Pharmacology, particle deposition and drug administration techniques of intranasal corticosteroids for treating allergic rhinitis.

This review presents an overview of the available literature regarding intranasal corticosteroids (INCs) for the treatment of allergic rhinitis (AR). Various treatment options exist for AR including INCs, antihistamines and leucotriene antagonists. INCs are considered to be the most effective therapy for moderate-to-severe AR, as they are effective against nasal and ocular symptoms and improve quality of life. Their safety has been widely observed. INCs are effective and safe for short-term use. Local adverse events are observed but generally well-tolerated. The occurrence of (serious) systemic adverse events is unlikely but cannot be ruled out. There is a lack of long-term safety data. INC may cause serious eye complications. The risk of INCs on the hypothalamic-pituitary-adrenal axis, on bone mineral density reduction or osteoporosis and on growth in children, should be considered during treatment. Pharmacological characteristics of INCs (e.g. the mode of action and pharmacokinetics) are well known and described. We sought to gain insight into whether specific properties affect the efficacy and safety of INCs, including nasal particle deposition, which the administration technique affects. However, advances are lacking regarding the improved understanding of the effect of particle deposition on efficacy and safety and the effect of the administration technique. This review emphasizes the gaps in knowledge regarding this subject. Advances in research and health care are necessary to improve care for patients with AR.

Risk Factors for Sustained Cholera Transmission, Juba County, South Sudan, 2014.

We conducted a case-control study to identify risk factors for the 2014 cholera outbreak in Juba County, South Sudan. Illness was associated with traveling or eating away from home; treating drinking water and receiving oral cholera vaccination were protective. Oral cholera vaccination should be used to complement cholera prevention efforts.

Free flap reconstruction for head and neck cancer can be safely performed in both young and elderly patients after careful patient selection.

Surgical treatment of head and neck cancer often results in complex defects requiring reconstruction with microvascular free tissue transfer. However, in elderly patients, curative treatment with radical surgery and free flap reconstruction is often withheld. The objective of this study is to assess the outcomes of free flap surgery in elderly patients, using a standard surgical complication classification system. A retrospective review was conducted of patients who underwent primary free flap reconstruction following major surgery for head and neck cancer between 1995 and 2010. Complications were assessed using the Clavien Dindo classification system, and grades III-V were classified as major complications. Comorbidity was classified according to the adult comorbidity evaluation index 27. A comparison was done between patients <70 and ≥70 years. Two hundred-two patients were included in this study. Multivariate analysis showed that only disease stage was a significant predictor of recipient site complications, and comorbidity was the only significant predictor of medical complications. Age was not a predictor of complications. There were no significant differences in disease specific or overall survival between young and elderly patients. Optimal patient selection for free flap surgery is essential. This requires thorough pre-operative assessment, including analysis of comorbidity in both young and elderly patients. Patients' biological age, and not chronological age, should be individually determined to assess feasibility of major surgery. Patients should not be denied surgery based on age alone.

Relation between age, comorbidity, and complications in patients undergoing major surgery for head and neck cancer.

BACKGROUND: Multiple factors have been identified as predictors of complication after head and neck surgery. However, little is known about the exact role of different comorbid conditions in the development of postoperative complications. This question is especially interesting in the elderly population. The aim of this study was to investigate the association between comorbidity and types of postoperative complications with special attention to age differences. METHODS: A retrospective analysis was performed of 1,201 major surgical interventions for head and neck malignancies in a tertiary referral center between 1995 and 2010. The Adult Comorbidity Evaluation 27 (ACE-27) index was used to analyze severity (mild, moderate, and severe comorbidity) and type (12 different organ systems) of comorbidity. The Clavien-Dindo index was used to evaluate grade and type of complications after treatment. RESULTS: In univariate analysis gender, comorbidity, stage, mandibulectomy, total laryngectomy, neck dissection, and length of surgery significantly predicted grade of complication. In a multivariate analysis, complication was predicted by age, stage, length of surgery, and various comorbidities. After specification of the complications, age was only a predictor of medical complications; tumor stage was a significant factor in surgical complications. Length of surgery was the only significant variable in all types of complications. CONCLUSIONS: Specific comorbidities are associated with specific complications; however, age itself seems not to be a contraindication for major head and neck surgery. With careful preoperative assessment and risk analysis, physicians can better individualize treatment recommendations.

