Elemental analysis of sage (herb) using calibration-free laser-induced breakdown spectroscopy.

In this work, laser-induced breakdown spectroscopy (LIBS) has been used for the quantitative and qualitative analysis of the sage sample using the calibration-free LIBS (CF-LIBS) technique. The sage plasma is generated by focusing the second harmonics (532 nm) of a Q-switched Nd:YAG laser with a repetition rate of 10 Hz and pulse duration of 5 ns. The emission spectra are recorded using a LIBS 2000 detection system spectrometer consisting of five high-resolution spectrometers covering a wavelength range from 200 to 720 nm. The optical emission spectra of the sage sample reveal the spectral lines of Fe, Ca, Ti, Co, Mn, Ni, and Cr. The plasma temperature and electron number density of the neutral spectral lines of the pertinent elements have been deduced using the Boltzmann plot and Stark-broadening line profile method, with average values 8855±885K and 3.89×1016cm-3, respectively. The average values of the plasma parameters were used for the quantification of the detected elements in the sample. Based on the calibration-free method, the measured results demonstrate that Fe is the major constituent in the sample, having a percentage concentration of 48.1%, while the remaining elements are Ca, Ti, Co, Mn, Ni, and Cr, with percentage concentrations 0.7%, 5.3%, 8%, 11%, 12.3%, and 14.6%, respectively. This study demonstrates the feasibility of LIBS for the compositional analysis of major and trace elements present in the plant samples and its further applications in medicine.

Post-trial Access in Maternal Vaccine Trials.

Provisions for post-trial access (PTA) of the experimental intervention are required before the start of a clinical trial. Although there has been ample attention for PTA in the context of preventive vaccine research, discussions on PTA barely include maternal vaccine trials in which mother-infant pairs are exposed to the intervention. In maternal vaccination trials, specific PTA arrangements are required because pregnancy is transient and PTA may apply to the next pregnancy or the child. In this article, we examine the application and adherence to PTA in the context of maternal vaccine trials. We focused on differences between publications before and after 2000 when international ethical guidance documents formalized PTA requirements. Randomized maternal vaccine trials were included after a systematic search for clinical trials in phases II and III with a maternal vaccine as intervention. We used PTA as defined at the time of publication in the World Medical Association's Declaration of Helsinki (DoH) or in the ethical guidelines of the Council for International Organizations of Medical Sciences (CIOMS). In addition, we investigated whether PTA was included in the trial design. Therefore, we contacted principal investigators (PI's) of the publications found in the review to fill out a questionnaire regarding provisions for PTA. Before and after 2000, no trial articles examined in the systematic review described PTA in their trial publication (0/7, 0% and 0/17, 0%, respectively). In addition, more than half of the PI's of the trials found were not familiar with PTA recommendations in international ethical guidelines. Most cases of PTA included making knowledge available by publishing the results of the trial. The revision of the DoH in 2002 and the CIOMS ethical guidelines in 2002 has not resulted in increased PTA provisions for maternal vaccination trials. PTA is a shared responsibility of various stakeholders including sponsors, Institutional Review Boards, regulators, political entities, and researchers. Inclusion of PTA provisions in trial protocols and publications on maternal vaccination trials is essential to increase transparency on the form and content of these provisions.

Right Atrial Myxoma: An Uncommon Presentation.

There are two types of tumors found in the cardiac chamber. These are divided into primary intra-cardiac tumors and secondary intra-cardiac tumors. Primary intra cardiac tumors are rare and among them 29% are myxomas. Majority of them are found in the left atrium. Here, we report a case of a myxoma in the right atrium with hepatomegaly and Hepatitis B virus infection. The coexistence of all these conditions is very rare. A 52 years old patient presented with history of shortness of breath on exertion along with fever and generalized weakness for 6 months which aggravated lately for last 2 months. He was then taken for better medical care and hospitalization. On cardiac evaluation he had soft S1 and S2 over the tricuspid region on the right lower parasternal region. He had bilateral mild pitting pedal edema. On further examination, it was revealed that he had mild tender hepatomegaly with jaundice. His blood analysis for HBsAg was positive. Echocardiogram showed right atrial myxoma of 14.3cm² almost completely occupying the right atrium and even protruding into the Inferior Venacava however not fully obstructing it. The inferior vena cava size was mildly dilated (22mm). Abdominal ultrasound report showed hepatomegaly (17.6cm) with coarse hepatic parenchyma. In this report, we emphasize the rarity of myxoma in the Right Atrium, its difficult diagnosis because of the location and the atypical presentation in the echocardiograph.

