Generalized pustular psoriasis: a review and update on treatment.

Generalized pustular psoriasis (GPP) is a subtype of pustular psoriasis characterized by painful and occasionally disfiguring cutaneous manifestations with sepsis-like systemic symptoms. Affecting any age and race, GPP can occur with other forms of psoriasis or by itself. Stimuli for flares include medications, infections and environmental triggers. The interleukin family and caspase recruitment domain family have been implicated in its pathogenesis. Other forms of pustular psoriasis include impetigo herpetiformis, palmoplantar pustular psoriasis, annular pustular psoriasis and acrodermatitis continua of Hallopeau. Treatment is not well established, but includes the use of retinoids, methotrexate, cyclosporine, corticosteroids, TNF-alpha inhibitors, topical therapy and phototherapy. The use of TNF-alpha inhibitors may result in the formation of antidrug antibodies and should be administered with methotrexate.

Defining vitamin D status by secondary hyperparathyroidism in the U.S. population.

BACKGROUND: Vitamin D is associated with a variety of health outcomes, but the exact definition of vitamin D sufficiency remains controversial. AIM: We sought to define skeletal-related vitamin D sufficiency by estimating maximum PTH suppression in the U.S. population. METHODS: We performed a cross-sectional analysis of the National Health and Nutrition Examination Survey (NHANES), 2003-2006. We examined the association between serum 25-hydroxyvitamin D (25OHD) level and serum PTH level in 14,681 participants aged ≥6 yr. We also evaluated the 25OHD-PTH association using 2 thresholds of hyperparathyroidism: PTH≥45 pg/ml and ≥75 pg/ml. RESULTS: The mean 25OHD level was 24 ng/ml and mean PTH was 42 pg/ml. PTH≥45 pg/ml was present in 35% of the population, while PTH≥75 pg/ml was present in 7%. The prevalence of 25OHD levels <40 ng/ml and <30 ng/ml was 95% and 77%, respectively. In both unadjusted and adjusted models, there was a strong inverse relationship between 25OHD and PTH. Compared to 25OHD≥40 ng/ml, the 25OHD-PTH association was 2.36 [95% confidence interval (CI), 2.08-2.67] times greater for 25OHD<5 ng/ml and 1.12 (95%CI, 1.07-1.17) times greater for 25OHD 30-39.9 ng/ml. Compared to 25OHD≥40 ng/ml, 25OHD levels of 20- 29.9 ng/ml [odds ratio (OR) 2.0 (95%CI, 1.4-2.8)] but not 30- 39.9 ng/ml [OR 1.1 (95%CI, 0.8-1.6)] were independently associated with PTH≥45 pg/ml. CONCLUSIONS: Optimal vitamin D status, defined by estimated maximum PTH suppression, does not occur until at least 25OHD levels ≥40 ng/ml. Using these thresholds, most of the U.S. population needs more vitamin D. Large, prospective studies are needed to determine optimal vitamin D supplementation.

Phosphorus extractability of soils amended with stockpiled and composted cattle manure.

Managing fertilizer applications to maintain soil P below environmentally unacceptable levels should consider the contribution of manure and synthetic fertilizer sources to soluble and extractable forms of P. Our objective was to evaluate soil and manure characteristics and application rates on P extractability in recently amended soils. Five soils of the U.S. southern High Plains were amended with beef cattle manures, composted beef manure, and inorganic fertilizers [Ca(H(2)PO(4))(2) or KH(2)PO(4)] at five rates and incubated under controlled conditions. Mehlich 3-, Olsen (NaHCO(3))-, Texas A&M extractant (TAM)-, and water-extractable P were determined for the soils after selected incubation periods. Except for TAM and some water extractions, P extractability as a function of total P applied was linear (P < 0.001) for a wide range of application rates. Mehlich-3, NaHCO(3), and water P extraction efficiencies of KH(2)PO(4)-amended soils averaged 22, 34, and 115% greater (P < or = 0.036), respectively, than efficiencies of soils amended with manures except for the Texline (calcareous) loam and Pullman clay loam soils. Phosphorus extraction efficiencies decreased with time for KH(2)PO(4)-amended soils (P < 0.05) but remained stable or increased for manure-amended soils during the 8-wk incubation period. Across all soils and manure sources, changes in water-extractable P per unit increase in Mehlich 3-, NaHCO(3)-, and TAM-extractable P averaged 100, 85, and 125% greater, respectively, for inorganic as compared with manure-amended soils. These source-dependent relationships limit the use of agronomic soil extractants to make correct inferences about water-extractable P and dissolved P in runoff.

