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Although clinical examination still represents the gold standard for the differential diagnosis of prolonged disorders of consciousness (pDoC), the introduction of innovative markers is essential for diagnosis and prognosis, due to the problem of covert cognition. We evaluated the brain-derived neurotrophic factor protein (BDNF) and the soluble cell adhesion molecules proteins (CAMs) in a cohort of prolonged disorders of consciousness patients to identify a possible application in the clinical context. Furthermore, peripheral blood determinations were correlated with imaging parameters such as white matter hyperintensities (WMH), cranial standardized uptake value (cSUV), electroencephalography (EEG) data and clinical setting. Our results, although preliminary, identify BDNF as a possible blood marker for the diagnosis of pDoC (p value 0.001), the soluble CAMs proteins CD44, Vcam-1, E-selectin (p value < 0.01) and Icam-3 (p value < 0.05) showed a higher peripheral blood value in pDoC compared with control. Finally, soluble Ncam protein could find useful applications in the clinical evolution of the pDoC, showing high levels in the MCS and EMCS subgroups (p value < 0. 001) compared to VS/UWS.

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Behavioral assessments during the clinical evaluation in prolonged disorders of consciousness patients could be not sufficient for a correct diagnosis and prognostication. To this aim, we used an innovative approach, involving the ultra-sensitive determination of biological markers, correlating them with imaging parameters to investigate the prolonged disorders of consciousness (pDoC).We assessed the serum concentration of neurofilament light chain(NF-L) and glial fibrillary acidic protein (GFAP) in pDoC (n = 16), and healthy controls (HC, n = 6) as well as several clinical imaging parameters such as Fractional Anisotropy (FA), Whole Brain SUV, and White Matter Hyperintensities volumes (WMH) using PET-MRI acquisition. As for differential diagnosis task, only the imaging WMH volume was able to discriminate between vegetative state/unresponsive wakefulness syndrome (VS/UWS), and minimally conscious state (MCS) patients (p-value < 0.01), while all selected markers (both imaging and in vitro) were able to differentiate between pDoC patients and HC. At subject level, serum NF-L concentrations significantly differ according to clinical progression and consciousness recovery (p-value < 0.01), highlighting a potential play for the longitudinal management of these patients.

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Obstetrician/gynecologists and gynecologic oncologists serve an integral role in the care of women at increased hereditary risk of cancer. Their contribution includes initial identification of high risk patients, screening procedures like bimanual exam, trans-vaginal ultrasound and endometrial biopsy, prophylaxis via TAH and/or BSO, and chemoprevention. Further, gynecologists also serve a central role in the management of the secondary repercussions of efforts to mitigate increased cancer risks, including vasomotor symptoms, sexual function, bone health, cardiovascular disease, and mental health. The past several years has seen multiple new high and moderate penetrance genes introduced into the clinical care of women at increased risk of gynecologic malignancy. Awareness of these new genes and the availability of new multi-gene panel tests is critical for providers on the front-line of women's health.

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The field of pulmonary drug delivery is ever progressing with technological advances in inhaler device design, the development of increasingly sophisticated techniques in targeted delivery and new opportunities in drug formulation, largely as a product of the rapidly advancing area of nanotechnology. Though pulmonary administration offers numerous advantages in terms of both local and systemic drug delivery, the translation of inhaled drugs from bench-to-bedside presents an ongoing challenge. Hannah Coaker, Assistant Commissioning Editor, spoke to six experts and discussed their motivations for becoming involved in the field, major obstacles in aerosol drug development and the evolving area of pulmonary drug delivery.