Cash transfers to enhance completion of TB screening among household contacts in rural Tanzania.

Tanzanian TB guidelines recommend facility-based TB screening for symptomatic household contacts (HHCs) or those aged <5 years, but cost remains a major barrier. In this study, we evaluate the use of unconditional cash transfers (UCTs) to facilitate completion of HHC TB screening.In this prospective interventional study, we enrolled index people diagnosed with TB (PWTB) within 8 weeks of TB treatment initiation from the TB clinic at Haydom Lutheran Hospital, Haydom, Tanzania, and surrounding TB dispensaries in rural Tanzania. The study provided at the time of enrollment an UCT up to 40,000 Tanzanian shillings (USD16.91) directly to heads of households with PWTB, covered medical costs from screening activities and provided three bi-weekly phone reminders to facilitate HHC TB screening. The primary outcome was TB screening completion for all HHCs compared to the same period of the preceding year.We enrolled 120 index PWTB, including 398 HHCs between July and December 2022. The median age for index PWTB was 35 years; 38% were females. Sixty-five (54%) households completed screening for all HHCs, compared to 7% during the same period of the preceding year.These interventions may considerably improve completion of HHC TB screening in rural Tanzania..

Isoniazid urine spectrophotometry for prediction of serum pharmacokinetics in adults with TB.

BACKGROUND: Isoniazid (INH) is an important drug in many TB regimens, and unfavorable treatment outcomes can be caused by suboptimal pharmacokinetics. Dose adjustment can be personalized by measuring peak serum concentrations; however, the process involves cold-chain preservation and laboratory techniques such as liquid chromatography (LC)/mass spectrometry (MS), which are unavailable in many high-burden settings. Urine spectrophotometry could provide a low-cost alternative with simple sampling and quantification methods. METHODS: We enrolled 56 adult patients on treatment for active TB. Serum was collected at 0, 1, 2, 4, 6, and 8 h for measurement of INH concentrations using validated LC-MS/MS methods. Urine was collected at 0-4, 4-8, and 8-24 h intervals, with INH concentrations measured using colorimetric methods. RESULTS: The median peak serum concentration and total serum exposure over 24 h were 4.8 mg/L and 16.4 mg*hour/L, respectively. Area under the receiver operator characteristic curves for urine values predicting a subtherapeutic serum concentration (peak <3.0 mg/L) were as follows: 0-4 h interval (AUC 0.85, 95% CI 0.7-0.96), 0-8 h interval (AUC 0.85, 95% CI 0.71-0.96), and 0-24 h urine collection interval (AUC 0.84, 95% CI 0.68-0.96). CONCLUSION: Urine spectrophotometry may improve feasibility of personalized dosing in high TB burden regions but requires further study of target attainment following dose adjustment based on a urine threshold.

CONTEXTE: L'isoniazide (INH) est un médicament important dans de nombreux schémas thérapeutiques contre la TB, et des résultats thérapeutiques défavorables peuvent être dus à une pharmacocinétique sous-optimale. L'ajustement de la dose peut être personnalisé en mesurant les concentrations sériques maximales ; cependant, le processus implique la conservation de la chaîne du froid et des techniques de laboratoire telles que la chromatographie liquide (LC)/spectrométrie de masse (MS), qui ne sont pas disponibles dans de nombreuses régions à forte charge de morbidité. La spec-trophotométrie urinaire pourrait constituer une alternative peu coûteuse avec des méthodes d'échantillonnage et de quantification simples. MÉTHODES: Nous avons recruté 56 patients adultes sous traitement pour une TB active. Le sérum a été prélevé à 0, 1, 2, 4, 6 et 8 h pour mesurer les concentrations d'INH à l'aide de méthodes LC-MS/MS validées. L'urine a été prélevée à des intervalles de 0­4, 4­8 et 8­24 h, et les concentrations d'INH ont été mesurées à l'aide de méthodes colorimétriques. RÉSULTATS: La concentration sérique maximale médiane et l'exposition sérique totale sur 24 h étaient respectivement de 4,8 mg/L et de 16,4 mg*heure/L. L'aire sous les courbes caractéristiques de l'opérateur récepteur a été mesurée à l'aide de méthodes color-imétriques. Les aires sous les courbes caractéristiques des récepteurs pour les valeurs urinaires prédisant une concentration sérique sous-thérapeutique (pic <3,0 mg/L) étaient les suivantes : intervalle 0­4 h (AUC 0,85 ; IC 95% 0,7­0,96), intervalle 0­8 h (AUC 0,85 ; IC 95% 0,71­0,96), et intervalle de collecte d'urine 0­24 h (AUC 0,84 ; IC 95% 0,68­0,96). CONCLUSION: La spectrophotométrie urinaire peut améliorer la faisabilité d'un dosage personnalisé dans les régions à forte charge de TB, mais nécessite une étude plus approfondie de l'atteinte de la cible après l'ajustement de la dose sur la base d'un seuil urinaire.