N-terminal processing is essential for release of epithin, a mouse type II membrane serine protease.

Epithin was originally identified as a mouse type II membrane serine protease. Its human orthologue membrane type-serine protease 1 (MT-SP1)/matriptase has been reported to be localized on the plasma membrane. In addition, soluble forms of matriptase were isolated from human breast milk and breast cancer cell-conditioned medium. In this paper, we report a processing mechanism that appears to be required for the release of epithin. CHO-K1 or COS7 cells transfected with single full-length epithin cDNA generated two different-sized proteins in cell lysates, 110 and 92 kDa. The 92-kDa epithin was found to be an N-terminally truncated form of the 110-kDa epithin, and it was the only form detected in the culture medium. The 92-kDa epithin was also found on the cell surface, where it was anchored by the N-terminal fragment. The results of in vivo cell labeling experiments indicate that the 110-kDa epithin is rapidly processed to the 92-kDa epithin. Using site-directed mutagenesis experiments, we identified Gly(149) of the GSVIA sequence in epithin as required for the processing and release of the protein. These results suggest that N-terminal processing of epithin at Gly(149) is a necessary prerequisite step for release of the protein.

Cefprozil versus high-dose amoxicillin/clavulanate in children with acute otitis media.

BACKGROUND: The recommendation of the Drug-Resistant Streptococcus pneumoniae Therapeutic Working Group that high-dose amoxicillin, with or without clavulanate, be used to treat acute otitis media (AOM) addressed concerns about the efficacy of existing therapies against drug-resistant S. pneumoniae. This recommendation relied on pharmacodynamic predictions of concentrations of amoxicillin in middle-ear fluid remaining higher than minimum inhibitory concentrations against intermediately resistant S. pneumoniae for >40% of the dosing interval. OBJECTIVE: This study compared the tolerability and efficacy of cefprozil and high-dose amoxicillin/clavulanate in patients with AOM. METHODS: Patients were randomized to receive 10 days of investigator-blinded oral treatment with either cefprozil suspension (30 mg/kg/d in 2 divided doses) or amoxicillin/clavulanate (45/6.4 mg/kg/d) plus amoxicillin (45 mg/kg/d) in 2 divided doses. The primary efficacy end point was the clinical cure rate 4 to 7 days after the end of treatment. Clinical response by age (6 months-<2 years vs > or =2-7 years), disease severity, and unilateral versus bilateral ear infection was also examined. The primary measures of tolerability were the frequency and severity of adverse events and their relation to study drug. Adverse events were either spontaneously reported or elicited during examination and questioning of the patient. Identified adverse events were coded and recorded using the COSTART (Coding Symbols for Thesaurus of Adverse Reaction Terms) system. RESULTS: Three hundred four children between the ages of 6 months and 7 years with > or =1 sign or symptom of AOM were enrolled in the study, and 303 (150 cefprozil, 153 amoxicillin/clavulanate) were treated. Twenty-three patients in each treatment group were not evaluable; thus, 257 children were included in the analysis of evaluable patients. Clinical cure rates were 87% (110/127) with cefprozil and 89% (116/130) with amoxicillin/clavulanate (95% CI for the difference in cure rate, -10.7% to 4.1%). No between-group differences in efficacy were noted by age, disease severity, or unilateral or bilateral involvement. The overall incidence of drug-related adverse events was significantly lower with cefprozil than with amoxicillin/clavulanate (19% vs 32%, respectively; P = 0.008), as was the incidence of diarrhea (9% vs 19%, respectively; P = 0.021). Adverse events prompted discontinuation of therapy in 4 (3%) cefprozil patients and 8 (5%) amoxicillin/clavulanate patients. CONCLUSIONS: Based on a search of MEDLINE, this study is the first direct comparison of cefprozil versus high-dose amoxicillin/clavulanate. Cefprozil was as effective as high-dose amoxicillin/clavulanate, with a lower incidence of adverse events.

