Good Practices for the Laboratory Performance Testing of Aqueous Oral Inhaled Products (OIPs): an Assessment from the International Pharmaceutical Aerosol Consortium on Regulation and Science (IPAC-RS).

Multiple sources must be consulted to determine the most appropriate procedures for the laboratory-based performance evaluation of aqueous oral inhaled products (OIPs) for the primary measures, dose uniformity/delivery, and aerodynamic particle (droplet) size distribution (APSD). These sources have been developed at different times, mainly in Europe and North America, during the past 25 years by diverse organizations, including pharmacopeial chapter/monograph development committees, regulatory agencies, and national and international standards bodies. As a result, there is a lack of consistency across all the recommendations, with the potential to cause confusion to those developing performance test methods. We have reviewed key methodological aspects of source guidance documents identified by a survey of the pertinent literature and evaluated the underlying evidence supporting their recommendations for the evaluation of these performance measures. We have also subsequently developed a consistent series of solutions to guide those faced with the various associated challenges when developing OIP performance testing methods for oral aqueous inhaled products.

Reducing g(2)(0) of a parametric down-conversion source via photon-number resolution with superconducting nanowire detectors.

Multiphoton contributions pose a significant challenge for the realisation of heralded single-photon sources (HSPS) based on nonlinear processes. In this work, we improve the quality of single photons generated in this way by harnessing the photon-number resolving (PNR) capabilities of commercial superconducting nanowire single-photon detectors (SNSPDs). We report a 13 ± 0.4% reduction of g(2)(τ = 0), even with a collection efficiency in the photon source of only 29.6%. Our work demonstrates the first application of the PNR capabilities of SNSPDs and shows improvement in the quality of an HSPS with widely available technology.

Measuring the Joint Spectral Mode of Photon Pairs Using Intensity Interferometry.

The ability to manipulate and measure the time-frequency structure of quantum light is useful for information processing and metrology. Measuring this structure is also important when developing quantum light sources with high modal purity that can interfere with other independent sources. Here, we present and experimentally demonstrate a scheme based on intensity interferometry to measure the joint spectral mode of photon pairs produced by spontaneous parametric down-conversion. We observe correlations in the spectral phase of the photons due to chirp in the pump. We show that our scheme can be combined with stimulated emission tomography to quickly measure their mode using bright classical light. Our scheme does not require phase stability, nonlinearities, or spectral shaping and thus is an experimentally simple way of measuring the modal structure of quantum light.

Single-shot discrimination of coherent states beyond the standard quantum limit.

The discrimination of coherent states is a key task in optical communication and quantum key distribution protocols. In this work, we use a photon-number-resolving detector, the transition-edge sensor, to discriminate binary-phase-shifted coherent states at a telecom wavelength. Owing to its dynamic range and high efficiency, we achieve a bit error probability that unconditionally exceeds the standard quantum limit (SQL) by up to 7.7 dB. The improvement to the SQL persists for signals containing up to approximately seven photons on average and is achieved in a single shot (i.e., without measurement feedback), thus making our approach compatible with larger bandwidths.

Quantum-enhanced interferometry with large heralded photon-number states.

Quantum phenomena such as entanglement can improve fundamental limits on the sensitivity of a measurement probe. In optical interferometry, a probe consisting of N entangled photons provides up to a N enhancement in phase sensitivity compared to a classical probe of the same energy. Here, we employ high-gain parametric down-conversion sources and photon-number-resolving detectors to perform interferometry with heralded quantum probes of sizes up to N = 8 (i.e. measuring up to 16-photon coincidences). Our probes are created by injecting heralded photon-number states into an interferometer, and in principle provide quantum-enhanced phase sensitivity even in the presence of significant optical loss. Our work paves the way towards quantum-enhanced interferometry using large entangled photonic states.

Functional Radionuclide Imaging, In-Vitro Radioiodine Uptake Estimation and RT-PCR in the Evaluation of Sodium Iodide Symporter (NIS) Expression and Functionality in Breast Cancer: A Pilot Study.

