Deliberately Losing Control of C−H Activation Processes in the Design of Small-Molecule-Fragment Arrays Targeting Peroxisomal Metabolism

Combined photochemical arylation, “nuisance effect” (S_NAr) reaction sequences have been employed in the design of small arrays for immediate deployment in medium-throughput X-ray protein–ligand structure determination. Reactions were deliberately allowed to run “out of control” in terms of selectivity; for example the ortho-arylation of 2-phenylpyridine gave five products resulting from mono- and bisarylations combined with S_NAr processes. As a result, a number of crystallographic hits against NUDT7, a key peroxisomal CoA ester hydrolase, have been identified.     

Real-time organic aerosol chemical speciation in the indoor environment using extractive electrospray ionization mass spectrometry

Understanding the sources and composition of organic aerosol (OA) in indoor environments requires rapid measurements, since many emissions and processes have short timescales. However, real-time molecular-level OA measurements have not been reported indoors. Here, we present quantitative measurements, at a time resolution of five seconds, of molecular ions corresponding to diverse aerosol-phase species, by applying extractive electrospray ionization mass spectrometry (EESI-MS) to indoor air analysis for the first time, as part of the highly instrumented HOMEChem field study. We demonstrate how the complex spectra of EESI-MS are screened in order to extract chemical information and investigate the possibility of interference from gas-phase semivolatile species. During experiments that simulated the Thanksgiving US holiday meal preparation, EESI-MS quantified multiple species, including fatty acids, carbohydrates, siloxanes, and phthalates. Intercomparisons with Aerosol Mass Spectrometer (AMS) and Scanning Mobility Particle Sizer suggest that EESI-MS quantified a large fraction of OA. Comparisons with FIGAERO-CIMS shows similar signal levels and good correlation, with a range of 100 for the relative sensitivities. Comparisons with SV-TAG for phthalates and with SV-TAG and AMS for total siloxanes also show strong correlation. EESI-MS observations can be used with gas-phase measurements to identify co-emitted gas- and aerosol-phase species, and this is demonstrated using complementary gas-phase PTR-MS observations.     

Murine thymic lymphoma is associated with a species-specific hematopoietic progenitor cell subpopulation

Many strains of laboratory mouse are uniquely susceptible to the development of T cell lymphoma/leukemia, either spontaneously or as a result of chemical or radiation exposure. In contrast, T cell leukemias or lymphomas which are relatively uncommon in human populations, are not easily induced by radiation, and are not generally associated with chemotherapy or chemical exposure. Evidence is presented to suggest that differences in the susceptibility to the development of these malignancies is related to subtle but important variations in the regulation of hematopoietic stem cell differentiation between these two species.     

Treatment of hypertension in nondiabetic renal disease

To clarify whether long-term impaired glucose tolerance (IGT) is associated with dysfunction of peripheral and autonomic nerves, age-matched men with IGT and diabetes mellitus were followed prospectively for 12-15 years, when peripheral and autonomic nerve function was assessed. The patients comprised four subgroups: (1) 51 IGT subjects (duration of IGT at least 12-15 years); (2) 35 diabetic patients, with IGT 12-15 years ago, who later developed diabetes; (3) 34 diabetic patients, duration of diabetes at least 12-15 years; and (4) 62 age-matched non-diabetic control subjects. Mean age of the whole study population was 61 +/- 2 years (mean +/- SD), not different in the four groups. Peripheral nerve function tests included nerve conduction velocities, amplitudes, distal latencies, F-reflexes, and sensory perception thresholds for heat, cold, and vibration. Autonomic nerve function tests included the heart rate reaction during deep breathing (expiration to inspiration ratio) and to tilt (acceleration and brake indices). Despite 12-15 years of IGT, peripheral nerve function did not differ between IGT and control subjects, whereas autonomic nerve function deviated; an abnormal expiration to inspiration ratio (a sign of vagal nerve dysfunction) was significantly more common (15/51 versus 5/62; p < 0.01) in IGT than in control subjects. Diabetic patients (groups 2 and 3) showed lower conduction velocities (in general 2-4 m s-1 lower) than IGT and control subjects in all tested nerves. In conclusion, diabetes but not IGT, is associated with peripheral nerve dysfunction.     