GATA-4 and serum response factor regulate transcription of the muscle-specific carnitine palmitoyltransferase I beta in rat heart.

Transcriptional regulation of nuclear encoded mitochondrial proteins is dependent on nuclear transcription factors that act on genes encoding key components of mitochondrial transcription, replication, and heme biosynthetic machinery. Cellular factors that target expression of proteins to the heart have been well characterized with respect to excitation-contraction coupling. No information currently exists that examines whether parallel transcriptional mechanisms regulate nuclear encoded expression of heart-specific mitochondrial isoforms. The muscle CPT-Ibeta isoform in heart is a TATA-less gene that uses Sp-1 proteins to support basal expression. The rat cardiac fatty acid response element (-301/-289), previously characterized in the human gene, is responsive to oleic acid following serum deprivation. Deletion and mutational analysis of the 5'-flanking sequence of the carnitine palmitoyltransferase Ibeta (CPT-Ibeta) gene defines regulatory regions in the -391/+80 promoter luciferase construct. When deleted or mutated constructs were individually transfected into cardiac myocytes, CPT-I/luciferase reporter gene expression was significantly depressed at sites involving a putative MEF2 sequence downstream from the fatty acid response element and a cluster of heart-specific regulatory regions flanked by two Sp1 elements. Each site demonstrated binding to cardiac nuclear proteins and competition specificity (or supershifts) with oligonucleotides and antibodies. Individual expression vectors for Nkx2.5, serum response factor (SRF), and GATA4 enhanced CPT-I reporter gene expression 4-36-fold in CV-1 cells. Although cotransfection of Nkx and SRF produced additive luciferase expression, the combination of SRF and GATA-4 cotransfection resulted in synergistic activation of CPT-Ibeta. The results demonstrate that SRF and the tissue-restricted isoform, GATA-4, drive robust gene transcription of a mitochondrial protein highly expressed in heart.

A comparison of carbon monoxide levels during the use of a multi-fuel camp stove.

OBJECTIVE: The use of camp stoves in an enclosed or poorly ventilated space is clearly not recommended due to the risk of carbon monoxide (CO) poisoning. Instances may arise, however, when use for a limited time is necessary. We sought to find differences in CO levels between various fuels used to power a commercially available camp stove. METHODS: A comparison was made between unleaded gasoline, kerosene, and white gas (Coleman fuel). The stove, fuels, and CO detector were all purchased from local retailers. A 0.4-m3 space was constructed with a cardboard box. Three trials were performed using each fuel in which water was heated over the stove for 5 minutes. Measurement of the CO level within the box was taken every 30 seconds. RESULTS: Kerosene created CO levels of 714 (SD = 113.5) parts per million (ppm) at 2 1/2 minutes but was out of the measurable range of >999 ppm within 4 minutes on each of its trials. White gas burned the cleanest, with an average of 212 ppm (SD = 27.8) at 2 1/2 minutes and 348 ppm (SD = 76.0) at 5 minutes. Unleaded gasoline created 305 ppm (SD = 27.1) at 2 1/2 minutes and 464 ppm (SD = 31.6) at 5 minutes. CONCLUSION: All of the fuels created a high level of CO in a short period of time. White gas burned the cleanest and would be preferred to unleaded gasoline or kerosene in the event that the unvented use of a camp stove was necessary.

Nedocromil sodium 2% ophthalmic solution for the treatment of ragweed pollen seasonal allergic conjunctivitis.

