Legionella pneumophila is able to survive inside phagocytic cells by an internalization route that bypasses fusion of the nascent phagosome with the endocytic pathway to allow formation of a replicative phagosome. The dot/icm genes, a major virulence system of L. pneumophila, encode a type IVB secretion system that is required for intracellular growth. One Dot protein, DotL, has sequence similarity to type IV secretion system coupling proteins (T4CPs). In other systems, coupling proteins are not required for viability of the organism. Here we report the first example of a strain, L. pneumophila Lp02, in which a putative T4CP is essential for viability of the organism on bacteriological media. This result is particularly surprising since the majority of the dot/icm genes in Lp02 are dispensable for growth outside of a host cell, a condition that does not require a functional Dot/Icm secretion complex. We were able to isolate suppressors of the ⌬dotL lethality and found that many contained mutations in other components of the Dot/Icm secretion system. A systematic analysis of dot/icm deletion mutants revealed that the majority of them (20 of 26) suppressed the lethality phenotype, indicating a partially assembled secretion system may be the source of ⌬dotL toxicity in the wild-type strain. These results are consistent with a model in which the DotL protein plays a role in regulating the activity of the L. pneumophila type IV secretion apparatus.The gram-negative bacterium Legionella pneumophila is the causative agent of a potentially fatal form of pneumonia called Legionnaires' disease. L. pneumophila is found in freshwater environments, where it parasitizes many different species of protozoa (17). Humans become infected with L. pneumophila by inhaling aerosols generated from contaminated water sources. Upon entry into the human lung, L. pneumophila is internalized into bactericidal, alveolar macrophages. In contrast to phagosomes bearing most bacterial species, the compartment harboring L. pneumophila does not traffic into the lysosomal network and is not significantly acidified in the first few hours after uptake (26,27). Instead, the phagosome interacts with early secretory vesicles at endoplasmic reticulum exit sites (29) and then undergoes a series of maturation events in which it sequentially associates with small vesicles, mitochondria, and eventually becomes surrounded by the rough endoplasmic reticulum (25, 60). Formation of this specialized compartment, called a "replicative phagosome," allows the microorganism to grow intracellularly (25, 28). Later in the infective cycle, a majority of the replicative phagosomes fuse with acidified compartments containing late endocytic markers, and this is believed to play an important role in the replicative cycle of this pathogen prior to exit from its host cell (59).The key to L. pneumophila's virulence is its ability to form a replicative phagosome, since mutants defective in this trait cannot replicate inside host cells and are thus unable to cause disease (24,26...

Purpose Bortezomib is a small-molecule proteasome inhibitor with single-agent activity in patients with non-small cell lung carcinoma (NSCLC) and synergy with gemcitabine in preclinical studies. This phase II study of bortezomib in combination with gemcitabine/carboplatin was conducted in chemotherapy-naïve advanced NSCLC patients to assess efficacy and safety. Patients and Methods Patients with selected stage IIIB/IV NSCLC, performance status 0–1, and no history of brain metastasis received up to six 21-day cycles of gemcitabine 1,000 mg/m2, days 1 and 8, carboplatin AUC 5.0, day 1, and bortezomib 1.0 mg/m2, days 1, 4, 8, and 11. Results 114 patients (52% adenocarcinoma, 85% stage IV) received a median of 3.6 treatment cycles. Median follow-up was > 3 years. Median overall survival (OS) was 11 months; 1-year and 2-year survival rates were 47% and 19%, respectively. Median PFS was 5 months; 1-year PFS rate was 7%. Response rate was 23%, and disease control rate (responses + stable disease) was 68%. The most common grade 3/4 toxicities were thrombocytopenia (63%) and neutropenia (52%). One patient experienced febrile neutropenia. Grade 3/4 neuropathy occurred in 4%. Conclusions Bortezomib plus gemcitabine/carboplatin resulted in a notable survival benefit in patients with advanced NSCLC, with the anticipated primary toxicity of myelosuppression. Further studies designed to investigate the role of bortezomib in advanced NSCLC are warranted.

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Venous malformations (VMs) are congenital anomalies of the venous vasculature, but not all are evident at birth. The factors that lead to presentation later in life are not well understood. The objective of this retrospective cohort study of patients with VMs evaluated at the University of California at San Francisco Birthmarks and Vascular Anomalies Center from 2005 to 2009 was to investigate the clinical presentation of VMs and correlate these features with different types of tissues (e.g., skin, subcutis, intramuscular). Main outcomes included the age at which lesions were first noticed, tissue type involved, presenting signs and symptoms, aggravating factors, and morbidities. A total of 115 subjects was included. The mean age when VM was first noted was 6.7 ± 0.9 years. Tissue types involved included skin/subcutaneous (46%); intramuscular (40%); and bone, tendon, or joint (14%). Presenting signs/symptoms included soft tissue swelling (44%), discrete mass (34%), pain (33%), and skin discoloration (26%). When compared with VMs limited to the skin or subcutis, those restricted to the intramuscular compartment were less likely to present at birth (27% vs 53%, p < 0.05) but were more frequently painful (79% vs 60%, p < 0.05) and contained more phleboliths (28% vs 11%, p < 0.05), and were associated with more exercise limitation (35% vs 16%, p < 0.05). VMs differ in age of onset, clinical features, and complications based on differing tissues and sites of involvement, with isolated intramuscular involvement associated with later presentation and greater morbidity.

Patients: Children with psoriasis ages 0 (birth) to 18 years. Main Outcome Measures: Demographics, physician specialty, and medications prescribed. Results: There were an estimated 3.8 million visits for psoriasis over the study interval with a median of 123 420 visits per year. Dermatologists saw 63% of patients, pediatricians saw 17%, and internists, 14%. The numbers of visits were equal between sexes but ranged by age group: patients ages 13 to 18 years accounted for 47% of visits, those ages 8 to 12 years for 35%, and those ages 0 to 7 for 18%. Ninety-three percent of patients were white. Topical corticosteroids were the most commonly prescribed medications. Children 0 to 9 years old received equally potent corticosteroids as children 10 to 18 years old. Among all patients, the most prescribed medication was topical betamethasone; among those ages 0 to 9 years, tacrolimus; and among those ages 10 to 18 years, betamethasone. By physician specialty, the most prescribed medications were high-potency steroids for dermatologists and internists, and topical tacrolimus for pediatricians. Topical calcineurin inhibitors were not among the top 20 most prescribed medications by dermatologists, and systemic antipsoriatic agents were not among the top 20 most prescribed medications in any age group. Conclusions: Over the 28-year interval, outpatient visits for pediatric psoriasis were attended primarily by white children older than 8 years in equal number by sex. Dermatologists and pediatricians saw the majority, and treatment approach differed by physician specialty and patient age. Treatment guidelines for childhood psoriasis may help reduce treatment variability.

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