Pulmonary and cardiovascular responses of rats to inhalation of a commercial antimicrobial spray containing titanium dioxide nanoparticles.

Our laboratory has previously demonstrated that application of an antimicrobial spray product containing titanium dioxide (TiO(2)) generates an aerosol of titanium dioxide in the breathing zone of the applicator. The present report describes the design of an automated spray system and the characterization of the aerosol delivered to a whole body inhalation chamber. This system produced stable airborne levels of TiO(2) particles with a median count size diameter of 110 nm. Rats were exposed to 314 mg/m(3) min (low dose), 826 mg/m(3) min (medium dose), and 3638 mg/m(3) min (high dose) of TiO(2) under the following conditions: 2.62 mg/m(3) for 2 h, 1.72 mg/m(3) 4 h/day for 2 days, and 3.79 mg/m(3) 4 h/day for 4 days, respectively. Pulmonary (breathing rate, specific airway resistance, inflammation, and lung damage) and cardiovascular (the responsiveness of the tail artery to constrictor or dilatory agents) endpoints were monitored 24 h post-exposure. No significant pulmonary or cardiovascular changes were noted at low and middle dose levels. However, the high dose caused significant increases in breathing rate, pulmonary inflammation, and lung cell injury. Results suggest that occasional consumer use of this antimicrobial spray product should not be a hazard. However, extended exposure of workers routinely applying this product to surfaces should be avoided. During application, care should be taken to minimize exposure by working under well ventilated conditions and by employing respiratory protection as needed. It would be prudent to avoid exposure to children or those with pre-existing respiratory disease.

National approaches to TB care in adolescents.

BACKGROUND: Adolescents bear a large burden of TB but high-prevalence countries differ significantly in their approach to address the specific needs of adolescent patients. We explore the national approaches to TB care in adolescents and compare them to the recommendations of the WHO.METHODS: We conducted a scoping review to describe the country-level guidelines to TB care in adolescents in high-burden countries. These guidelines were obtained through open sources. Information on TB care in adolescents were extracted from guidelines and compared to WHO recommendations.RESULTS: We found a lack of consensus in defining adolescents and that many national guidelines do not address the special healthcare needs of adolescents nor align with the WHO recommendations. Recently updated country guidelines are more likely to recommend short-course regimens for TB preventive treatment and countries with a higher level of income were more likely to follow WHO guidance for microbiological confirmation of TB disease in adolescents.CONCLUSION: A clear understanding of the burden of TB in adolescents that is reflected in disaggregated data reported at the country level is imperative in order to address the specific challenges to care in this high-risk group.

Impact of Cell Culture and Copper Dose on Gene Expression in Bovine Liver.