PURPOSE: To determine the efficacy and safety of nedocromil sodium 2% ophthalmic solution in the treatment of seasonal allergic conjunctivitis. METHODS: A combined analysis of two multicenter, randomized, comparative, double-masked, placebo-controlled clinical trials involving 261 patients diagnosed with seasonal allergic conjunctivitis was used. Patients were randomly assigned to receive either topical 2% nedocromil sodium or placebo twice daily for eight weeks. Diary card scores and clinician assessments of allergic symptoms were recorded throughout the study; efficacy was determined by comparing symptom severity at the peak pollen period with symptom severity at baseline. Clinician and patient evaluations of treatment effectiveness were used as secondary measurements of efficacy. RESULTS: Patients treated with nedocromil sodium experienced improvement in allergy symptoms, with reductions in the summary symptom score, itch, redness, conjunctival injection, and conjunctival edema significantly (p<0.05) greater than those observed in the patients treated with placebo. Clinicians' and patients' opinions of nedocromil sodium treatment effectiveness were significantly (p<0.02) superior to those of placebo treatment effectiveness. CONCLUSION: Nedocromil sodium is effective in the management of seasonal allergic conjunctivitis.

Pharmacology and therapeutic use of trastuzumab in breast cancer.

The development, pharmacology, safety, efficacy, and dosage and administration of trastuzumab are reviewed. The discovery of HER2 gene amplification in up to 30% of women with breast cancer led to the development of trastuzumab, a humanized recombinant monoclonal antibody directed against the HER2-receptor protein on breast cancer cells. In large, multicenter trials of trastuzumab as a single agent or in combination with chemotherapy as first-line or second-line therapy for metastatic breast cancer (MBC), response rates have ranged from 12% to 23% for single-agent trastuzumab and from 25% to 62% for trastuzumab plus chemotherapy. Trastuzumab increased time to disease progression and survival time when administered in combination with chemotherapy. The National Comprehensive Cancer Network guidelines for the treatment of breast cancer now include trastuzumab and paclitaxel as an option for patients with MBC or recurrent breast cancer in which the HER2-receptor protein is overexpressed. Trastuzumab is administered weekly, with an initial i.v. dose of 4 mg/kg followed by weekly doses of 2 mg/kg. Most clinical trials continued treatment until disease progression occurred. Adverse effects include infusion-related reactions manifested by fever and chills, exacerbation of chemotherapy-induced gastrointestinal toxicity and myelosuppression, and cardiotoxicity. Trastuzumab, either as a single agent or in combination with chemotherapy, can be an effective therapeutic option for MBC patients who overexpress the HER2-receptor protein and has changed the standard of care.

Nutritional rickets in African American breast-fed infants.

OBJECTIVE: To analyze the characteristics of infants and children diagnosed with nutritional rickets at two medical centers in North Carolina in the 1990s. STUDY DESIGN: The physical and radiographic findings, calcium, phosphorus, alkaline phosphatase, and 25-hydroxyvitamin D levels of infants and children diagnosed with nutritional rickets at two medical centers were reviewed. Breast-feeding data were obtained from the North Carolina Women, Infants and Children Program (WIC). RESULTS: Thirty patients with nutritional rickets were first seen between 1990 and June of 1999. Over half of the cases occurred in 1998 and the first half of 1999. All patients were African American children who were breast fed without receiving supplemental vitamin D. The average duration of breast-feeding was 12.5 months. The age at diagnosis was 5 to 25 months, with a median age of 15.5 months. Growth failure was common: length was <5th percentile in 65% of cases, and weight was <5th percentile in 43%. CONCLUSION: Factors that may have contributed to the increase in referrals of children with nutritional rickets include more African American women breast-feeding, fewer infants receiving vitamin D supplements, and mothers and children exposed to less sunlight. We recommend that all dark-skinned breast-fed infants and children receive vitamin D supplementation.

Efficacy and safety of nedocromil sodium 2% ophthalmic solution b.i.d. in the treatment of ragweed seasonal allergic conjunctivitis.