Breast cancer is a common malignancy in females, which is considered as a systemic disease, whose treatment involves combined modality including systemic as well as local treatment. Recent studies have shown that breast cancer also expresses Sodium Iodide Symporter (NIS) gene, like in the thyroid, which is the factor responsible for the uptake of iodide by the thyroid, enabling radioiodine therapy of thyroid disorders. This study aimed to evaluate various radionuclide imaging characteristics, in vitro radioiodine uptake (RAIU) and evaluation of NIS expression by using Reverse Transcriptase-Polymerase Chain Reaction (RT-PCR) to explore sodium iodide symporter (NIS) expression and iodine uptake in breast cancer and to explor e whether radioiodine can be used for the diagnosis and treatment of breast cancer. Ways of differential regulation of NIS expression in breast cancer has also been explored. Female patients with palpable breast lump and histologically proven infiltrating duct carcinoma were taken up for the study, which included 50 females of mean age 49 years. (range: 23-73 years). The patients were categorized into different groups, depending on the type of the study performed. The uptake patterns in various imaging modalities were analyzed and compared with invitro and RT-PCR studies. 68 % of breast cancer cases showed (99m)Tc-pertechnetate uptake at the initial images. This finding could partly be due to tumor vascularity, which is usually higher compared to the normal tissues. The uptake in the delayed imaging could be related to that due to NIS in the breast. Use of perchlorate or stable iodine did not alter the pertechnetate uptake pattern in breast tumor. Good correlation between (99m)Tc-pertechnetate and (99m)Tc-tetrofosmin uptake in breast cancer was demonstrated. In vitro radioactive iodine uptake in the breast tumor was significantly higher than that in the normal breast tissue. Only 42 % of breast tumor samples studied using RT-PCR showed NIS expression. Correlation between (99m)Tc-pertechnetate uptake and NIS expression could not be well established. Further studies with higher dose of radioiodine and/or mechanisms of differentially blocking the thyroid are required to assess the feasibility of radioiodine therapy for breast cancer.

Non-obstructed femoral hernia containing ascending colon, caecum, appendix and small bowel with concurrent bilateral recurrent inguinal hernia.

Femoral hernias, which are less common than inguinal hernias and more often found in females, occasionally contain more than just small intestine and omentum. Uncommon contents reported in femoral hernia sacs include caecum, appendix, Meckel's diverticulum (Littre hernia), testis, ovary, transverse colon and even stomach or kidney. Strangulation of femoral hernias containing appendix, small intestine and caecum, and Meckel's diverticulum are well reported in the literature. Here, we report a case of a male patient having bilateral femoral hernia with bilateral recurrent inguinal hernia. A huge, right-sided femoral hernia contained terminal ileum, appendix, caecum and ascending colon, which were irreducible but neither obstructed nor strangulated. The patient was operated on with a Pfannenstiel incision together with an infrainguinal incision. For reduction of content, an inguinal ligament was also incised. Bilateral preperitoneal, polypropylene mesh hernioplasty was performed along with rolled plug placement in the right femoral canal. The patient had an uneventful post operative recovery and no recurrence in 6 months of follow up.

Inlay osmotic pump tablets containing metformin and glipizide.

The goal of diabetes therapy today is to achieve and maintain as near normal glycemia as possible to prevent the long-term microvascular and macrovascular complications of an elevated blood glucose. A newly developed inlay osmotic pump tablet (IOPT) can deliver glipizide (GLZ) and metformin HCl (MET) gradually in controlled manner. The aim of present investigation was to prepare the IOPT that can deliver >75% of GLZ in 2 h, whereas MET released after 2 h and sustained up to 12 h. In the present work, HP-ß-CD was used to modify the solubility of GLZ before incorporating in the osmotic system and MET was spray-dried with HPMC A15C to modify its release profile, flow property, and compressibility. Various parameters mainly G(75%) (75% GLZ release), t(LMET) (lag time of MET release from device), Q(10 h) (percent of MET released within 10 h), and RSQ(ZERO) (R(2) of release data fitted to zero-order equation) were used to compare different formulations. The effects of different formulation variables, that is, osmagents, concentration of hydrophilic polymer, diameter of drug releasing orifice, and coating composition on the drug release profile were investigated. The release rate of GLZ could be effectively modified by the addition of sodium carbonate and sodium chloride, whereas the release rate of MET was adjusted by dual-coating system and by addition of hydrophilic polymer. The developed inlay osmotic system could be effective in the multidrug therapy of diabetes by delivering both drugs in a controlled manner.

Postselective two-photon interference from a continuous nonclassical stream of photons emitted by a quantum dot.

We report an electrically driven semiconductor single-photon source capable of emitting photons with a coherence time of up to 400 ps under fixed bias. It is shown that increasing the injection current causes the coherence time to reduce, and this effect is well explained by the fast modulation of a fluctuating environment. Hong-Ou-Mandel-type two-photon interference using a Mach-Zehnder interferometer is demonstrated using this source to test the indistinguishability of individual photons by postselecting events where two photons collide at a beam splitter. Finally, we consider how improvements in our detection system can be used to achieve a higher interference visibility.

Airway function and markers of airway inflammation in patients with treated hypothyroidism.