The objectives of these experiments were to investigate (1) the relative abundance of transcripts for Cu-responsive genes in whole bovine liver vs. cultured hepatocytes and (2) the influence of Cu dose on the relative abundance of transcripts for Cu-responsive genes in cultured bovine hepatocytes. Experiment 1: Liver samples were obtained immediately post-mortem from one healthy Angus steer. Half of the tissue samples were placed in RNAlater solution; the remaining half was used to isolate hepatocytes. Experiment 2: A subset of cultured hepatocytes was incubated in media containing: 0 mg/L, 0.10 mg/L, 1.0 mg/L, 10.0 mg/L, and 100 mg/L Cu for 1 h. Transcripts analyzed were aldehyde dehydrogenase (ALDH2), apolipoprotein A-1 (APOA1), antioxidant 1 (ATOX1), ATPase copper transporting alpha (ATP7A), ATPase copper transporting beta (ATP7B), betaine homocysteine methyltransferase (BHMT), flavin reductase (BLVRB), carbonic anhydrase II (CA2), copper chaperone for superoxide dismutase (CCS), cytochrome c oxidase copper chaperone (COX17), Cu transporter 1 (CTR1), glutamate dehydrogenase (GLUD1), glutathione synthetase (GSS), protein disulfide isomerase A3 (PDIA3), and superoxide dismutase (Cu-Zn) (SOD1). Β-Actin (ACTB) was selected as the endogenous control in both experiments. Experiment 1: Whole liver had greater (P < 0.01) relative abundance of mRNA for APOA1, ATOX1, ATP7A, ATP7B, COX17, CTR1, ALDH2, BHMT, BLVRB, CA2, GLUD1, and GSS when compared with cultured hepatocytes. Experiment 2: Copper dose impacted all identified transcripts. These results indicate that the relative abundance of Cu-responsive transcripts is different in whole vs. cultured hepatocytes and that the relative abundance of Cu-responsive genes is dependent on Cu dose in cultured hepatocytes.

Clinical standards for the dosing and management of TB drugs.

BACKGROUND: Optimal drug dosing is important to ensure adequate response to treatment, prevent development of drug resistance and reduce drug toxicity. The aim of these clinical standards is to provide guidance on 'best practice´ for dosing and management of TB drugs.METHODS: A panel of 57 global experts in the fields of microbiology, pharmacology and TB care were identified; 51 participated in a Delphi process. A 5-point Likert scale was used to score draft standards. The final document represents the broad consensus and was approved by all participants.RESULTS: Six clinical standards were defined: Standard 1, defining the most appropriate initial dose for TB treatment; Standard 2, identifying patients who may be at risk of sub-optimal drug exposure; Standard 3, identifying patients at risk of developing drug-related toxicity and how best to manage this risk; Standard 4, identifying patients who can benefit from therapeutic drug monitoring (TDM); Standard 5, highlighting education and counselling that should be provided to people initiating TB treatment; and Standard 6, providing essential education for healthcare professionals. In addition, consensus research priorities were identified.CONCLUSION: This is the first consensus-based Clinical Standards for the dosing and management of TB drugs to guide clinicians and programme managers in planning and implementation of locally appropriate measures for optimal person-centred treatment to improve patient care.

The Relation Between Tinnitus and a Neurovascular Conflict of the Cochleovestibular Nerve on Magnetic Resonance Imaging.

INTRODUCTION: Magnetic resonance (MR) imaging is often used in diagnostic evaluation of tinnitus patients. Incidental findings like a neurovascular conflict (NVC) in the cerebellopontine angle are often found; however, the diagnostic value of this finding remains unclear. The aim of this study is to investigate whether the type or degree of compression of the vestibulocochlear nerve is of diagnostic value in patients with a NVC. METHODS: A retrospective study was performed in 111 tinnitus patients with available MR imaging between 2013 and 2015. Clinical and audiometric variables were gathered and MR imaging was reevaluated by two neuroradiologists. NVCs were analyzed using a grading system based on previous research by Sirikci et al. RESULTS:: In total, 220 ears were available for assessment. In patients with unilateral tinnitus a loop compression and an indentation of the cochleovestibular nerve were more frequent than in patients with bilateral tinnitus. However, there was no significant difference in distribution of the type of compression between tinnitus and nontinnitus ears. Patient with unilateral tinnitus had a significantly higher degree of hearing loss in the symptomatic ear, compared with the asymptomatic ear and with the bilateral tinnitus group. Also, it was found that the degree of hearing loss did not differ between the various types of compression. CONCLUSION: This study did not find a diagnostic value of specific types of compression in patients with a NVC. Although the distribution of NVC classification was different in patients with unilateral and bilateral tinnitus, there was no definite relation between the type of NVC and the presence of ipsilateral tinnitus. Also, the degree of hearing loss was not related to specific types of NVC.

Expression of a protein tyrosine phosphatase in normal and v-src-transformed mouse 3T3 fibroblasts.