Analysis of pulmonary non-tuberculous mycobacterial infections after lung transplantation.

PURPOSE: Non-tuberculous mycobacteria (NTM) are important pathogens in lung transplant recipients. This study describes the spectrum of NTM respiratory tract infections and examines the association of NTM infections with lung transplant complications. METHODS: Data from 208 recipients transplanted from November 1990 to November 2005 were analyzed. Follow-up data were available to November 2010. Lung infection was defined by bronchoalveolar lavage, sputum, or blood cultures in the appropriate clinical setting. All identified NTM respiratory tract infections were tabulated. The cohort of patients with NTM lung infections (NTM+) were compared to the cohort without infection (NTM-). Univariate and multivariate analysis was performed to determine characteristics associated with NTM infection. Survival analyses for overall survival and development of bronchiolitis obliterans syndrome (BOS) were also performed. RESULTS: In total, 52 isolates of NTM lung infection were identified in 30 patients. The isolates included Mycobacterium abscessus (46%), Mycobacterium avium complex (MAC) (36%), Mycobacterium gordonae (9%), Mycobacterium chelonae (7%), and Mycobacterium fortuitum (2%), with multiple NTM isolates seen on 3 different occasions. The overall incidence was 14%, whereas cumulative incidences at 1, 3, and 5 years after lung transplantation were 11%, 15%, and 20%, respectively. Comparisons between the NTM+ and NTM- cohorts revealed that NTM+ patients were more likely to be African-American and have cytomegalovirus mismatch. Although no difference was seen in survival, the NTM+ cohort was more likely to develop BOS (80% vs. 58%, P = 0.02). NTM+ infection, however, was not independently associated with development of BOS by multivariate analysis. CONCLUSION: With nearly 20 years of follow-up, 14% of lung recipients develop NTM respiratory tract infections, with M. abscessus and MAC more commonly identified. M. gordonae was considered responsible for nearly 10% of NTM infections. Although survival of patients with NTM infections is similar, a striking difference in BOS rates is present in the NTM+ and NTM- groups.

Tuberculosis in women from Pashtun region: an ecological study in Pakistan.

SUMMARY In general, tuberculosis (TB) is more common in men than women. However, for reasons currently not understood, women are 1.5-2 times more likely to report TB compared to men in Pashtun region (Afghanistan, adjacent provinces Pakistan and Iran). We explored whether or not gender disparity in TB notifications in the Pashtun region of Pakistan can be explained by Pashtun ethnicity. Using an ecological linear regression design, we estimated the effect of Pashtun ethnicity on female-to-male ratio (FMR) in TB notifications after adjusting for other determinants of women's health, in Pakistan. Districts with a high proportion of women of Pashtun ethnicity had a 44% (95% confidence interval 27-61) increase in FMR of notified TB cases compared to those with low proportions, after controlling for confounders. Genetic predisposition and distinct socio-cultural determinants could be possible causative factors. However, these hypotheses need further evaluation through rigorous longitudinal studies.

Second-hand smoke and the risk of tuberculosis: a systematic review and a meta-analysis.

There is limited evidence and lack of consensus whether second-hand smoke (SHS) increases risk of tuberculosis (TB), which has substantial implications for unrestricted smoking indoors and TB control policies. We aimed to establish the association between SHS and the risk of acquiring and worsening of TB in non-smokers. We identified 428 articles in the initial search and 12 comparative epidemiological studies met our inclusion criteria. Exposure to SHS was found to have a higher risk of TB infection [risk ratio (RR) 1·19, 95% confidence interval (CI) 0·90-1·57] compared to non-exposure; however, this did not reach statistical significance. There was marked variability (I 2 = 74%, P = 0·0008) between studies' results, which could be explained by the differences in the diagnostic criteria used. Exposure to SHS was found to be statistically significantly associated (RR 1·59, 95% CI 1·11-2·27) with the risk of TB disease. There was significant heterogeneity (I 2 = 77%, P = 0·0006) between studies' results, which was sourced to the internal characteristics of the studies rather than combining different study designs. We did not find any studies for SHS and TB treatment-related outcomes. Thus, we conclude that SHS exposure may increase the risk of acquiring TB infection and progression to TB disease; however, the evidence remains scanty and weak.

Airway complication contributing to disseminated fusariosis after lung transplantation.