The efficacy and safety of twice-daily nedocromil sodium 2% ophthalmic solution and vehicle were compared in the treatment of ragweed seasonal allergic conjunctivitis. Two separate multicenter, randomized, double-masked, placebo-controlled studies were subjected to a combined analysis. Following a one-week baseline period during the beginning of the ragweed pollen season, 189 patients with seasonal allergic conjunctivitis received either nedocromil sodium or vehicle b.i.d. for eight weeks. Efficacy was evaluated by patient diary cards and clinical eye examinations. Safety was assessed by reports of adverse events. Compared with vehicle, nedocromil sodium produced significantly greater decreases in summary symptom score (p = 0.005), itch (p = 0.005), tearing (p = 0.004), overall eye condition (p = 0.001), and clinician-evaluated conjunctival edema (p = 0.018), and significantly better (p = 0.001), and patient (p = 0.001) opinions of treatment effectiveness at the peak pollen period. Additionally, the superiority of nedocromil sodium compared to vehicle approached statistical significance in redness reduction (p = 0.087) and clinician-evaluated conjunctival injection (p = 0.087). There were no serious treatment-related adverse events in either treatment group. In summary, nedocromil sodium 2% ophthalmic solution b.i.d. was found to be effective and to have a favorable safety profile in the treatment of seasonal allergic conjunctivitis.

Attentional grasp in far extrapersonal space after thalamic infarction.

Studies of animals and humans with focal brain damage suggest that attention in near and far extrapersonal space may be mediated by anatomically separate systems. Thalamic lesions have been associated with spatial neglect, but whether asymmetric attention specific to near or far space occur after thalamic damage has not been explored. It is also unclear if thalamic injury can induce contralesional defective response inhibition. We tested a woman with a left thalamic infarction who reported that, when driving, she had a tendency to veer towards people or objects on the right side of the road. Our patient and four controls performed a line bisection task with a laser pointer in near and far extrapersonal space. The experimenter marked each bisection either from the right of the presented line (right-distractor, RD) or the left (left-distractor, LD). RD and LD trials were pseudo-randomized. Our patient performed similarly to controls (mean -0.7 mm, controls -0.6 mm) on the line bisection task in near space. In far space she erred significantly rightward compared to her performance in near space (p<0.001). Controls performed similarly in near and far space. The experimenter position did not affect our patient's performance on near line bisections, nor did controls demonstrate a distractor effect for the near condition. In the far condition, however, our patient showed a significant distractor effect (LD -3.3 mm, RD 35.3 mm, p<0.001). Controls also demonstrated a distractor effect in the far condition (LD -6.4 mm, RD 0.7 mm, p<0.01), though of much smaller magnitude. Our results suggest that frontal-thalamic systems regulating visual attention may be disrupted by thalamic infarction. Such damage may produce an attentional grasp specific to far extrapersonal space.

Interventional and intraoperative magnetic resonance imaging.

The goal of the Image Guided Therapy Program, as the name implies, is to develop the use of imaging to guide minimally invasive therapy. The program combines interventional and intraoperative magnetic resonance imaging (MRI) with high-performance computing and novel therapeutic devices. In clinical practice the multidisciplinary program provides for the investigation of a wide range of interventional and surgical procedures. The Signa SP 0.5 T superconducting MRI system (GE Medical Systems, Milwaukee, WI) has a 56-cm-wide vertical gap, allowing access to the patient and permitting the execution of interactive MRI-guided procedures. This system is integrated with an optical tracking system and utilizes flexible surface coils and MRI-compatible displays to facilitate procedures. Images are obtained with routine pulse sequences. Nearly real-time imaging, with fast gradient-recalled echo sequences, may be acquired at a rate of one image every 1.5 s with interactive image plane selection. Since 1994, more than 800 of these procedures, including various percutaneous procedures and open surgeries, have been successfully performed at Brigham and Women's Hospital (Boston, MA).

Hypocalcemic tetany in a toddler with undiagnosed rickets.

A 17-month-old black girl presented to the pediatric emergency department with sudden onset of her hands and feet "drawing up." A diagnosis of vitamin D deficiency rickets with tetany was made on a history of exclusive breast-feeding, low serum calcium, phosphorus, and 25-hydroxyvitamin D levels, and bone radiographs. Nutritional rickets should be considered in the differential diagnosis of acute hypocalcemia.

Sparfloxacin versus ciprofloxacin for the treatment of community-acquired, complicated skin and skin-structure infections.