A rat cDNA encoding a 51-kD protein tyrosine phosphatase (PTP1) was cloned into a mammalian expression vector and transfected into normal and v-src-transformed mouse NIH 3T3 fibroblasts. In the stable subclones isolated, PTP1 expression at the mRNA level was elevated twofold to 25-fold. The highest constitutive level of phosphotyrosine-specific dephosphorylating activity observed without cytotoxic effects or significant clonal instability was approximately 10-fold over the endogenous activity. The expressed PTP1 was found to be associated with the particulate fraction of the fibroblasts. Subcellular fractionation and immunofluorescent microscopic examination of PTP1-overexpressing cells has shown the phosphatase to be localized to the reticular network of the ER. PTP1 was readily solubilized by detergents, but not by high salt. Limited proteolysis of membrane-associated PTP1 resulted in the release of lower molecular mass (48 and 37 kD) forms of the enzyme to the cytosol. Thermal phase partitioning of isolated membranes with Triton X-114 indicated that the full-length PTP1 was strongly integrated into the membrane in contrast to the proteolytically derived fragments of PTP1. Overexpression of PTP1 caused little apparent change in the rate of cell proliferation, but did induce changes in fibroblast morphology. A substantial increase in the proportion of bi- and multinucleate cells in PTP1-expressing cell populations was observed, and, in the case of the v-src-transformed cells, cell flattening and loss of refractibility occurred. Although no apparent difference in the tyrosine phosphorylation of pp60v-src was noted in v-src-transformed control and PTP1-overexpressing fibroblasts, the phosphotyrosine content of a 70-kD polypeptide was decreased in PTP1-overexpressing cells.

An alternative technique for creating the gastrojejunostomy in laparoscopic Roux-en-Y gastric bypass: experience with 28 consecutive patients.

BACKGROUND: This study illustrates our experience in laparoscopic Roux-en-Y gastric bypass (LRYGBP) using a new technique for creating the gastro-jejunostomy. METHODS: Between April and November 1999, 28 patients underwent LRYGBP. In the first 10 patients the transoral route with endoscopic guidance was utilized for placement of the anvil in the gastric pouch. A new totally intra-peritoneal approach was utilized in the next 18 patients, avoiding the trans-oral route. RESULTS: There were 23 women and 5 men with an average age of 36 years (range 24-51). The mean BMI was 47, with range 41-64. Of the patients, 82% had one or more associated co-morbid conditions (hypertension, diabetes, sleep apnea, arthritis). Average operative time in the first 10 patients using the trans-oral route with endoscopic guidance was 340 minutes (range 240-390 min). The next 18 patients underwent totally intra-peritoneal anvil placement with a 240-minute average operating time (range 150-310 min). There were no open conversions or mortalities. There were 4 complications, including 2 wound infections, one urinary tract infection, and one intra-abdominal abscess. The two wound infections occurred in the first 10 patients that underwent trans-oral introduction of the anvil. CONCLUSIONS: LRYGBP was a safe and feasible operation. We believe that our technique is easily reproducible, avoiding the trans-oral route for introducing the anvil. This technique may also decrease operative time and possibly the incidence of wound infections, although we are still in the learning curve and final conclusions cannot be made.

An investigation into opioid systems in the pregnant rat.

The role of opioid peptides during pregnancy and parturition has not been defined. They may function as natural analgesics during parturition. Pain thresholds were tested during pregnancy but, in contrast with a previous study, were found not to change. Plasma Beta-endorphin-like-immunoreactivity (B-ELI) was measured and towards the end of pregnancy a significant increase was recorded. Peptide levels returned to the pre-gestational concentration just prior to parturition. Pituitary B-ELI was also measured and was only significantly raised on the day before expected parturition. These changes add to the evidence that opioid peptides have a physiological function during pregnancy and parturition.

Schemes for the identification of tissue types and boundaries at the tool point for surgical needles.

Precise control of automated invasive surgical tools requires real-time identification of tissue types and their deformation. At the focus of this paper is the epidural puncture, for which it is shown that the tissue type and deformation can respectively be determined from laser-based spectroscopy and the change in force required to push the needle through the various tissues. Studies have shown that physiological variations from one patient to another are too great to allow absolute values to be reliably used to indicate the position of the needle tip. However, the pattern of force variation during penetration is shown to be similar between specimens. Interpretation of this information in conjunction with spectroscopic techniques can be used to discriminate between tissues and tissue structure at the needle tip. This paper describes results from an investigation on automatic techniques for interpreting the type and deformation of tissues under tool action.