Fungal infections are common after lung transplantation. However, disseminated fusariosis is rare and we report the first case of airway complications associated with this infectious process. A 77-year-old Caucasian woman, who was status post left single-lung transplant for emphysema, presented to clinic 8 months after lung transplantation with pleurisy, shortness of breath, and declining lung function. Bronchoscopy showed narrowing of the left anastomotic site with dynamic compression during exhalation. An AERO stent was deployed successfully, but 3 weeks later, her symptoms recurred. Bronchoscopy showed total stent occlusion with thick tenacious mucus. Fusarium solani was isolated from cultures, and a new 1.5 cm skin nodule was found on the anteromedial midportion of the patient's left lower leg. Voriconazole and anidulafungin were started. No evidence of mucus accumulation was seen during a follow-up bronchoscopy. It is likely that Fusarium infection contributed to the initial anastomotic complication as well as to obstruction of the stent. Furthermore, the stent may have contributed to establishment and development of disseminated fusariosis. With antifungal therapy, stent patency was maintained and the patient improved clinically.

Gd2O3-modulated borate glass for the enhancement of near-infrared emission via energy transfer from Gd3+ to Nd3.

(Li2O)0.20(SrO)0.30(Nd2O3)0.01(B2O3)0.49-x(Gd2O3)x, where x = 0, 3, 5, 7, and 10 mol%, glass was melt-quenched to test it as a laser source in the near-infrared (NIR) region. The structural modification, absorption spectra, Judd-Ofelt (J-O) parameters, luminescence spectra, radiative laser parameters, lifetimes, XRD, and FTIR spectra were studied. Luminescence spectra excited at λexc = 584 nm revealed the highest intensity peak at 1073 nm due to the transition of 4F3/2 → 4I11/2. An important phenomenon of concentration quenching was observed and optimized luminescence was achieved with the sample having the concentration x = 07 mol%. The lifetimes of the donor and acceptor and energy transfer from gadolinium to neodymium were obtained from the luminescence decay kinetics. The findings show that Nd-doped Gd2O3-modified glass materials have potential as NIR laser sources.

Probable Phaeoacremonium parasiticum as a cause of cavitary native lung nodules after single lung transplantation.

Lung nodules after lung transplantation most often represent infection or post-transplant lymphoproliferative disorder in the allograft. Conversely, native lung nodules in single lung transplant recipients are more likely to be bronchogenic carcinoma. We present a patient who developed native lung cavitary nodules. Although malignancy was anticipated, evaluation revealed probable Phaeoacremonium parasiticum infection. Phaeoacremonium parasiticum is a dematiaceous fungus first described as a cause of soft tissue infection in a renal transplant patient. Lung nodules have not been previously described and this is the first case, to our knowledge, of P. parasiticum identified after lung transplantation.

Ethical tradeoffs in trial design: case study of an HPV vaccine trial in HIV-infected adolescent girls in lower income settings.

The Declaration of Helsinki and the Council of the International Organization of Medical Sciences provide guidance on standards of care and prevention in clinical trials. In the current and increasingly challenging research environment, the ethical status of a trial design depends not only on protection of participants, but also on social value, feasibility, and scientific validity. Using the example of a study assessing efficacy of a vaccine to prevent human papilloma virus in HIV-1 infected adolescent girls in low resource countries without access to the vaccine, we compare several trial designs which rank lower on some criteria and higher on others, giving rise to difficult trade-offs. This case demonstrates the need for developing more nuanced guidance documents to help researchers balance these often conflicting criteria.

A comparative study of sexual dysfunction in schizophrenia patients taking aripiprazole versus risperidone.

BACKGROUND: Sexual dysfunction due to antipsychotics is a significant problem encountered with first-generation antipsychotics. Even the second-generation antipsychotics like risperidone are not free of sexual dysfunction due to its D2 blocking properties leading to hyperprolactinaemia. Newer antipsychotic aripiprazole, partial dopamine agonist, with neutral effect on prolactin level or even decreasing it, is associated with avoidance of sexual dysfunction. OBJECTIVES: To assess the effect of risperidone and aripiprazole on sexual function of schizophrenic patients. METHODS: This was an open-label, cross-sectional, observational study conducted at College of Medical Sciences, Bharatpur. Schizophrenic patients attending OPD and inpatient, taking risperidone or aripiprazole for at least two months were included in this study. Forty one patients, without chronic medical illness and sexual dysfunction before starting drugs, with informed consent were studied during Jan 2012 and Aug 2012. RESULTS: Changes in sexual activity was found in 11(55%) of those taking risperidone while, only 3(14.3%) had any kind of sexual difficulty. This was statistically significant (p=0.006). Majority, 92.7% of the patients did not report about changes in sexual activity spontaneously. CONCLUSION: Sexual dysfunction was statistically significantly higher in those taking risperidone. Prevalence of sexual dysfunction was low with aripiprazole. Except those having poor sexual functions due to the drugs, the majority had to be specifically inquired about the effects of drug on sex life.

