucidate and study the causative elements of complex immune-mediated diseases.

[Management of suicidal orbital gunshot wounds to the temple]. / Management suizidaler orbitaler Schläfen-Schussverletzungen.

BACKGROUND: Orbital gunshot wounds are rarely found after suicide. A gunshot fired at point blank range into the temple has devastating effects on all intraorbital and neighboring structures. CASE REPORTS: This article reports on two cases of gunshot wounds to the lateral orbit in attempted suicides with different weapons from 2012 and 2013 and treated at the Ruhr University Eye Hospital in Bochum. In both cases treatment was carried out in cooperation with the department of oral and maxillofacial surgery, Ruhr University Hospital, Bochum. In the first case a 7.65 mm gun was used. The patient presented with a double penetration of both orbits with total destruction of both globes and a reconstruction was not possible. The second patient presented with multiple shots to the head from a small caliber gun (5.6 mm) where one bullet entered the right orbit behind the globe. The bullet could be localized using computed tomography (CT) and surgically removed with preservation of the globe and with a postoperative visual acuity of 20/60. CONCLUSION: The preservation of visual function after orbital gunshot wounds depends on both the projectile channel and the characteristics of the gun and bullet. Close collaboration in surgical management between ophthalmologists, maxillofacial surgeons and neurosurgeons in specialized centers is necessary because patients often present with multiple trauma and prompt interdisciplinary treatment is needed.

Prospective, blinded comparison of cytology and DNA-image cytometry of brush biopsies for early detection of oral malignancy.

OBJECTIVES: Adjunctive techniques like DNA image cytometry (DNA-ICM) have been attributed to enhance the diagnostic performance of oral brush biopsies. The aim of the study was an evaluation of brush biopsies, analysed according to morphological criteria and by DNA-ICM vs. histological findings in a blinded prospective trial. MATERIALS AND METHODS: Eighty eight brush biopsies of 70 patients were sampled. Only clinical suspicious but not evident malignant oral lesions were included. Clinical diagnosis was leukoplakia (n = 36), lichen planus (n = 18), verruciform erythroplakia (n = 12), erythroleukoplakia (n = 9), erosion (n = 7) and induration (n = 6). Evaluation was conducted via histology, cytology and DNA-ICM. RESULTS: Histological diagnosis revealed eight cases of squamous intraepithelial dysplasia (SIN 1 n = 6, SIN 2 n = 2), four cases of carcinoma-in situ and 25 cases of oral T1-cancer. Remaining cases were leukoplakia (n = 28), lichen planus (n = 15) and local inflammation (n = 8). Brush biopsy detected malignant lesions including SIN>1 with a sensitivity of 55% and a specificity of 100%. DNA-ICM had a sensitivity of 70% and a specificity of 100%. The combination of both methods showed a sensitivity of 76% and a specificity of 100%. The predominant reason for false negative results were sampling errors with insufficient cells (86% in brush biopsy and 100% in DNA-ICM). CONCLUSION: DNA-ICM has the potential to substantially improve the sensitivity of a pure morphological interpretation of oral brush biopsies. Method inherent sampling errors may be accountable for a lower sensitivity compared to conventional histological diagnosis. Therefore, DNA-ICM should not be used to rule out malignancy, when lesions are already clinically suspicious for oral cancer.

Bisphosphonate-related osteonecrosis of the maxilla and sinusitis maxillaris.

Bisphosphonates (BPs) are widely used as bone-stabilizers, but side effects of BP therapy include bisphosphonate-related osteonecrosis of the jaw (BRONJ), which is resistant to therapy. The aim of this study was to evaluate the outcome of maxillary BRONJ involving sinusitis maxillaris. 21 patients presenting with maxillary BRONJ, from 2005 to 2008, were included in the study. In 18 cases BP had been administered for carcinoma and in 3 cases for osteoporosis, with an average exposure time of 47.4 months. 12 patients spontaneously developed BRONJ. The 10 patients diagnosed with stage III BRONJ presented with concomitant sinusitis maxillaris. Despite treatment, there were six recurrences of BRONJ, four of them with additional sinusitis maxillaris. Whether BRONJ occurred spontaneously or after extraction there was no difference in the outcome. Patients with advanced maxillary BRONJ often suffer from sinusitis maxillaris, both of which are frequently resistant to therapy.

[Metabolit-induced bioluminescence for tumor prediction: detection of metabolites in tumors of the head and neck region]. / Metabolitinduzierte Biolumineszenz zur Tumorprädiktion: Detektion von Metaboliten in Tumoren des Kopf-Hals-Bereiches.

