Background: Older adults commonly face challenges in understanding, obtaining, administering, and monitoring medication regimens after hospitalization. These difficulties can lead to avoidable morbidity, mortality, and hospital readmissions. Pharmacist-led peri-discharge interventions can reduce adverse drug events, but few large randomized trials have examined their effectiveness in reducing readmissions. Demonstrating reductions in 30-day readmissions can make a financial case for implementing pharmacist-led programs across hospitals. Methods/Design: The PHARMacist Discharge Care, or the PHARM-DC intervention, includes medication reconciliation at admission and discharge, medication review, increased communication with caregivers, providers, and retail pharmacies, and patient education and counseling during and after discharge. The intervention is being implemented in two large hospitals: Cedars-Sinai Medical Center and the Brigham and Women's Hospital. To evaluate the intervention, we are using a pragmatic, randomized clinical trial design with randomization at the patient level. The primary outcome is utilization within 30 days of hospital discharge, including unforeseen emergency department visits, observation stays, and readmissions. Randomizing 9776 patients will achieve 80% power to detect an absolute reduction of 2.5% from an estimated baseline rate of 27.5%. Qualitative analysis will use interviews with key stakeholders to study barriers to and facilitators of implementing PHARM-DC. A costeffectiveness analysis using a time-and-motion study to estimate time spent on the intervention will highlight the potential cost savings per readmission. Discussion: If this trial demonstrates a business case for the PHARM-DC intervention, with few barriers to implementation, hospitals may be much more likely to adopt pharmacist-led peri-discharge medication management programs.

In 2007, 2.5 million people have been newly infected with HIV and 2.1 million people died from AIDS, worldwide. HAART has turned AIDS into a manageable disease. However, numerous questions remain unanswered, such as the when to initiate HAART and what are the most effective doses of antiretroviral drugs. HIV reservoirs and how they could be attacked by therapeutic strategies is another issue. The 5th International AIDS Society (IAS) Conference in Cape Town, South Africa, focused on these subjects as well as on the hotly discussed funding budget. As has been indicated in the Sydney Declaration 2 years ago, 10% of the funding budget must be spent on clearly defined fields of HIV research. The following article presents highlights of the IAS Conference 2009.

ObjectivesThough progressive multifocal leucencephalopathy (PML) may manifest with visual impairment, including bilateral visual loss as the presenting manifestation, in single patients, it has not been described in association with left ventricular hypertrabeculation/noncompaction (LVHT).Case reportA 37 years old HIV-positive Caucasian male developed visual impairment, which continuously progressed to near blindness within two weeks. He could differentiate bright and dark but was unable to count fingers, and there was bradydiadochokinesia. Ophthalmologic investigations exclusively revealed severe visual field defects bilaterally. Visually-evoked-potentials were absent bilaterally. MRI of the cerebrum revealed bilateral occipital, non-enhancing T2-hyperintensities, which extended towards the temporal lobe. On diffusion weighted imaging hyperintense areas were intermingled with hypointense areas. H-MR-spectroscopy disclosed an increased lactate peak, but reduced creatine, cholin, and N-acetyl-aspartate peaks. CSF-protein was slightly elevated, oligoclonal bands were positive, and PCR positive for the JC-virus. T-helper cells were markedly reduced. Cardiologic investigations revealed right bundle-branch-block, left ventricular wall thickening and LVHT in the left ventricular apex and the lateral wall. During follow-up visual acuity transiently improved but lastly deteriorated again despite a highly-active anti-retroviral therapy.ConclusionsThis case shows that cortical blindness may be the initial clinical manifestation of PML and that isolated LVHT is not causally related to a HIV-infection but rather to a subclinical neuromuscular disorder.

1,444,920 new cases of cancer were projected in 2007 in the U.S., half of these patients are suffering from cancers of the prostate, the breast, the lung, and the colon/rectum. Colorectal and lung cancer are the most frequent solid tumors in both women and men. However, the US cancer statistics offer some hope. The incidence rates of colorectal and lung cancer rose till 1985 and 1991, respectively after which they fell.Global statistics is the one side of the coin but successful prevention and treatment of solid tumors requires the acceptance that these are not single diseases.This review focuses on the following topics: 1) Tumor biology: inflammation, growth factors (EGF, VEGF, IGF and its receptors), and epigenetic events. 2) Management strategies in diagnosis: Is early diagnosis feasible? a) Tumor-specific antigens. b) Radiological methods. c) Endoscopy. d) Contributions of pathology to diagnosis and treatment decisions. 3) Appropriate patient selection for treatment purposes. a) Evaluation of tumor tissue. b) Tumor staging. 4) Therapy sequencing: drugs, beams, surgery. 5) Clinical trials a) Phase I trials. b) What are the best inclusion criteria and endpoints? 6) The pipeline. 7) New drugs and manifold consequences. 8.) Prevention strategies. 9.) Future directions.