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AIM: This observational study was performed to evaluate the efficacy and safety of intra-vitreal injections of pegaptanib during a 12-month follow-up period. PATIENTS AND METHODS: Forty eyes (20 patients) affected by diabetic macular edema were monitored. Twenty were subjected to treatment, and 20 were controls. The treatment involved a cycle of three intravitreal injections of pegaptanib (0.3 mg every 6 weeks), at the end of which treated patients were submitted to a monthly follow-up for a period of 12 months. The aim was to evaluate the clinical condition of the eye after therapy and gauge the efficacy of the long-term use of this drug. Specific criteria were used to measure the efficacy and safety of pegaptanib. Regarding efficacy, we considered the following: an average improvement in the power of vision, or visual acuity, of →10 letters (2 lines), equivalent to an average logMAR score of →0.2, and a reduction in the central macular thickness of →250 µm. Regarding safety, we considered the occurrence of undesired eye and systemic side effects correlated to either the drug itself or the injection procedure. RESULTS: The logMAR score for the measurement of visual acuity at T3 (third intra-vitreal injection at week 13) with respect to T0 decreased from 0.7 ± 0.277 to 0.445 ± 0.216, suggesting an improvement, while the mean Early Treatment Diabetic Retinopathy Study (ETDRS) score increased from 25.75 ± 13.046 to 34.300 ± 11.770 letters. The central macular thickness was reduced from the initial value of 746.95 ± 293.601 to 334.050 ± 93.997 µm. In seven controls, we registered a worsening both in terms of visual acuity and macular thickness in some eyes, justifying a continuation of therapy in eight eyes of the control group. CONCLUSIONS: Pegaptanib proved to be efficacious and safe for the treatment of diabetic macular edema throughout the 12-month followup. To evaluate its long-term efficacy, further studies are required with larger numbers of patients and longer observational follow-up periods.

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The Authors report three cases of ophthalmic neurosyphilis in patients who complained a visual decrease monocular. The diagnosis was performed with physical and fundus examination, electrophysiological, hemato-chemical and microbiological tests, fluorangiografy and RMN. The physical examination provided standard results about eyes interested while the fundus examination, as well as the electrofunctional and fuorangiografy examinations, showed some alterations. The sockets and encephalon RMN were normal. Moreover; the patients were submitted to specific haematic and microbiological laboratory tests which showed positivity for syphilis. To sum up all patients received an incidental diagnosis of syphilis. This trend could be attributable to an extensive use of antibiotics that changing the natural course of disease, mask clinical evidences and make them harder to diagnose.

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Post-lung transplant use of aerosol cyclosporin (ACsA) is considered by examining the relationship between deposited aerosol dose and effect. In a sub-study of placebo controlled trials of ACsA as a rejection prophylaxis, 15 drug subjects received aerosol dose quantification tests to gage their ability to effectively deposit the nebulised drug in their transplanted lung(s). A total of seven placebo subjects received mock deposition tests. The deposited doses and mock doses were compared to changes in the forced expiratory volume in one second, at six time points during the 2-yr trial period (ACsA was started within 6 weeks post-transplant). Linear relationships were demonstrated between deposited dose and improvement in lung function in the drug subjects at all intervals. Mock dose data from placebo subjects did not demonstrate similar correlation. Based on these results, subjects were grouped by dose and compared. Subjects depositing > or = 5 mg of the drug in the periphery of their transplant(s) had improving pulmonary function on average. Low-dose and placebo subjects demonstrated declines, more A2-A4 rejection events in the latter portion of the trial, and more chronic rejection beyond the end of the trial. A dose-to-effect relationship is demonstrated for aerosol cyclosporin in terms of pulmonary function and biopsy proven rejection.

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The majority of patients who develop bronchiolitis obliterans, after lung transplantation, die within 2-3 yrs after onset since treatment with conventional immunosuppression is typically ineffective. A case/control study was conducted in lung transplant recipients with biopsy-documented bronchiolitis obliterans to determine whether aerosol cyclosporin use contributed to increased survival. The cases comprised 39 transplant recipients who received open-label aerosol cyclosporin treatment in addition to conventional immunosuppression. The controls were transplant recipients treated with conventional immunosuppression alone. There were 51 controls from the University of Pittsburgh Medical Center and 100 from a large multicentric database (Novartis Lung Transplant Database). Forced expiratory volume in one second expressed as a percentage of the predicted value was an independent predictor of survival in all patients with bronchiolitis obliterans. Cox proportional-hazards analysis revealed a survival advantage for aerosol cyclosporin cases compared to the Pittsburgh control group. A survival advantage was also seen when comparing study cases to multicentric controls. Aerosol cyclosporin, given with conventional immunosuppression to lung transplant recipients with bronchiolitis obliterans, provides a survival advantage over conventional therapy alone.