Antioxidant and hepatoprotective action of Asparagus racemosus Willd. root extracts.

The antioxidant activities of the crude hydro-alcoholic extract (CE) and its four fractions viz. methanol (MF), ethyl acetate (EF), n-Butanol (BF), and precipitated aqueous (PAF) of A.racemosus roots tested decreased in the order of EF > MF > CE > BF > PAF when investigated by DPPH free radical scavenging assay. Under iron induced lipid peroxidation almost similar results were observed except that the activity was more in PAF than BF. Hepatoprotective activity of the extracts was also demonstrable in vivo by the inhibition of-CCl4 induced formation of lipid peroxides in the liver of rats by pretreatment with the extracts. CCl4-induced hepatotoxicity in rats, as judged by the raised serum enzymes viz. glutamate oxaloacetate transaminase, glutamate pyruvate transaminase, alkaline phosphatase and total and direct bilirubin as well as oxidant enzyme viz. malon dialdehyde were prevented, while antioxidant enzymes viz. superoxide dismutase, reduced glutathione and catalase were elevated by pretreatment with the extracts, demonstrating the potent hepatoprotective action of the roots of A. racemosus.

Antibiotic resistance in patients with chronic ear discharge awaiting surgery in Nepal.

SETTING: Biratnagar Eye Hospital, Biratnagar, Nepal, which offers ear surgery for chronic suppurative otitis media (CSOM). OBJECTIVE: In patients with CSOM awaiting surgery, to determine the 1) sociodemographic characteristics 2) bacterial isolates and their antibiotic resistance patterns and 3) characteristics of those refused surgery, including antibiotic resistance. DESIGN: A cohort study using hospital data, January 2018-January 2020. RESULTS: Of 117 patients with CSOM and awaiting surgery, 64% were in the 18-35 years age group, and 79% were cross-border from India. Of 118 bacterial isolates, 80% had Pseudomonas aeruginosa and 16% had Staphylococcus aureus. All isolates showed multidrug resistance to nine of the 12 antibiotics tested. The lowest antibiotic resistance in P. aeruginosa was for vancomycin (29%) and moxifloxacin (36%), and for S. aureus, this was vancomycin (9%) and amikacin (17%). Fourteen (12%) patients underwent surgery: myringoplasty (n = 7, 50%), cortical mastoidectomy with tympanostomy (n = 4, 29%) and modified radical mastoidectomy (n = 3, 21%). Those infected with P. aeruginosa and with resistance to over six antibiotics were significantly more likely to be refused for surgery. CONCLUSION: Patients awaiting ear surgery were predominantly infected with multidrug-resistant P. aeruginosa and were consequently refused surgery. This study can help inform efforts for improving surgical uptake and introducing cross-border antimicrobial resistance surveillance.

LIEU: Hôpital ophtalmologique de Biratnagar, Népal, qui propose des interventions chirurgicales de l'oreille aux patients atteints d'otite moyenne chronique suppurée (CSOM). OBJECTIF: Déterminer 1) les caractéristiques sociodémographiques, 2) les isolats bactériens et leurs profils de résistance aux antibiotiques et 3) les caractéristiques des patients se voyant refuser la chirurgie (dont résistance aux antibiotiques) chez les patients atteints de CSOM en attente de chirurgie. MÉTHODE: Étude de cohorte réalisée à l'aide de données hospitalières, janvier 2018-janvier 2020. RÉSULTATS: Sur les 117 patients atteints de CSOM en attente de chirurgie, 64% appartenaient à la tranche d'âge des 18­35 ans et 79% étaient des patients transfrontaliers en provenance d'Inde. Sur 118 isolats bactériens, 80% étaient des isolats de Pseudomonas aeruginosa et 16% de Staphylococcus aureus. Tous les isolats ont montré une résistance à neuf des 12 antibiotiques testés. Les plus faibles résistances chez P. aeruginosa étaient celles à la vancomycine (29%) et à la moxifloxacine (36%). Pour S. aureus, il s'agissait de celles à la vancomycine (9%) et à l'amikacine (17%). Quatorze (12%) patients ont subi une intervention chirurgicale : myringoplastie (n = 7, 50%), mastoïdectomie corticale avec tympanotomie (n = 4, 29%) et mastoïdectomie radicale modifiée (n = 3, 21%). Les patients infectés par P. aeruginosa avec une résistance à plus de six antibiotiques étaient significativement plus susceptibles de se voir refuser la chirurgie. CONCLUSION: Les patients en attente de chirurgie de l'oreille étaient principalement infectés par un isolat multirésistant de P. aeruginosa, et se sont donc vu refuser la chirurgie. Cette étude peut permettre d'orienter les efforts visant à améliorer le taux de chirurgies réalisées et à mettre en place une surveillance transfrontalière des résistances antimicrobiennes.