Twenty-four years after the identification of HIV-1 as causative agent of the acquired immunodeficiency syndrome (AIDS) the pandemic continues to call for novel drugs and for new management strategies. Several steps in the HIV-1 replication cycle are potential targets for treatment interventions. Twenty-five compounds are approved by the FDA but there is still urgent need for new classes of antiretroviral drugs. Major concerns are long-term toxicity and development of resistant HIV-1 strains. Currently treatment regimens are combinations of inhibitors of two viral enzymes – the reverse transcriptase and the protease. According to their mechanism of action antiretroviral substances can be divided into the following groups: 1.) Nucleoside reverse transcriptase inhibitors. 2.) Non-nucleoside reverse transcriptase inhibitors. 3.) Nucleotide reverse transcriptase inhibitors. 4.) HIV-1 protease inhibitors. 5.) Entry inhibitors. 6.) Integrase inhibitors, and 7.) Maturation inhibitors. Further subjects of investigation are the development of an AIDS vaccine and the evaluation of preventive strategies like pre-exposure prophylaxis and male circumcision. In contrast to the favourable results of the male circumcision studies the recent suspension of two vaccine trials, the STEP and the Phambili trial, and of the first placebo-controlled study of a vaginal microbicide for prevention of HIV-1 acquisition represents a serious draw back in the fields of vaccine development and prophylaxis. This review summarizes the following topics: 1.) Natural history and immune pathogenesis of HIV-1 infection. 2.) Development of antiretroviral therapy and its viral targets. 3.) Mechanisms of action of antiretroviral drugs. 4.) Approved and novel compounds of existing and new classes. 5.) AIDS vaccine development. 6.) Management strategies with respect to antiretroviral therapy and HIV-1 transmission. Keywords: HIV-1 infection, antiretroviral therapy, management strategies, prevention

BackgroundPulmonary tumorlets are usually an incidental pathologic curiosity of no clinical importance, but may be mistaken for epithelial and nonepithelial neoplasms. Fine needle aspiration (FNA) of this cell proliferation has rarely been reported. We describe a pulmonary tumorlet associated with bronchocentric granulomatosis presenting as a tumorous consolidation on chest radiograph.CaseIn a hitherto healthy 70-year old man admitted for acute respiratory infection, a solid consolidation was found on chest radiograph. Medical history was uneventful except right-sided pleurisy in 1949. Computed tomography-guided FNA sample was composed of loose clusters of small columnar cells with cyanophilic cytoplasm. and centrally located round to oval nuclei. With a tentative diagnosis of well-differentiated adenocarcinoma, lumpectomy was performed. Intraoperative Cytology demonstrated lymphocytes, epithelioid cells, giant cells of Langerhans type and clusters of columnar cells. Definitive histologic examination confirmed the intraoperative diagnosis of necrotizing granulomatosis and tumorlet. Neuroendocrine origin of the cells was confirmed by immunocytochemical and immunohistochemical studies resulting in strong reactivity of the cells to syptophysin, NSE, chromogranin A and N-Cam.ConclusionKnowledge of the cytomorphologic presentation of tumorlets in, FNA and consideration of the appropriate differential diagnoses combined with ancillary studies might have prevented lung resection.

INTRODUCTION:In adults, peripheral primitive neuroectodermal tumors (pPNETs) represent a rare and heterogeneous group of neoplasms exhibiting neuronal and glial differentiation.PATIENTS AND METHODS:We present the clinicopathologic features of four examples of the Ewing's sarcoma (EWS)/pPNET group in adults. Hematoxylin and eosin staining, immunohistochemical and molecular studies were reviewed in every case. Immunohistochemical stains were performed on formalin-fixed, paraffin-embedded sections, molecular studies were done using fluorescence in situ hybridization (FISH).RESULTS:Three patients presented with tumors of the thoracopulmonary region, one patient showed EWS of the soft tissue. Microscopically, tumor tissue was composed of round, small, blue cells with fine granular chromatin texture and inconspicuous nucleoli. Mitotic figures and rosettes were present. Tumor cells strongly coexpressed CD99 and vimentin, but due to technical reasons t(22q12) translocation studies proved the presumptive diagnosis of EWS/pPNET in one case only. Despite similar multimodality treatment survival time ranged from 6 to 42 months, two patients were alive at the time of reporting.CONCLUSIONS:As tumors of the EWS/pPNET family behave aggressively, rapid diagnosis is warranted. Since diagnosis of EWS/pPNET requires ancillary studies, it is necessary to consider it even in adult patients.