BACKGROUND: There is increasing evidence of an association between organ specific autoimmune diseases, particularly autoimmune thyroid disease and respiratory morbidity. A study was undertaken to determine whether patients with autoimmune thyroid disease have objective evidence of airway inflammation and dysfunction. METHODS: Twenty six non-smoking women with treated hypothyroidism and 19 non-smoking controls completed a symptom questionnaire and underwent full lung function tests, capsaicin cough reflex sensitivity measurement, methacholine challenge test, and sputum induction over two visits. RESULTS: Symptoms of cough (p = 0.01), dyspnoea (p = 0.01), sputum production (p = 0.004), and wheeze (p = 0.04) were reported more commonly in patients than controls. Patients with hypothyroidism had heightened cough reflex sensitivity compared with controls (geometric mean concentration of capsaicin causing five coughs: 40 v 108 mmol/l; mean difference 1.4 doubling doses; 95% confidence interval of difference 0.4 to 2.5; p = 0.008) and a significantly higher proportion of patients had airway hyperresponsiveness (methacholine provocative concentration (PC(20)) <8 mg/ml: 38% v 0%; p = 0.016). Patients with hypothyroidism also had a significantly higher induced sputum total neutrophil cell count (p = 0.01), total lymphocyte count (p = 0.02), and sputum supernatant interleukin-8 concentrations (p = 0.048). CONCLUSION: Patients with treated hypothyroidism report more respiratory symptoms and have objective evidence of airway dysfunction and inflammation.

Chronic tonsillar enlargement and cough: preliminary evidence of a novel and treatable cause of chronic cough.

Tonsillar enlargement is sometimes seen in patients with otherwise unexplained chronic cough although its significance is unclear. In this study, the authors set out to test the hypothesis that cough symptoms and cough reflex sensitivity will improve after tonsillectomy in patients with otherwise unexplained chronic cough and enlarged tonsils. Eight consecutive patients with unexplained chronic cough and enlarged tonsils were recruited from 236 patients seen in a cough clinic between 2000 and 2001. Six patients with enlarged tonsils and no cough who were undergoing tonsillectomy for other reasons were recruited as a control group. All patients rated cough severity on a cough visual analogue score (0-100 mm) and had capsaicin cough reflex sensitivity measurement twice before and again 3 months after tonsillectomy. Patients with a chronic cough had heightened cough reflex sensitivity compared with the control group at baseline. There was a significant improvement in mean cough visual analogue score 3 months after tonsillectomy in patients with chronic cough (mean difference 30 mm; 95% confidence interval of difference 8-51 mm). The geometric mean concentration of capsaicin required to cause five coughs increased from 4 to 207 micromol L(-1) after tonsillectomy in patients with chronic cough (mean difference from baseline 5.6 doubling concentrations; 95% confidence interval of difference 3.1-8.2). There was no change in cough reflex sensitivity in control patients after tonsillectomy. These preliminary findings suggest for the first time a possible role for tonsillectomy in patients with enlarged tonsils in whom other causes of cough have been ruled out.

Spontaneous cerebrospinal fluid leakage and middle ear encephalocele in seven patients.

Isolated cases of spontaneous cerebrospinal fluid (CSF) leakage with and without middle ear encephalocele have been reported. These leaks are usually accompanied by episodes of recurrent meningitis, hearing loss, or chronic headache. In this article, we report seven new cases of spontaneous CSF leakage. Six of these patients had conductive hearing loss and serous otitis media, and three had recurrent meningitis. Prior to a definitive diagnosis, six patients had received myringotomy tubes, which produced profuse clear otorrhea. Three patients had positive beta-2 transferrin assays. Computed tomography and magnetic resonance imaging confirmed a defect in the temporal bone tegmen. A combined transmastoid and middle fossa surgical approach with a three-layer closure was used to repair the tegmen defect. All patients had a lumbar drain placed prior to surgery. In addition to describing the seven new cases, we review the history of CSF leakage and discuss diagnostic methods, surgical findings, and our recommendations for management.

Animal model for liver dysfunction using lomustine in Wistar rats.

AIM: To induce intrahepatic cholestasis in rats using lomustine 1(2-chloroethyl)-3-cyclohexyl-l-nitrosourea (CCNU). METHODS: Doses of 10 mg, 20 mg and 30 mg/Kg body weight of CCNU were injected intraperitoneally in separate groups of animals. RESULTS: With 10 mg/Kg body weight of CCNU, serum bilirubin levels increased for up to 72 hours and then slowly returned to normal. With a dose of 20 mg/Kg body weight of CCNU, serum bilirubin, AST, ALT and alkaline phosphatase levels increased for 72 hours and then returned to normal over 4-5 weeks. With a dose of 30 mg/Kg body weight peak levels of serum bilirubin were reached on day 17. Pathological studies were carried out after injection of 30 mg/Kg body weight of CCNU. After 72 hours hepatocytes were normal, with minimal nonspecific inflammation and bile duct proliferation. After 16 days, triaditis was observed with deposition of collagen. Focal fibrosis was also noticed. There was no significant abnormality of hepatocytes. After 75 days, hepatocytes showed focal ballooning. Bile duct proliferation was seen invading the parenchyma. Nodules of hepatocytes separated by irregular fibrous bands indicated cirrhosis. CONCLUSIONS: An animal model of intrahepatic cholestasis has been developed using CCNU; this model may be used to assess the utility of hepatobiliary radiopharmaceuticals.