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Respiratory medical societies throughout the world have an important role in helping governments to develop public policy to counter the threat of bioterrorism.

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Bioavailability of an aerosolized anti-inflammatory protein, soluble interleukin-4 receptor (IL-4R), was measured in patients with asthma using two different aerosol delivery systems, a prototype aerosol delivery system (AERx tethered model, Aradigm, Hayward, CA) and PARI LC STAR nebulizer (Pari, Richmond, VA). Regional distribution of the drug in the respiratory tract obtained by planar imaging using gamma camera scintigraphy was utilized to explain the differences in bioavailability. The drug, an experimental protein being developed for asthma, was mixed with radiolabel 99mTechnetium diethylene triaminepentaacetic acid (99mTc-DTPA). Aerosols were characterized in vitro using cascade impaction (mass median aerodynamic diameter [MMAD] and geometric standard deviation [GSD]); the AERx MMAD 2.0 microm (GSD 1.35), the PARI 3.5 microm (GSD 2.5). Four patients with asthma requiring maintenance aerosolized steroids were studied. First, regional volume was determined utilizing equilibrium 133Xe scanning. Then, after a brief period of instruction, patients inhaled four breaths of protein using AERx (0.45 mg in total) followed 1 week later by inhalation via PARI (3.0 mg nebulized until dry). Each deposition image was followed by a measurement of regional perfusion using injected 99mTc albumin macroaggregates. Deposition of 99mTc-DTPA in the subjects was determined by mass balance. Regional analysis was performed using computerized regions of interest. The regional distribution of deposited drug was normalized for regional volume and perfusion. Following each single inhalation, serial blood samples were drawn over a 7-day period to determine area under the curve (AUC) of protein concentration in the blood. Median AUC(AERx)/AUC(PARI) was 7.66/1, based on the amount of drug placed in each device, indicating that AERx was 7.66 times more efficient than PARI. When normalized for total lung deposition (AUC per mg deposited) the ratio decreased to 2.44, indicating that efficiencies of the drug delivery system and deposition were major factors. When normalized for sC/P and (pU/L)xe ratios (central to peripheral and upper to lower ratios are parameters of regional distribution of deposited particles and regional per- fusion ['p']), AUC(AER)x/AUC(PARI) further decreased to 1.35, demonstrating that peripheral sites of deposition with the AERx affected the final blood concentration of the drug. We conclude that inhaled bioavailability of aerosolized protein, as expressed by AUC, is a quantifiable function of lung dose and regional deposition as defined by planar scintigraphy.

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Prospective longitudinal studies measuring aerosol behavior in the respiratory tract as humans age have not been performed. The present paper reviews observations related to aging of the respiratory tract and other effects more likely due primarily to disease and iatrogenic causes. Upper airway deposition was found to approximate 50% in children during inhalation of drugs thought to be designed primarily for deposition in the lower respiratory tract. In older subjects, aging per se did not have a major impact on the deposition of aerosols. Disease processes that develop with age were shown to be the primary cause of deposition abnormalities. Flow-limitation in central airways was proposed as a major factor responsible for central airway deposition as well as abnormal clearance in common obstructive lung diseases. The oral cavity, a source of pathogenic organisms causing pneumonia, was also studied in the elderly. Salivary clearance, often abnormal in the aged, was related to colonization with pathogenic bacteria. Salivary clearance was not obviously reduced by aging per se but by iatrogenic sources such as drug therapy for other diseases.