Solid tumors show an altered metabolism with respect to glycolysis in comparison to normal tissue. Recently, the determination of different glycolytic metabolites for tumor diagnosis and therapeutic decision-making became the focus of interest for various research groups. In particular an increased lactate concentration in tumor tissue appears to be a predictor of an adverse prognosis. Imaging of induced bioluminescence in rapidly frozen tumor biopsies is an established technique for the detection of selected substances. In this method the metabolites of interest are biochemically linked to luciferases. A microscopic photon counting system registers the light intensity and after calibration reflects the concentration distribution of metabolites. In contrast to other methods it is possible to detect different metabolites from one specific area of tissue. Preliminary results of a pilot study on oral cancer patients suggest a prognostic impact in terms of high lactate concentrations being associated with poor survival. This technique could increase the validity and significance of tumor grading and might be supportive decision guidance for tumor therapy in the future.

Historical development of alloplastic temporomandibular joint replacement after 1945 and state of the art.

The variety of temporomandibular joint (TMJ) prostheses and condylar reconstruction plates available is in contradiction to their rare application. This emphasizes that alloplastic TMJ reconstruction is still evolving. This article reviews the history of TMJ reconstruction. Medline as well as public and private libraries have been searched. Current systems are reviewed. Prosthetic devices can be differentiated into fossa-eminence prostheses, ramus prostheses and condylar reconstruction plates, and total joint prostheses. Fossa and total joint prostheses are recommended when the glenoid fossa is exposed due to excessive stress (degenerative disorders, arthritis, ankylosis, multiply operated pain patients). Singular replacement of the condyle is preferred as a temporary solution in ablative surgery. The use of prosthetic devices for long-term replacement should be restricted to selected cases, taking care to retain the disk, in order to prevent penetration into the middle cranial fossa. The term 'condylar reconstruction plate' reflects this more clearly than 'ramus prosthesis' which suggests permanent reconstruction. Long-term studies comparing the functional and aesthetic results of the various prostheses and condylar reconstruction plates are not available, which leaves the choice to personal experience.

Orbital complications due to an acute odontogenic focus in a child. A case report.

The full clinical manifestations of complications due to odontogenic foci are rarely seen in daily dental practice and can take a clinically foudroyant course of development in young people owing to anatomic conditions, as demonstrated in this clinical case in a 12-year-old girl. Endodontic treatment of the first right upper molar was started owing to increasing toothache and swelling of fossa canina and the periorbital region. During the course of treatment, the patient exhibited an acute increase in orbital inflammation, which required immediate surgical intervention with postsurgical intravenous antibiotic administration. This case should serve to emphasize the crucial requirement for intensive attention to orbital symptoms after dental procedures.

Progression of breast tumors is accompanied by a decrease in expression of the Rho guanine exchange factor Tiam1.

In this study, we investigated the expression level of Ras-homologous (Rho) GTPases and the Rho guanine exchange factor (GEF) T-cell lymphoma invasion and metastasis 1 (Tiam1) in breast tumor specimens (n=106) by immunohistochemistry. Rho and Rho-GEF expression scores were compared to clinically established diagnostic and prognostic parameters. We found that RhoA and RhoB scores slightly increased with tumor grade, whereas the Rac1 score remained unaffected. The most significant effects were observed for the Rac1-specific GEF Tiam1. Tiam1 expression scores significantly decreased with the increase in tumor grade, tumor spreading and proliferation. Furthermore, Tiam1 expression was inversely related to the plasminogen activator inhibitor (PAI-1) and estrogen receptor (ER) expression but not the progesterone receptor (PR) and urokinase plasminogen activator (uPA). A low Tiam1 expression was associated with p53 positivity without being related to HER2/neu status. The data show that Tiam1 expression decreases with the progression of breast carcinomas and is inversely associated with several established breast tumor markers. Therefore, we suggest that Tiam1 counteracts the progression of breast carcinomas and is suitable as a novel breast tumor marker.

Using robotic systems in order to determine biomechanical properties of soft tissues.

Biomechanical properties of soft tissue are important not only during computer simulation for medical training but also for systems where tissue deformation must be estimated in real-time, for example, Robot Assisted Surgery. The purpose of this paper is to describe some biomechanical tests consisting in the measurement of contact forces and deformations in tissue phantoms and porcine soft tissues (liver, brain, stomach and intestine). During the measurements two different procedures were applied. First, we have used a 5DOF micromanipulator instrumented with a spherical probe and a 6-axis force/torque ATI sensor. In the second procedure instead of the micromanipulator a Stäubli RX60 robot was used to apply the force over the samples. During this last test a high noise-signal relationship was detected and in order to improve the accuracy of the experiments some results were obtained using a Stäubli TX40 robot. Major accuracy in research in the field of soft tissue could be reached using standard procedures. Robotic systems allow precise movements to carry on biomechanical tests, and also permit a wide range of tasks to be implemented.

