De novo subacute cutaneous lupus erythematosus-like eruptions in the setting of programmed death-1 or programmed death ligand-1 inhibitor therapy: clinicopathological correlation.

Immune checkpoint inhibitors (ICI) may cause eruptions resembling cutaneous autoimmune diseases. There are six cases of immunotherapy-associated subacute cutaneous lupus erythematosus (SCLE) in the literature. We present details of five patients referred to the Skin Toxicity Program at the Dana-Farber Cancer Institute/Brigham and Women's Cancer Center who developed de novo immunotherapy-associated SCLE-like eruptions, along with clinicopathological correlation and highlight potential mechanistic features and important diagnostic points. Two patients were maintained on topical corticosteroids, antihistamines and photoprotection. One had complete clearance and two had improvement with addition of hydroxychloroquine. Four patients continued their immunotherapy uninterrupted, while one had immunotherapy suspended for a month before restarting at full dose. Histopathologically, this series illustrates the temporal evolution of ICI-induced immune cutaneous reactions with SCLE subtype. Looking beyond the universally present lichenoid infiltrate, features of evolving SCLE were evident. We hypothesize that programmed death-1 blockade may induce immunological recognition of previously immunologically tolerated drug antigens, leading to epitope spreading and the SCLE phenotype.

Charged nanoparticle dynamics in water induced by scanning transmission electron microscopy.

Using scanning transmission electron microscopy we image ~4 nm platinum nanoparticles deposited on an insulating membrane, where the membrane is one of two electron-transparent windows separating an aqueous environment from the microscope's high vacuum. Upon receiving a relatively moderate dose of ~10(4) e/nm(2), initially immobile nanoparticles begin to move along trajectories that are directed radially outward from the center of the field of view. With larger dose rates the particle motion becomes increasingly dramatic. These observations demonstrate that, even under mild imaging conditions, the in situ electron microscopy of aqueous environments can produce electrophoretic charging effects that dominate the dynamics of nanoparticles under observation.

Probing Planck's law with incandescent light emission from a single carbon nanotube.

We present thermal and electron micrographs of an incandescent lamp constructed from a multiwalled carbon nanotube, and correlate the subwavelength optical information with the underlying nanoscopic structure. Remarkably, the heat equation and Planck's law together give a precise, quantitative description of the light intensity as a function of input power, even though the nanotube's small size places it outside the thermodynamic limit.

Metallic stents in the treatment of duodenal obstruction: technical issues and results.

OBJECTIVE: To evaluate the efficacy of duodenal stenting procedures and to review technical issues with these procedures in a series of cases over a 1-year period. METHODS: Expandable metallic stents (Wallstents) of varying sizes were introduced and deployed in 4 patients (1 man and 3 women 42 to 81 years of age). Each patient underwent a separate method of stent introduction with either fluoroscopic or endoscopic guidance, either perorally, transgastrically and transhepatically. RESULTS: All procedures were technically successful, allowing patients to continue eating normally. In 1 patient, stent foreshortening necessitated the introduction of a second stent. Another patient experienced transient stent obstruction by food; this resolved spontaneously and required no additional intervention. Based on the patients' continuing ability to tolerate food, it was believed that the stents remained patent until the time of death (from 3 days to 9 weeks with a mean of 5.25 weeks). CONCLUSIONS: Duodenal stenting procedures provide a relatively new, technically feasible and efficacious method of managing duodenal obstructions, especially in patients who are poor candidates for surgery.

Pediatric tetracycline-induced pseudotumor cerbri.

BACKGROUND: Tetracyclines have long been recognized as a cause of pseudotumor cerebri in adults, but the role of tetracyclines in the pediatric age group has not been well characterized in the literature and there have been few reported cases. We present 6 cases to better delineate the problem, the patient profile, the response to treatment, and the sequelae. METHODS: We retrospectively analyzed the records of all patients admitted with a diagnosis of pseudotumor cerebri who had documented usage of a tetracycline-class drug immediately before presentation at the Hospital For Sick Children in Toronto, Canada, from January 1, 1986, to March 1, 1996. RESULTS: Six patients (5 female, 1 male) who met all inclusion and exclusion criteria were identified; their ages ranged from 12 to 17 years. All were being treated for acne vulgaris. Duration of use before diagnosis was as short as 2 weeks and as long as 10 months, with a mean of 4.4 months. Duration of symptoms ranged from 0.57 to 4 weeks. Symptoms included headache (6 of 6), nausea (5 of 6), and diplopia (4 of 6). All for whom height and weight data were known (5 of 6) were in the upper quartile for body mass index. Visual acuity was 6/6 in all but 1 eye of one patient (6/9) at diagnosis, and final visual acuity was 6/6 in all patients. All had normal color vision, where this was recorded (5 of 6). The only recorded field defect was enlargement of the blind spot (4 of 6). All patients responded to treatment, with loss of symptoms in 1 day to 4 weeks. CONCLUSIONS: Pseudotumor cerebri as a result of tetracycline-class drugs does occur in the pediatric population. With prompt and appropriate medical treatment, long-term sequelae can almost always be avoided. Physicians who treat patients with tetracyclines need to be aware of the potential complications in children.

Outbreak of ceftazidime resistance due to a novel extended-spectrum beta-lactamase in isolates from cancer patients.