Leuprolide acetate in the management of cesarean scar endometriosis.

BACKGROUND: Progestin or estrogen-progestin combination therapy has not proven useful in the treatment of endometriosis of the abdominal scar after cesarean delivery. We report our experience in managing this condition with a gonadotropin agonist. CASE: A 22-year-old black woman with a history of two previous cesareans developed endometriosis of the abdominal scar. The extent of the lesion was estimated by computed tomographic (CT) scan, and a 6-month preoperative course of leuprolide acetate was administered. The patient exhibited prompt symptomatic response to the gonadotropin agonist, but the physical examination and CT scan findings were unchanged. Pathologic examination after surgical removal of the lesion confirmed the clinical diagnosis. CONCLUSION: Leuprolide acetate administered to a patient with cesarean scar endometriosis was associated with an improvement in symptoms, but there was no change in lesion size.

Leuprolide acetate depot for the treatment of uterine leiomyomas. Changes in bone density, uterine volume and uterine vascular resistive index.

This study measured the changes in uterine volume, uterine vascular resistive index and lumbar vertebral bone density before and after a six-month course of leuprolide acetate depot in women with uterine leiomyomas. All nine patients studied were black. The high baseline bone density of black women may provide a greater scope for the use of gonadotropin agonists as compared to women in the general population. A significant reduction in uterine volume was achieved in the patients with leuprolide therapy. Uterine vascular resistive indices were not altered consistently following leuprolide therapy in women with leiomyomas.

Pharmacokinetics of gentamicin in rabbits pretreated with nonsteroidal anti-inflammatory drugs: an interaction study.

Interaction between nonsteroidal anti-inflammatory drugs (NSAIDs) and other drugs occurs relatively frequently because of the wide use of NSAIDs. Such interactions with drugs of narrow therapeutic index used in serious disease states may lead to toxicity. Gentamicin toxicity is based on its concentration in serum, and any alteration in pharmacokinetic parameters may lead to gentamicin accumulation in the body and subsequently to severe nephrotoxicity and ototoxicity. To test this hypothesis, the effect of pretreatment with NSAIDs on gentamicin pharmacokinetics was examined in rabbit. Gentamicin sulfate (5 mg/kg) was administered to rabbits pretreated with aspirin (300 mg/kg), ketorolac tromethamine (3 mg/kg), ibuprofen (20 mg/kg), and piroxicam (2 mg/kg) twice a day for 1 week. The pretreatment with NSAIDs had significant effects on the body clearance and maximum concentration. Aspirin, piroxicam and ketorolac tromethamine pretreatment had significant effects on the area under the curve of gentamicin versus time. Aspirin and ketorolac tromethamine pretreatment had significant effects on the half-life of gentamicin. Aspirin had a significant effect on the volume of distribution of gentamicin. These results suggest that pretreatment with NSAIDs alters the pharmacokinetics of gentamicin and leads to accumulation inside the body, which could result in toxicity.

Significance of MRI changes after surgery of the skull base.

Magnetic resonance (MR) imaging is commonly used in the followup of patients who have undergone surgical removal of tumors from the cranial base to assess the possibility of tumor recurrence, persistence, or surgical complications. Interpretations of this study must be cautious because postoperative enhanced signals are encountered frequently. Although technological improvements continue to enhance the usefulness of MR images for followup, problems remain in differentiating between fibrotic, reconstructive changes, and tumor recurrence. In this study, the hospital records and MR findings of 215 patients who had undergone skull base surgery were reviewed. The study was prompted by negative operative exploration in three patients in whom postoperative MR images strongly suggested tumor recurrence. One-year follow-up images were available in 174 patients. Of these, 94% showed signal enhancement on the 1-year follow-up study. Progressive changes were observed in 14% of patients. The correlation of preoperative MR findings and surgery, with regard to dural involvement, vascular involvement, cranial nerve infiltration, and extent of intracranial infiltration, was analyzed in 28 patients. Methods to facilitate the detection of tumor recurrence using MR images are reviewed.

Acute urinary retention due to a free-standing broad ligament leiomyoma.

A 38-year-old woman who had used oral contraceptives continuously since age 22 presented with acute urinary retention. Physical examination revealed a bladder outlet obstruction due to a large paravaginal/broad ligament mass. Magnetic resonance imaging (MRI) demonstrated that the mass was separate from the uterus which was confirmed at surgery when an isolated free-standing leiomyoma was removed.