Late thrombosis of drug-eluting stents (DES) has been reported to occur up to 26 months after implantation [1]. Stent thrombosis is a life-threatening emergency, and risk factors for late thrombosis in DES are the premature discontinuation of antiplatelet therapy, renal failure, bifurcation lesions, diabetes and low ejection fraction [1–3]. Whether HIV-positive patients are more prone to stent thrombosis than individuals without HIV infection is unknown [4]. We describe the occurrence of a stent thrombosis 23 months after DES implantation, and 6 weeks after the discontinuation of clopidogrel in an HIV-infected patient under HAART. Case report A 61-year-old male patient was admitted in October 2005 because of an acute anterior wall infarction. As a result of angina pectoris diagnosed in November 2003, coronary angiography had been performed and two polymer-based paclitaxel-eluting stents were implanted in the proximal part of the left anterior descending artery. A combination therapy with acetylsalicylic acid (100 mg/day) and clopidogrel (75 mg/day) was initiated. Because of hypercholesterolemia pravastatin (20 mg/day) was started. The patient continued to smoke two to three cigarettes a day. Clopidogrel was discontinued after 21 months for exceeding the recommended therapy duration of 6–12 months. In November 2003, he was diagnosed as being HIV infected, possibly as a result of non-tested blood transfusions that he had received 15 years previously. He denied using illicit drugs and anabolic steroids. The patient was without HIV-related symptoms and had a CD4 cell count of 263 cells/μl and a plasma viral load of 5.6 log. In June 2004, HAART was initiated, consisting of stavudine extended release 100 mg, tenofovir 245 mg and efavirenz 600 mg all administered once a day. HAART was well tolerated, and 4 months later the patient's viral load was suppressed below the level of detection and his CD4 cell count had risen to 337 cells/μl. In May 2005, stavudine was substituted by lamivudine 300 mg as a result of early signs of polyneuropathy. In October 2005, the patient arrived at the hospital 10 h after the sudden onset of chest pain. His blood pressure was 90/60 mmHg. A complete blood cell count was within normal ranges. Blood chemistry revealed increased levels of fasting glucose (8.16 mmol/l, normal 3.9–6.1 mmol/l), potassium (5.6 mmol/l, normal 3.5–5.5 mmol/l), creatine phosphokinase (1409 U/l, normal up to 170 U/l) and lactate dehydrogenase (432 U/l, normal up to 247 U/l). Serum cholesterol, high-density and low-density lipoprotein cholesterol levels showed normal results in contrast to elevated triglyceride levels (2.41 mmol/l, normal < 1.8 mmol/l). Activity of antithrombin III, protein C, factor XI and factor VIII, and levels of protein S antigen, activated protein C-resistance ratio and homocysteine were all normal. Tests for lupus-sensitive activated partial thromboplastin time, dilute Russell viper venom time and beta 2-glycoprotein antibody were negative, as well as mutation screening for 1.691 G→A and 20.210 G→A. An oral glucose tolerance test was normal. The electrocardiogram showed sinus tachycardia 125/min, negative T-waves in V1–V3 and ST elevations in V2–V6. Coronary angiography revealed a complete thrombotic occlusion of the DES in the left anterior descending artery. A stent-in-stent implantation of a polymer-based paclitaxel-eluting stent was performed after recanalization. Clopidogrel medication was recommended indefinitely. Creatine phosphokinase peaked up to 9575 U/l. Echocardiographically and by radionuclide ventriculography a large akinesia of the left ventricular apex, the anterior wall and the middle and apical region of the interventricular septum was found. The further course was complicated by pulmonary congestion. Therapy with angiotensin-converting enzyme inhibitors, beta antagonists and diuretics was started. At the time of writing the patient was still in heart failure New York Heart Association class III and the implantation of a cardiac defibrillator was being considered. In the absence of acknowledged risk factors, the case raises the question as to whether either HIV infection or HAART contributed to the stent thrombosis. Impaired endothelial function that results in decreased flow-mediated dilation may be caused either by the HIV infection itself or by HAART [5,6]. In addition, endothelial cells have been reported to be direct targets of certain HIV-1 isolates [7]. HAART decreases the morbidity and mortality of HIV infection but is associated with the premature manifestation of coronary artery disease [8]. Endothelial cells possibly play an important role in this process [9]. The degree of endothelialization of the DES remains unknown because of the lack of an intravascular ultrasound investigation. Coagulation studies showed normal results, making stent thrombosis caused by an underlying coagulation disorder unlikely [10]. A case–control study demonstrated altered neo-intima formation after DES resulting in an increasing risk of late stent thrombosis in HIV-infected patients [4]. In HIV-infected patients with DES, lifelong therapy with acetylsalicylic acid and clopidogrel is recommended. Because of the bleeding risk of this combination therapy, bare metal stents instead of DES should be considered in HIV-infected patients.