Photometric calibration for quantitative spectral microscopy under transmitted illumination.

Over the past decade, there have been significant developments in the mechanisms for examination of biological and material samples. These developments exploit techniques in light microscopy to elucidate specific parts of cells and tissues, as well as inorganic particles. In recent years, spectral microscopy has become more prevalent for characterization of samples. Simultaneously, sensor technology has progressed as well and modern charge-coupled devices (CCD) cameras are now capable of achieving high spatial resolution and high sensitivity measurements of signals in the optical microscope. One major impediment in obtaining absolute quantitative information of imaged samples is the lack of automated photometric calibration mechanisms for spectral microscopes. In this paper, we present a methodology for achieving photometric calibration of an automated spectral imaging system targeted towards examination of biological samples. By acquiring spatial and spectral data simultaneously, spectral imaging allows one to exploit physical connections between a particle's morphology and its characteristic response to the optical spectrum. In composite biological material, the interpretation of the spectra is a complicated problem. This is because any light source and charge-coupled device camera used for data acquisition does not have a uniform illumination spectra and quantum efficiency, respectively, across the emitted light spectra. To balance the spectral response across individual wavelengths, our method modulates the exposure duration for the charge-coupled device camera during image acquisition. We present an image similarity based method to calibrate the system. Experiments to test the effectiveness of the calibration method under the various image similarity metrics are presented along with results to show the calibrated system's ability to accurately measure spectra based on the measured transmission profiles of optical filters.

Vascular endothelial growth factor is up-regulated after status epilepticus and protects against seizure-induced neuronal loss in hippocampus.

Vascular endothelial growth factor (VEGF) is a protein factor which has been found to play a significant role in both normal and pathological states. Its role as an angiogenic factor is well-established. More recently, VEGF has been shown to protect neurons from cell death both in vivo and in vitro. While VEGF's potential as a protective factor has been demonstrated in hypoxia-ischemia, in vitro excitotoxicity, and motor neuron degeneration, its role in seizure-induced cell loss has received little attention. A potential role in seizures is suggested by Newton et al.'s [Newton SS, Collier EF, Hunsberger J, Adams D, Terwilliger R, Selvanayagam E, Duman RS (2003) Gene profile of electroconvulsive seizures: Induction of neurotrophic and angiogenic factors. J Neurosci 23:10841-10851] finding that VEGF mRNA increases in areas of the brain that are susceptible to cell loss after electroconvulsive-shock induced seizures. Because a linear relationship does not always exist between expression of mRNA and protein, we investigated whether VEGF protein expression increased after pilocarpine-induced status epilepticus. In addition, we administered exogenous VEGF in one experiment and blocked endogenous VEGF in another to determine whether VEGF exerts a neuroprotective effect against status epilepticus-induced cell loss in one vulnerable brain region, the rat hippocampus. Our data revealed that VEGF is dramatically up-regulated in neurons and glia in hippocampus, thalamus, amygdala, and neocortex 24 h after status epilepticus. VEGF induced significant preservation of hippocampal neurons, suggesting that VEGF may play a neuroprotective role following status epilepticus.

Comparison of IOL power calculation formulae for pediatric eyes.