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The elderly have an increased incidence of oropharyngeal colonization with respiratory pathogens, a well-known risk factor for the development of pneumonia. Changes in the oral milieu may occur secondary to decreased salivary production and abnormalities in swallowing. These abnormalities, common in the elderly, may result in impaired clearance of organisms, allowing pathogenic colonization. To test this hypothesis, we performed a prospective cross-sectional analysis of 75 elderly institutionalized patients and measured oral clearance using (99m)Tc-human serum albumin (HSA) administered to the oropharynx. Oropharyngeal cultures, salivary cell populations, elastase activity, and clinical parameters were measured simultaneously. Retention of radiolabel ranged from 100% to 2.3% over 120 min of observation. Clearance in the oropharynx was significantly decreased in those patients who had oropharyngeal colonization with gram-negative bacilli (GNB), Staphylococcus aureus (SA), or yeast compared with those demonstrating normal flora by 95% confidence intervals. Decreased clearance was also seen in patients on antidepressants by 95% confidence levels. The absolute number of salivary lymphocytes/ml and buccal cells/ml was increased in colonized patients versus noncolonized persons (mean +/- SEM, 128 x 10(3) +/- 49 x 10(3), 25.4 +/- 11.6 x 10(3)). Elastase activity was elevated in patients who had GNB compared with patients without GNB (mean +/- SEM, 10.6 nM +/- 5.7, versus 2.2 nM +/- 1.2, p = 0.036). We conclude that a decrease in salivary clearance of potentially pathogenic organisms may be a major risk factor for the development of colonization in the elderly.

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The use of breathing simulators for the in vitro determination of the inhaled mass of drug from nebulizers has become widely accepted. Their use is, however, based on the assumption that there is a correlation between the in vitro and in vivo inhaled mass of drug. The aim of the study was therefore to investigate whether a new breathing simulator--the MIMIC Breathing Emulator (Medic-Aid Limited, Bognor Regis, UK)--could accurately emulate the in vivo inhaled mass of budesonide suspension for nebulization. Eight adult healthy subjects were included. Each subject inhaled for 2 min from a Spira Module 1 jet nebulizer (Respiratory Care Center, Hämeenlinna, Finland), charged with 1.0 mg of budesonide suspension for nebulization (0.5 mg mL-1, 2 mL suspension, AstraZeneca, Sweden) and supplied with an inhaled mass filter between the nebulizer and the subject. The breathing patterns were recorded during the nebulization and simulated in vitro at two different experimental sites (simulations A and B) with the breathing simulator. With the patients breathing through the filters (in vivo test), inhaled mass of budesonide averaged 103.6 micrograms. The two in vitro experiments using the simulator revealed similar results with in vitro simulation A equal to 101.0 micrograms and simulation B 99.1 micrograms. There were no statistically significant differences between the in vivo results and those of in vitro simulation A. Results were significantly different for simulation B (p = 0.032) although the difference was less than 4.5%. These data indicate that the breathing simulator can be used to accurately simulate sine waveforms, human breathing patterns, and the in vitro and in vivo inhaled mass of budesonide suspension for nebulization.

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Aerosolized antibiotic therapy appears to have potential for targeted therapy to the airways and deep lung to prevent VAP in patients at high risk for this disease. The definition of that high-risk population is important if this model is to be successful. We are attempting to define susceptible patients by measuring the volume of airway secretions, which mirrors the inflammation milieu of the central airways. Elevated sputum volume is marked by heavy growth of pathogenic organisms and high levels of inflammatory cytokines. Large-scale clinical trials are necessary to define the usefulness of these surrogates in defining a targeted population and for assessing the potential of aerosolized antibiotic prophylactic therapy for preventing pneumonia and mortality. If successful, the aerosol approach may avoid systemic therapy and its associated complications.

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Ischemic heart disease is the most common underlying cause of congestive heart failure, and thus aspirin (acetylsalicylic acid [ASA]) and angiotensin-converting enzyme (ACE) inhibitors are commonly used together for treatment in this setting. The issue of possible attenuation of the effect of ACE inhibitors by ASA has been an area of intense debate. Currently, it is perceived that a significant part of the beneficial effect of ACE inhibitors is related to augmentation of bradykinin levels, which among other effects stimulate the release of prostacyclin. Aspirin, on the other hand, inhibits the production of prostacyclin by blocking cyclooxygenase. Prostaglandins play an important endogenous vasodilatory role and counteract the enhanced peripheral vasoconstriction state in congestive heart failure. Thus, the counteracting effect of ASA on the augmentation of prostacyclin synthesis by ACE inhibitors could result in a potential reduction of the beneficial effects of the ACE inhibitor's and could be of great importance. This article reviews reports from large clinical trials pertaining to this issue and relates their findings to the currently available theoretical bases for support of the counteracting effect of ASA on augmentation of prostacyclin synthesis by ACE inhibitors. The clinical implications of such an interaction are discussed.

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