Ceftazidime is widely used in the therapy of infectious complications in neutropenic patients. We studied an outbreak of ceftazidime-resistant gram-negative bacillary infections in pediatric cancer patients receiving empirical ceftazidime therapy for neutropenic fever. Fourteen isolates (12 Klebsiella pneumoniae and 2 Escherichia coli) from 13 patients were studied. Specimens were obtained from multiple clinical sites including blood, urine, throat, and lung. The organisms were resistant to ceftazidime, aztreonam, and penicillins but remained susceptible to cephamycins and imipenem. All resistant isolates produced a novel beta-lactamase (TEM-26) with a pI of approximately 5.58, which was transferred by transformation to E. coli on a 7.9-kb nonconjugative plasmid which cotransferred resistance to trimethoprim-sulfamethoxazole. This enzyme readily hydrolyzed ceftazidime, aztreonam, and penicillins in a spectrophotometric assay. DNA sequencing data suggest that TEM-26 is derived from TEM-1.

Effect of clavulanic acid on activity of beta-lactam antibiotics in Serratia marcescens isolates producing both a TEM beta-lactamase and a chromosomal cephalosporinase.

An isolate of Serratia marcescens that produced both an inducible chromosomal and a plasmid-mediated TEM-1 beta-lactamase was resistant to ampicillin and amoxicillin and also demonstrated decreased susceptibility to extended-spectrum beta-lactam antibiotics (ESBAs). Clavulanic acid did not lower the MICs of the ESBAs, but it decreased the MICs of the penicillins. The TEM-1-producing plasmid was transferred to a more susceptible S. marcescens strain that produced a well-characterized inducible chromosomal beta-lactamase. The MICs of the ESBAs remained at a low level for the transconjugant. Ampicillin and amoxicillin which were good substrates for the plasmid-mediated enzyme, were not well hydrolyzed by the chromosomal enzymes; the ESBAs were hydrolyzed slowly by all the enzymes. When each of the S. marcescens strains was grown with these beta-lactam antibiotics, at least modest increases in chromosomal beta-lactamase activity were observed. When organisms were grown in the presence of clavulanic acid and an ESBA, no enhanced induction was observed. The increases in the MICs of the ESBAs observed for the initial clinical isolate may have been due to a combination of low inducibility, slow hydrolysis, and differences in permeability between the S. marcescens isolates. When clavulanic acid and a penicillin were added to strains that produced both a plasmid-mediated TEM and a chromosomal beta-lactamase, much higher levels of chromosomal beta-lactamase activity were present than were observed in cultures induced by the penicillin alone. This was due to the higher levels of penicillin that were available for induction as a result of inhibition of the TEM enzyme by clavulanate.

Substitution of lysine at position 104 or 240 of TEM-1pTZ18R beta-lactamase enhances the effect of serine-164 substitution on hydrolysis or affinity for cephalosporins and the monobactam aztreonam.

By site-directed mutagenesis, TEM-1 beta-lactamase was altered to contain single amino acid changes of E104K, R164S, and E240K, in addition to double changes of E104K/R164S or R164S/E240K and the triple change of E104K/R164S/E240K. Hydrolysis rates for cephaloridine and benzylpenicillin were lowered at least 1 order of magnitude for all enzymes containing R164S substitutions. All mutant enzymes exhibited increased kcat values for beta-lactam antibiotics containing an aminothiazole oxime side chain. Hydrolysis of ceftazidime was most affected, with kcat values increased 3-4 orders of magnitude in all enzymes with the substituted R164S moiety. Km values decreased for all substrates except ceftazidime in the enzymes with multiple mutations. Aztreonam was most affected, with Km values lowered 23-56-fold in the enzymes bearing multiple mutations. When the crystal structures of aztreonam and related monobactams were studied and projected into an active-site model of the PC1 beta-lactamase, it became apparent that the two lysine residues might serve equivalent roles by interacting with the carboxylate of the aminothiazole oxime side chain. Hydrogen-bonding interactions involving the oxime and N7 of the lysine, particularly Lys-104, may also be important in some antibiotics. Ser-164 apparently serves an indirect role, since it is somewhat distant from the active-site cleft.

Biochemical characteristics of extended broad spectrum beta-lactamases.

Extended broad spectrum beta-lactamases such as TEM-3 (CTX-1), TEM-5 (CAZ-1), TEM-10 and RHH-1 were purified and found to have lower specific activities than the TEM-1 or TEM-2 beta-lactamases. Total hydrolytic activity in crude extracts was also lower for the extended broad spectrum enzymes. These beta-lactamases hydrolyzed not only penicillins such as carbenicillin, cloxacillin and piperacillin, but also cephalosporins and monobactams. The most notable differences in substrate profiles between the extended broad spectrum enzymes and TEM-2 enzymes occurred with oxime-containing antibiotics. Although all the extended broad spectrum enzymes described above hydrolyzed cefotaxime, ceftazidime and aztreonam, the four enzymes could be easily differentiated: TEM-3 hydrolyzed cefotaxime preferentially, TEM-5 and RHH-1 hydrolyzed ceftazidime approximately three times faster than cefotaxime, whereas TEM-10 hydrolyzed ceftazidime 42 times faster than cefotaxime. All the enzymes were inhibited well by clavulanic acid, with I50 values ranging from 4.3 to 12 nM, compared to 130 nM for TEM-2. Inhibition by sulbactam was also better for the extended broad spectrum than for the TEM-2 beta-lactamases, with I50 values of 12-940 nM for the extended broad spectrum enzymes, compared to 1600 nM for the TEM-2 beta-lactamase.