PurposeTo evaluate and compare the accuracy of modern intraocular lens (IOL) power calculation formulae in pediatric eyes and compare prediction error (PE) obtained with manufacturer's vs personalized lens constant.Patients and methodsAn observational case study was conducted in 117 eyes (117 patients) undergoing pediatric cataract surgery with IOL implantation. PE was calculated as predicted refraction minus actual postoperative refraction, and absolute PE as absolute difference independent of the sign, (APE)=predicted refraction minus actual postoperative refraction. This was done for each formula using manufacturer's and personalized lens constant. Further, PE and APE were evaluated according to axial length (AL).ResultsMean age of children was 2.97 years. About 66/117 eyes (56.4%) were below 2 years of age. Using Holladay 2, Holladay 1, Hoffer Q, and SRK/T formulae with manufacturer's lens constant, mean PE was 0.36, 0.41, 0.69, and 0.28 diopter (D), respectively. With personalized lens constant, it was 0.16, 0.15, 0.50, and -0.12 D, respectively. Difference in mean PE between the formulae was statistically significant (P<0.0001). SRK/T and Holladay 2 formulae had the least PE, both with manufacturer's and personalized constant. For eyes with AL<20 mm, SRK/T and Holladay 2 formulae gave the least PE. Personalizing the lens constant led to a decrease in mean PE in all formulae, except the Hoffer Q formula. However, personalizing the lens constant did not significantly improve the APE. At least 21% eyes had an APE of >2 D with all formulae, even with personalized lens constants.ConclusionIn pediatric eyes, SRK/T and the Holladay 2 formulae had the least PE. Personalizing the lens formula constant did reduce the PE significantly for all formulae except Hoffer Q. In extremely short eyes (AL<20 mm), SRK/T and Holladay 2 formulae gave the best PE.

Rhabdomyolysis Due to Severe Hypophosphatemia in Diabetic Ketoacidosis.

Rhabdomyolysis is a syndrome characterized by injury to skeletal muscle fibers with disruption and release of toxic metabolites into circulation. It is characterized by triad of muscle weakness, myalgia and dark urine and is associated with increased creatine kinase and lactate dehydrogenase. A severely malnourished 10 year old girl with severe diabetic ketoacidosis as hemr initial presentation of type 1 diabetes mellitus developed rhabdomyolysis (CK- 12,000 U/L) with non-oliguric renal failure during her initial course of hospital stay. The possible cause of her RM was attributed to severe hypophosphatemia (minimum serum phosphate, 0.8 mg/dL). Management of diabetic ketoacidosis phosphate supplementation and urinary alkalinization with diuresis improved her clinical course. She was discharged on Day 9 with Insulin. We recommend frequent monitoring of serum phosphate during early period of DKA, particularly in malnourished children, and its normalization in case of severe hypophosphatemia.

Inhibition of human leukocyte elastase. 2. Inhibition by substituted cephalosporin esters and amides.

A variety of 7 alpha-methoxycephalosporin ester and amide sulfones were prepared and tested to determine the structure-activity relations for inhibition of human leukocyte elastase (HLE), a serine protease which has been implicated in several degenerative lung and tissue diseases. The most potent IC50 values were obtained with neutral, lipophilic derivatives, with the esters being more active than the amides. However, the best time-dependent inhibition in this series was observed with the p- and m-carboxybenzyl esters 7b and 7c. These results are discussed in terms of the proposed mechanism of inhibition as well as a molecular modeling study using the recently solved X-ray crystal structure of HLE.

Inhibition of human leukocyte elastase. 3. Synthesis and activity of 3'-substituted cephalosporins.

Several 3'-substituted cephalosporin sulfones were synthesized from 3-(hydroxymethyl)cephalosporin, which was prepared by Ti(OiPr)4 hydrolysis of the corresponding acetate. A method was also developed to prepare a 3-vinylcephalosporin. Some of these compound were found to be potent time-dependent inhibitors of human leukocyte elastase (HLE). The HLE inhibitory activity was correlated with sigma 1 and it was concluded that the potency was determined by the electron-withdrawing ability as well as the size of the substituent. A mechanism for inhibition of HLE by cephalosporin sulfones is proposed.

Inhibition of human leukocyte elastase. 4. Selection of a substituted cephalosporin (L-658,758) as a topical aerosol.

Human leukocyte elastase (HLE) is a serine protease which has been implicated as a causative agent in several pulmonary diseases. The continued modification of our previously reported cephalosporin-based HLE inhibitors has led to the identification of a series of C-2 amides with potent, topical activity in an in vivo hamster lung hemorrhage model. While the most potent in vitro HLE inhibition had previously been obtained with lipophilic ester derivatives, it was found that the less active, but more polar and stable, amide derivatives were much more effective in vivo. The development of the structure--activity relations for optimization of these activities is discussed. These results led to the selection of 3-(acetoxymethyl)-2-[(2(S)-carboxypyrrolidino)carbonyl]-7 alpha-methoxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene, 5,5-dioxide (3, L-658,758) as a selective, potent, time-dependent HLE inhibitor suitable for formulation as a topical aerosol drug for possible clinical use.