Are rates of psychiatric disorders in the homeless population changing?

OBJECTIVES: We examined the prevalence of psychiatric illness among 3 homeless populations in St. Louis, Mo, in approximately 1980, 1990, and 2000. The 3 studies were conducted with the same systemic research methodology. METHODS: We compared selected demographics and lifetime substance abuse and dependence and other mental illness among the 3 populations. RESULTS: Among the homeless populations we studied, the prevalence of mood and substance use disorders dramatically increased, and the number of minorities within these populations has increased. CONCLUSIONS: The prevalence of psychiatric illness, including substance abuse and dependence, is not static in the homeless population. Service systems need to be aware of potential prevalence changes and the impact of these changes on service needs.     

Parental social determinants of risk for intentional injury: a cross-sectional study of Swedish adolescents

OBJECTIVES: We investigated the effect of family social and economic circumstances on intentional injury among adolescents. METHODS: We conducted a cross-sectional register study of youths aged 10 to 19 years who lived in Sweden between 1990 and 1994. We used socioeconomic status, number of parents in the household (1- or 2-parent home), receipt of welfare benefits, parental country of birth, and population density as exposures and compiled relative risks and population-attributable risks (PARs) for self-inflicted and interpersonal violence-related injury. RESULTS: For both genders and for both injury types, receipt of welfare benefits showed the largest crude and net relative risks and the highest PARs. The socioeconomic status-related PAR for self-inflicted injury and the PAR related to number of parents in the household for interpersonal violence-related injury also were high. CONCLUSIONS: Intentional-injury prevention and victim treatment need to be tailored to household social circumstances.     

Novel MYOC gene mutation, Phe369Leu, in Japanese patients with primary open-angle glaucoma detected by denaturing high-performance liquid chromatography

PURPOSE: To screen for mutations in the MYOC gene in Japanese patients with primary open-angle glaucoma (POAG) using denaturing high-performance liquid chromatography (DHPLC). PATIENTS AND METHODS: Blood samples were collected from 171 patients with POAG and 100 controls from seven institutions in Japan. For high-throughput analysis, seven exonic regions were amplified by polymerase chain reaction using DNA pooled from three patients; each DNA pool was then analyzed chromatographically. For analysis of a small number of samples, 7 exonic regions were amplified separately but simultaneously with annealing at 58 degrees C in each patient and then chromatographed, using 7 wells of the same 96-well plate per sample. When chromatographic patterns were abnormal by either method, the PCR products of the individual samples were sequenced. RESULTS: Four glaucoma-causing mutations were identified in five POAG patients (2.9%). One missense mutation, Phe369Leu, is new; and three others, Ile360Asn, Ala363Thr, and Thr448Pro, have been reported in Japanese patients. Phe369Leu was associated with adult onset POAG. CONCLUSIONS: Mutations in the MYOC gene were demonstrated chromatographically in 2.9% of our Japanese POAG patients. The use of pooled DNAs with DHPLC analysis is a time- and labor-saving technique. All mutations detected appear to be specific to Japanese patients.     

Cytotoxic lymphocytes; instigators of dramatic target cell death

Most mammalian cells are constantly threatened by viral infection and oncogenic transformation. To maintain healthy function of organs and tissues it is critical that afflicted cells are efficiently detected and removed. Cytotoxic lymphocytes (CL) are chiefly responsible for efficiently seeking out and eliminating damaged or infected cells. It is known that CLs must specifically recognize and bind to their targets, but the molecular events that occur within the target cell that lead to its death are still poorly understood. The two main processes initiated by CLs to induce target cell death are mediated by ligation of surface receptors or release of toxic proteins from secretory granules (granule exocytosis) of the CL. Here we review some of the key findings that have defined our knowledge of the granule exocytosis-mediated pathways to CL-mediated killing and discuss recent insights that challenge conventional views in the important area of CL effector function.     

Synthesis and biological evaluation of novel membrane-permeant cyclic ADP-ribose mimics: N1-[(5''-O-phosphorylethoxy)methyl]-5'-O-phosphorylinosine 5',5''-cyclicpyrophosphate (cIDPRE) and 8-substituted derivatives

N1-[(5' '-O-Phosphorylethoxy)methyl]-5'-O-phosphorylinosine 5',5'-cyclicpyrophosphate (cIDPRE 2a) and the 8-substituted derivatives 8-bromo-, 8-azido-, 8-amino-, and 8-Cl-cIDPRE (2b-e) were synthesized from N1-[(5'-acetoxyethoxy)methyl]-2',3'-O-isopropylideneinosine (5) in good yields. The pharmacological activities of cIDPRE and the 8-substituted derivatives (2a-e) were analyzed in intact and permeabilized human Jurkat T-lymphocytes. The results indicate that cIDPRE permeates the plasma membrane, releases Ca2+ from an intracellular, cADPR-sensitive Ca2+ store, and subsequently initiates Ca2+ release-activated Ca2+ entry. The Ca(2+)-releasing activity of cIDPRE was confirmed directly in permeabilized cells. Using time-resolved confocal Ca2+ imaging at the single cell level, the development of global Ca2+ signals starting from local small Ca2+ signals evoked by cIDPRE was observed. 8-N3-cIDPRE 2c and 8-NH2-cIDPRE 2d were similarly effective in their agonistic activity as compared to cIDPRE 2a, showing almost indistinguishable concentration-response curves for 2a, 2c, and 2d and very similar kinetics of Ca2+ signaling. In contrast, the halogenated derivatives 8-Br- and 8-Cl-cIDPRE (2b and 2e) did not significantly elevate [Ca2+]i. Therefore, cIDPRE 2a, 8-N3-cIDPRE 2c, and 8-NH2-cIDPRE 2d are novel membrane permeant cADPR mimic and may provide important novel tools to study cADPR-mediated Ca2+ signaling in intact cells.     