Dose response study of subarachnoid diamorphine for analgesia after elective caesarean section.

Subarachnoid diamorphine provides excellent analgesia after elective caesarean section but the optimum dose is still uncertain. We therefore investigated the effects of three regimens of subarachnoid diamorphine. Forty parturients were assigned to one of four groups. A control group received no diamorphine in their subarachnoid bupivacaine and three study groups received 0.1 mg, 0.2 mg or 0.3 mg diamorphine added to 12.5 mg hyperbaric bupivacaine 0.5% in a semi-blind randomised design study. All women received a 100 mg diclofenac suppository at the end of the caesarean section and were provided with morphine patient controlled analgesia (PCA) postoperatively. The patients were assessed for pain, morphine usage and side-effects at 2, 4, 8 and 24 h after the subarachnoid injection. Postoperative visual analogue scores for pain and PCA morphine consumption were significantly lower, and mean time to first use of morphine was significantly longer in the 0.3 mg diamorphine group. The mean (SD) dose of PCA morphine used over 24 h was 39.4 (14.7), 25.6 (16.5), 21.6 (15.9) and 3.1 (3.6) mg, and mean time to first use of morphine was 1.6 (0.5), 3.0 (1.4), 3.4 (2.4) and 14.1 (9.4) h, in the 0, 0.1 mg, 0.2 mg and 0.3 mg groups respectively. Side-effects of pruritus, nausea and vomiting were dependent on the dose of spinal diamorphine but did not require treatment in any patients. We conclude that 0.3 mg subarachnoid diamorphine provides significantly better postoperative pain relief than the smaller doses with an acceptable increase in side-effects.

Simulation of resistance forces acting on surgical needles.

High precision in the manual control of needles and biopsy probes in medical treatment requires high skill and dexterity levels. In anaesthesia, force sensation is an important feedback mechanism, and the practitioner needs to refresh or develop skills to improve on the interpretation of needle progress towards the target site. This paper describes an experimental tactile force simulator for uniaxial needle action for which the force resisting progress of the needle is derived from measured data. As an example, the approach taken to develop the simulation of the insertion of epidural needles is described. Adaptation to other procedures would be possible by adopting new reference models based on appropriate measured force data.

Alternative operative techniques in laparoscopic Roux-en-Y gastric bypass for morbid obesity.

The only effective treatment for patients with morbid obesity is surgery. Laparoscopic bariatric surgery has become quite popular in attempts to decrease the morbidity associated with laparotomy. In this article, we describe the technical details of laparoscopic Roux-en-Y gastric bypass with three different techniques for creating the 15-cc gastric pouch. These techniques avoid upper endoscopy for the transoral introduction of the 21-mm circular stapler anvil down to the gastric pouch.

Outbreak of pyrazinamide-monoresistant tuberculosis identified using genotype cluster and social media analysis.

SETTING: Monoresistance to pyrazinamide (PZA) has infrequently been associated with Mycobacterium tuberculosis. OBJECTIVE: To report an outbreak of PZA-monoresistant M. tuberculosis in Virginia involving two genotype clusters from December 2004 to August 2010. RESULTS: Thirty cases were identified involving a predominantly young, US-born population with histories of substance use and incarceration and a large proportion of children aged <15 years (n= 6, 20%); of these, 23 cases (77%) were culture-confirmed as M. tuberculosis complex. DNA fingerprinting and molecular analysis of the PZA resistance gene, pncA, demonstrated a clonal strain that was not M. bovis. Genotypic data provided the initial link between seemingly unrelated cases, and helped reveal a historic genotype cluster of cases from 2004. Further genotype cluster and contact investigation procedures, including the novel use of the social networking website Facebook.com, revealed additional links between the 2004 and 2009 genotype clusters and described an ongoing, extensive outbreak necessitating an enhanced screening and treatment protocol for contacts. CONCLUSIONS: This outbreak demonstrates how tuberculosis can spread through a young, vulnerable population. The use of genotypic data and the novel incorporation of social media investigations were critical to understanding the settings and context of infectivity.