Fluoroquinolones have been shown to be effective in the treatment of complicated skin and skin-structure infections, in part because of their broad-spectrum antibacterial activity against causative pathogens that are resistant to older antimicrobial agents. We enrolled 603 adult patients (>58% male, >85% white) in a double-masked, double-dummy, randomized, multicenter trial to compare the efficacy and tolerability of sparfloxacin (400-mg loading dose followed by 200 mg once daily) with those of ciprofloxacin (750 mg twice daily) for 10 days in the treatment of community-acquired, complicated skin and skin-structure infections. The primary efficacy variable was clinical response, based on assessment of signs and symptoms, in the clinically assessable population. Patients in the sparfloxacin and ciprofloxacin groups were comparable with respect to demographic characteristics, underlying diseases, medical history, and laboratory test results. Wound infection was the most common diagnosis, and Staphylococcus aureus was the most frequently isolated pathogen. For the 475 clinically assessable patients, the clinical success rate (percentage of patients cured or improved) was 90.1% (210/233) with sparfloxacin and 87.2% (211/242) with ciprofloxacin. In this analysis (95% confidence interval [CI], -2.8 to 8.6) and the intent-to-treat analyses (95% CI, -4.2 to 6.2), results with sparfloxacin were statistically equivalent to those with ciprofloxacin (95% CI, -1 to 15.3). For bacteriologically assessable patients, eradication rates were 87.0% (141/162) with sparfloxacin and 79.9% (123/154) with ciprofloxacin (95% CI, -1 to 15.3). Eradication rates of S. aureus and coagulase-negative staphylococcal infections were 90.2% (101/112) with sparfloxacin and 77.9% (88/113) with ciprofloxacin. For patients with 2 or more pathogens at baseline (mixed infections), bacteriologic success was 87.6% for sparfloxacin and 77.9% for ciprofloxacin. Pseudomonas aeruginosa infections were eradicated or presumed eradicated in 71.4% (10/14) of sparfloxacin-treated patients and 87.5% (7/8) of ciprofloxacin-treated patients. Overall success rates in the bacteriologically assessable patients for sparfloxacin (84.6% [137/162]) and ciprofloxacin (78.6% [121/154]) were statistically equivalent (95% CI, -2.5 to 14.5). Tolerability was assessed in all patients who received study medication. The overall frequency of treatment-related adverse events was comparable in the 2 treatment groups (26.5% sparfloxacin, 23.3% ciprofloxacin). Drug-related adverse events involving the digestive system occurred in 7.1% of sparfloxacin-treated patients and 19.0% of ciprofloxacin-treated patients; photosensitivity reactions were reported in 11.1% of patients in the sparfloxacin group and 0.7% of patients in the ciprofloxacin group (P < 0.001). The mean change in QTc interval from baseline to the maximum on-treatment value was greater in the sparfloxacin group (9 milliseconds) than in the ciprofloxacin group (3 milliseconds) (P = 0.005; 95% CI, 0.002 to 0.010). The efficacy of sparfloxacin was comparable to that of ciprofloxacin in the treatment of community-acquired, complicated skin and skin-structure infections, including those caused by staphylococci, the most common pathogens. Sparfloxacin's once-daily regimen, high skin-tissue penetration, and improved activity against gram-positive cocci make it a therapeutic alternative to ciprofloxacin for patients who are not at risk for photosensitivity reactions or adverse events associated with prolongation of the QTc interval.

Effects of a positron-emitting vanadium-48 nitinol stent on experimental restenosis in porcine coronary arteries: an injury-response study.