Mantle cell lymphoma: a clinicopathologic study of 80 cases

Mantle cell lymphoma (MCL) is a relatively uncommon yet distinct type of malignant lymphoma whose clinical and pathological characterization has been limited by the small numbers of cases published to date. We studied 80 cases of MCL seen at a single institution over 7 years to determine both clinical and pathological prognostic factors. The patients in this study were predominantly male (70%) and older (mean age, 63 years) and presented with advanced-stage disease (88%). Extranodal involvement was common. Median overall survival (OS) was 43 months. Except for performance status, prognosis was not significantly influenced by clinical prognostic factors. Histologically, MCL architecture was classified as diffuse (78%), nodular (16%), or mantle zone (6%); the OS among these groups was identical. Increased mitotic activity (>20 mitotic figures per 10 high power fields), blastic transformation, and peripheral blood involvement at diagnosis also predicted for a worse outcome, but bone marrow involvement did not. The presence or absence of a translocation t(11; 14) by cytogenetic analysis or a bcl-1 rearrangement by Southern analysis did not significantly predict outcome. In summary, this study of 80 cases of MCL highlights its distinctive clinicopathologic features and shows that increased mitotic activity, blastic morphology, and peripheral blood involvement at diagnosis are prognostically important factors.     

Infections in patients with cystic fibrosis following lung transplantation

BACKGROUND: There is controversy over whether colonization with drug-resistant organisms is a contraindication to lung transplantation. METHODS: We undertook a retrospective review of the results of lung transplantation for patients with cystic fibrosis (CF) at Duke University Medical Center. RESULTS: As of May 1996, 21 patients with CF underwent bilateral lung transplantation. The first patient died within 24 h of transplantation from sepsis due to Stenotrophomonas maltophilia. Of the remaining 20 patients, 17 (85%) are alive and in stable condition. The three deaths were related primarily to bronchiolitis obliterans at 4 and 18 months in two patients and to cytomegalovirus pneumonitis at 5 months in the other patient. The 17 surviving patients have been followed up for a mean of 13 months (range, 0.5 to 34 months). Most of them were colonized and infected with multidrug-resistant organisms before transplantation. Following transplantation, 11 patients had complications from infections. One patient had bacteremia due to a panresistant Burkholderia cepacia and was treated successfully. Two patients had bacteremia and wound infection due to Burkholderia gladioli, previously thought to be pathogenic only in plants. Both patients were treated successfully. Of the six patients with Aspergillus fumigatus isolated from cultures before transplantation, only one had invasive disease following transplantation and responded to treatment. CONCLUSION: The organisms present before transplantation were not the primary cause of mortality in our patient population. Our findings suggest that lung transplantation should be considered in CF patients infected with multidrug-resistant organisms.     

Review of thymic pathology in 30 cats and 36 dogs

Data are presented from 30 cats and 36 dogs in which thymic disease was recognised clinically or on postmortem examination. The diagnoses included thymic lymphoma (19 cats, 12 dogs), thymoma (five cats, 18 dogs), thymic branchial cyst formation or cystic change (one cat, four dogs), thymic hyperplasia (two cats), congenital hypoplasia (one cat, one dog), thymic haemorrhage (one cat, one dog) and thymic amyloidosis (one cat). Thymic lymphoma occurred in younger dogs and cats, and was recorded equally among domestic shorthaired and purebred (especially Siamese) cats. Eight cats with thymic lymphoma were tested for feline leukaemia virus and four were positive. Thymoma occurred more frequently in older cats and dogs, and in Labradors and German shepherd dogs. Thymic tumours were associated with paraneoplastic hypercalcaemia (six dogs), megaoesophagus (two dogs) or interface dermatitis with basement membrane immune complex deposition (one cat). Non-neoplastic thymic diseases were associated with myasthenia gravis (one cat), pemphigus foliaceus (one cat) and superficial necrolytic dermatitis (one cat).