[Evaluation of force data with a force/torque sensor during FESS. A step towards robot-assisted surgery]. / Sensorbasierte Messung mechanischer Kräfte am Endoskop während FESS. Schritte zur robotergestützten Nasennebenhöhlenchirurgie.

BACKGROUND: To relieve the surgeon during functional endoscopic endonasal sinus surgery (FESS), the endoscope should be guided by autonomous robot assistance. The surgeon will thus have two hands free for suctioning and manipulation during FESS. PATIENTS/METHODS: With a force/torque sensor mounted on the endoscope, we measured forces in six degrees of freedom in five cadaver heads and in 20 actual endoscopic sinus procedures. On the cadaver heads we performed complete endoscopic endonasal dissection of all paranasal sinuses. All forces at the endoscope were monitored continuously. RESULTS: The mean forces occurring at the endoscope were 3.2 N. There were only slight differences between the in vivo and ex vivo data. We measured peak forces up to 25.2 N. In 95% of all cases, forces were lower than 7 N. CONCLUSION: Forces up to 7 N are sufficient for endoscopic guidance during FESS. Peak forces are distinctive for endoscopic guidance by humans and could be optimised by sensor-based intraoperative robot guidance. Higher forces are required for surgical endoscopy of the frontal and maxillary sinuses compared with the ethmoid sinuses.

[Performance of conventional oral brush biopsies]. / Wertigkeit der konventionellen oralen Bürstenbiopsie.

BACKGROUND: This study evaluated the performance of oral brush biopsies using standard morphological analysis and haematoxylin and eosin (HE) staining for detecting oral squamous cell carcinomas and their respective precursor lesions PATIENTS AND METHODS: Brush biopsies were obtained in 169 consecutive patients who underwent routine biopsies and histological examination for clinically suspicious oral lesions. Air-dried smears were processed by acetone fixation and HE staining. Cytological assessment used well-established criteria of atypia to classify the specimen as either "tumor negative" (no signs of atypia, no malignant cells) or "tumor positive" (malignant cells, any sign of atypia or doubtful cells). RESULTS: Despite a sufficient number of cells, a definite cytological diagnosis could not be established in six cases. According to the criteria specified above, these specimens were classified as "tumor positive." The cytological analysis identified 49 out of 62 oral malignancies (sensitivity 79%). Seven out of 107 benign lesions were classified as false positive (specificity 93%). The positive and negative predictive values were each 88%. CONCLUSION: Oral brush biopsies will identify only about 80% of oral malignancies when the smears are processed by routine HE stains and are analysed via standard morphological criteria. Thus, this technique should not be used for diagnostic proof or to exclude malignant cells in a lesion suspicious for cancer. However, oral brush biopsy provides a versatile back-up strategy to uncover the true nature of the disease if a lesion is clinically considered benign by mistake.

3D endoscopic approach for endonasal sinus surgery.

Functional endoscopic sinus surgery (FESS) is a minimal invasive approach adopted in case of chronic sinusitis (inflammation of the paranasal sinuses). The paranasal sinuses are hollow structures within the bones surrounding the nasal cavity. During FESS the surgeon moves the endoscope and other surgical instruments within the nasal cavity following specific paths to approach each one of the paranasal sinuses. The purpose of this study was to reconstruct these paths to access the paranasal sinuses using volumetric CT data. The results will be used for Finite Element modeling and simulations for Robot Assisted Endonasal Surgery.

Comparison between manual and semi-automatic segmentation of nasal cavity and paranasal sinuses from CT images.

Segmentation of medical image data is getting more and more important over the last years. The results are used for diagnosis, surgical planning or workspace definition of robot-assisted systems. The purpose of this paper is to find out whether manual or semi-automatic segmentation is adequate for ENT surgical workflow or whether fully automatic segmentation of paranasal sinuses and nasal cavity is needed. We present a comparison of manual and semi-automatic segmentation of paranasal sinuses and the nasal cavity. Manual segmentation is performed by custom software whereas semi-automatic segmentation is realized by a commercial product (Amira). For this study we used a CT dataset of the paranasal sinuses which consists of 98 transversal slices, each 1.0 mm thick, with a resolution of 512 x 512 pixels. For the analysis of both segmentation procedures we used volume, extension (width, length and height), segmentation time and 3D-reconstruction. The segmentation time was reduced from 960 minutes with manual to 215 minutes with semi-automatic segmentation. We found highest variances segmenting nasal cavity. For the paranasal sinuses manual and semi-automatic volume differences are not significant. Dependent on the segmentation accuracy both approaches deliver useful results and could be used for e.g. robot-assisted systems. Nevertheless both procedures are not useful for everyday surgical workflow, because they take too much time. Fully automatic and reproducible segmentation algorithms are needed for segmentation of paranasal sinuses and nasal cavity.