BACKGROUND: The major limitation of coronary stenting is restenosis due to exaggerated neointimal thickening. We evaluated a positron-emitting V48 nitinol stent in a porcine coronary model of restenosis. METHODS AND RESULTS: Pigs (n = 16) received a control nonradioactive and a V48 stent (1.5 or 10.6 muCi) randomized to the left anterior descending artery (LAD) and right coronary artery (RCA). Histology, morphometric variables, and strut injury scores were evaluated after 32 days. Peristrut fibrinoid deposits were greater in the high-dose group (p < 0.0001). Control stent area stenosis (AS) and mean neointimal thickness (NIT) correlated with injury (r = 0.81 and 0.79, respectively). Higher-dose stents reduced AS by 20% (0.57 +/- 0.13 vs. 0.71 +/- 0.16; p = 0.029) and mean NIT by 35% (0.44 +/- 0.16 vs. 0.71 +/- 0.24mm; p = 0.001) compared with controls. Lower-dose 1.5-muCi stents did not differ from controls. NIT over individual struts was reduced in the high-dose group compared with controls by 0.18 mm for grade 1 injury, 0.31 mm for grade 2, and 0.38 mm for grade 3 (p < 0.02 for all comparisons). CONCLUSIONS: 1.5-muCi V48 nitinol stents did not influence vessel histology or restenotic parameters in pig coronary arteries. In contrast, 10.6-muCi stents created a distinctive histological picture consisting of increased fibrinoid deposits on the neointimal-facing side of the struts without cellular organization. Higher dose radioactive stents significantly reduced AS and mean NIT. The reduction in neointimal thickening was greatest when the depth of strut penetration into the vascular wall was most severe.

Novel nonnucleoside inhibitors of HIV-1 reverse transcriptase. 8. 8-Aryloxymethyl- and 8-arylthiomethyldipyridodiazepinones.

Nevirapine (I) is the first human immunodeficiency virus type 1 (HIV-1) nonnucleoside reverse transcriptase (RT) inhibitor to reach regulatory approval. As a result of a second generation program around the tricyclic core system of nevirapine, 2-chloro-5, 11-dihydro-11-ethyl-5-methyl-8-(2-(pyridin-4-yl)ethyl)-6H-dipyrido[3, 2-b:2',3'-e][1,4]diazepin-6-one (II)1a and 2-chloro-5, 11-dihydro-11-ethyl-5-methyl-8-phenylethyl-6H-dipyrido[3,2-b:2', 3'-e][1,4]diazepin-6-one (III)1a were identified as broad spectrum HIV-1 RT inhibitors. A detailed examination of replacing either of the methylenes of the 8-ethyl linker of II or III is presented. It was found that 8-aryloxymethyl and 8-arylthiomethyl are the preferred pattern of substitution for potency against RT. The most potent compounds were further evaluated against a panel of clinically significant mutant RT enzymes (K103N, V106A, G190A, P236L) and in cytotoxicity and in vitro metabolism assays. The most potent compound was 2-chloro-8-phenylthiomethyl analogue 37 which displayed sub-100 nM activity against all HIV-1 RT enzymes tested.

Hemp oil ingestion causes positive urine tests for delta 9-tetrahydrocannabinol carboxylic acid.

A hemp oil product (Hemp Liquid Gold) was purchased from a specialty food store. Fifteen milliliters was consumed by seven adult volunteers. Urine samples were taken from the subjects before ingestion and at 8, 24, and 48 h after the dose was taken. All specimens were screened by enzyme immunoassay with SYVA EMIT II THC 20, THC 50, and THC 100 kits. The tetrahydrocannabinol carboxylic acid (THCA) concentration was determined on all samples by gas chromatography-mass spectrometry (GC-MS) (5). A total of 18 postingestion samples were submitted. Fourteen of the samples screened above the 20-ng cutoff, seven were above the 50-ng cutoff, and two screened greater than the 100-ng cutoff. All of the postingestion samples showed the presence of THCA by GC-MS.

Extensive reversible brain magnetic resonance lesions in a patient with HELLP syndrome.

A severe form of toxemia of pregnancy with microangiopathic hemolytic anemia, elevated liver enzymes, and low platelets has been called the HELLP syndrome. A patient with the HELLP syndrome developed a severe, reversible encephalopathy. Brain computed tomography and magnetic resonance imaging showed abnormalities consistent with edema limited to the posterior circulation territory. The location of the lesions and their occurrence in the HELLP syndrome support suggestions that the vulnerability of posterior structures in eclamptic encephalopathy is due to a vascular susceptibility of the posterior circulation and that endothelial cell dysfunction plays an important role in the pathogenesis of eclamptic encephalopathy.