BACKGROUND:The broadly neutralizing recombinant human HIV-1 antibodies 4E10, 2F5 and Igh1b12 are reported to have autoreactive potential, which is significant for HIV-1 vaccine development and passive immunotherapy using these antibodies.OBJECTIVE:To investigate the clinical relevance of these findings in subjects receiving passive immunotherapy with these antibodies.METHODS:Four types of investigations were performed: (1) Investigation of clotting parameters in an ongoing clinical study with 4E10, 2F5 and 2G12. (2) Mixing experiments of pooled plasma with the same antibodies. (3) Retrospective analysis of serum from patients who received passive immunotherapy with 4E10, 2F5 and 2G12 either alone or in combination. (4) Assessment of clinical safety data obtained after 418 infusions with these antibodies.RESULTS:Standard clinical assays confirmed that 4E10 showed low-level cross-reactivity with cardiolipin, while previously reported cardiolipin cross-reactivity for 2F5 could not be confirmed. High serum titers of 4E10 induced mild prolongation of the activated partial thromboplastin time, which resolved with the wash out of 4E10. Neither 2F5 nor 2G12 affected coagulation. Repeated high-dose infusions of the monoclonal antibody combination were well tolerated with no incidence for thrombotic complications after 418 infusions in 39 subjects.CONCLUSIONS:Monoclonal antibody 4E10 but not 2F5 or 2G12 showed autoreactive binding specificities. Infusion of 4E10 resulted in transient low anticardiolipin titers. Although an increased thromboembolic risk cannot definitely be excluded, this risk appears to be low and likely depend on underlying disorders.

ABSTRACT While certain antibodies directed against the human immunodeficiency virus (HIV) envelope have the potential to suppress virus replication in vitro, the impact of neutralizing antibodies in vivo remains unclear. In a recent proof-of-concept study, the broadly neutralizing monoclonal antibodies 2G12, 4E10, and 2F5 exhibited inhibitory activities in vivo, as exemplified by a delay of the viral rebound following the interruption of antiretroviral therapy. Unexpectedly, the antiviral effect seen was most prominently due to 2G12 activity. To further investigate whether differential HIV-inhibitory activity was due to different pharmacokinetic properties of the antibodies, we performed a formal pharmacokinetic analysis with 14 patients. Repeated infusions at high dose levels were well tolerated by the patients and did not elicit an endogenous immune response against the monoclonal antibodies. The pharmacokinetic parameters of all three antibodies correlated with each other. Mean estimates were 0.047, 0.035, and 0.044 liter/kg for the central volume of distribution of 2G12, 4E10, and 2F5, respectively, and 0.0018, 0.0058, and 0.0077 liter/kg · day for the systemic clearance of 2G12, 4E10, and 2F5, respectively. Monoclonal antibody 2G12 had a significantly longer elimination half-life (21.8 ± 7.2 days [P < 0.0001]) than monoclonal antibodies 4E10 (5.5 ± 2.2 days) and 2F5 (4.3 ± 1.1 days). The comprehensive pharmacokinetic data from this long-term multiple-dose phase II study were coherent with those from previous short-term phase I studies, as assessed by compartmental and noncompartmental techniques. The anti-HIV type 1 antibodies studied showed distribution and elimination kinetics similar to those seen for other human-like antibodies. Further studies examining tissue concentrations to explain the differential in vivo activity of the anti-gp120 antibody compared with those of the two anti-gp41 antibodies are warranted.

Neurosarcoidosis is often a diagnostic dilemma, especially in the absence of other organ involvement. We report a 64-year-old patient who had suffered from paraplegia due to an intramedullar process since 1995. The presumptive diagnosis based on computed tomography was spinal cord infarction. Six years later, he complained about increasing paresthesia. Magnetic resonance imaging of the spinal cord showed nodular meningeal enhancement. Computed tomography of the thorax revealed mediastinal and hilar lymphadenopathy. Bronchoscopy under generalized anesthesia was performed. The differential cell count in bronchoalveolar lavage fluid showed 39% lymphocytes and a CD4(+)/CD8(+) ratio of 17.7. Histological examination of biopsy specimens from the hilar lymph nodes revealed non-necrotizing granulomas with epitheloid cells and Langerhans-type giant cells, consistent with the diagnosis of sarcoidosis. As a result of these findings, lumbar puncture was undertaken and a raised protein concentration and pleocytosis were found in the cerebrospinal fluid. The number of lymphocytes (9,250 lymphocytes/l) and a CD4(+)/CD8(+) ratio of 10.78 led to the diagnosis of neurosarcoidosis. Paralysis might have been prevented if the correct diagnosis of neurosarcoidosis had been established earlier in this patient.