Design and synthesis of potent inhibitors of the malaria aspartyl proteases plasmepsin I and II. Use of solid-phase synthesis to explore novel statine motifs

Picomolar to low nanomolar inhibitors of the two aspartic proteases plasmepsin (Plm) I and II, from the malaria parasite Plasmodium falciparum, have been identified from sets of libraries containing novel statine-like templates modified at the amino and carboxy terminus. The syntheses of the novel statine templates were carried out in solution phase using efficient synthetic routes and resulting in excellent stereochemical control. The most promising statine template was attached to solid support and diversified by use of parallel synthesis. The products were evaluated for their Plm I and II inhibitory activity as well as their selectivity over cathepsin D. Selected inhibitors were, in addition, evaluated for their inhibition of parasite growth in cultured infected human red blood cells. The most potent inhibitor in this report, compound 16, displays Ki values of 0.5 and 2.2 nM for Plm I and II, respectively. Inhibitor 16 is also effective in attenuating parasite growth in red blood cells showing 51% inhibition at a concentration of 5 microM. Several inhibitors have been identified that exhibit Ki values between 0.5 and 74 nM for both Plm I and II. Some of these inhibitors also show excellent selectivity vs cathepsin D.     

Structure-activity relationships of N-acyl pyrroloquinolone PDE-5 inhibitors

The discovery of the potent and selective PDE-5 inhibitory activity of a pyrroloquinolone scaffold prompted us to explore the SAR of its acyl derivatives. During the course of these studies, three structural series were found with K(i) values for PDE-5 in the subnanomolar range. Systematic modification of one of these leads produced a compound with excellent selectivity for PDE-5 over other phosphodiesterases and oral bioavailability of 15% in male rats. This compound also displayed in vivo efficacy in an anesthetized canine model of erection when dosed intravenously.     

The pharmacokinetics of nebulized nanocrystal budesonide suspension in healthy volunteers

Nanocrystal budesonide (nanobudesonide) is a suspension for nebulization in patients with steroid-responsive pulmonary diseases such as asthma. The pharmacokinetics and safety of the product were compared to those of Pulmicort Respules. Sixteen healthy volunteers were administered nanobudesonide 0.5 and 1.0 mg, Pulmicort Respules 0.5 mg, and placebo in a four-way, randomized crossover design. All nebulized formulations were well tolerated, with no evidence of bronchospasm. Nebulization times were significantly shorter for nanobudesonide compared to Pulmicort Respules. Because of a low oral bioavailability, plasma concentration of budesonide is a good marker of lung-delivered dose. The pharmacokinetics of nanobudesonide 0.5 and 1.0 mg were approximately dose proportional with respect to Cmax, AUC(0-t), and AUC(0-infinity). Nanobudesonide 0.5 mg and Pulmicort Respules 0.5 mg exhibited similar AUCs, suggesting a similar extent of pulmonary absorption. A higher Cmax was noted with nanobudesonide 0.5 mg, and the tmax was significantly different, suggesting a more rapid rate of drug delivery of nanobudesonide 0.5 mg than Pulmicort Respules. In conclusion, nebulized nanobudesonide 0.5 mg was safe in healthy volunteers, with a similar extent of absorption as Pulmicort Respules.     

Imported Plasmodium vivax malaria: demographic and clinical features in nonimmune travelers

BACKGROUND: Imported malaria is an important problem in nonendemic countries due to increasing travel to and immigration from malaria-endemic countries. Plasmodium vivax malaria is relatively common in travelers but there are few published data regarding the outcome of P. vivax malaria in this group. METHODS: We analyzed 209 cases of P. vivax malaria that were reported to the GeoSentinel network and the VIDS database, Royal Melbourne Hospital. Analyses were performed on data including demographics, pretravel encounter, antimalarial prophylaxis, exposure history, type of travel, countries of recent and past travel, clinical presentation, treatment, outcome and final diagnoses. RESULTS: The majority of patients were travelers (61%), followed by expatriates (13%) and recent immigrants or foreign visitors (12%). Recent travel to Oceania, sub-Saharan Africa, and South and Central America was significantly more likely to be associated with P. vivax malaria than travel to all other regions. The clinical presentation of P. vivax malaria acquired in the Pacific region is indistinguishable from infection with P. falciparum. The use of chloroquine prophylaxis did not prolong the incubation period. Relapse of infection was not infrequent, and the only significant predictor of relapse was travel to Papua New Guinea (PNG), regardless of primaquine dose. Travelers returning from PNG were eight times more likely to relapse after primaquine treatment compared to travelers with P. vivax malaria acquired elsewhere. CONCLUSIONS: We have presented details of the epidemiology, clinical presentation and management of infection with P. vivax malaria in travelers. P. vivax malaria is an important cause of morbidity in travelers, and relapse following primaquine treatment is especially problematic with P. vivax malaria acquired in PNG.