To characterize steady-state indinavir pharmacokinetics in cerebrospinal fluid and plasma, 8 adults infected with human immunodeficiency virus underwent intensive cerebrospinal fluid sampling while receiving indinavir (800 mg every 8 hours) plus nucleoside reverse transcriptase inhibitors. Nine and 11 serial cerebrospinal fluid and plasma samples, respectively, were obtained from each subject. Free indinavir accounted for 94.3% of the drug in cerebrospinal fluid and 41.7% in plasma. Mean values of cerebrospinal fluid peak concentration, concentration at 8 hours, and area under the concentration-time profile calculated over the interval 0 to 8 hours [AUC(0-8)] for free indinavir were 294 nmol/L, 122 nmol/L, and 1616 nmol/L x h, respectively. The cerebrospinal fluid-to-plasma AUC(0-8) ratio for free indinavir was 14.7% +/- 2.6% and did not correlate with indexes of blood-brain barrier integrity or intrathecal immune activation. Indinavir achieves levels in cerebrospinal fluid that should contribute to control of human immunodeficiency virus type 1 replication in this compartment. The cerebrospinal fluid-to-plasma AUC(0-8) ratio suggests clearance mechanisms in addition to passive diffusion across the blood-cerebrospinal fluid barrier, perhaps by P-glycoprotein-mediated efflux.

A body of research demonstrates examples of in vitro and in vivo synergy between natural products and anti-neoplastic drugs for some cancers. However, the underlying biological mechanisms are still elusive. To better understand biological entities targeted by natural products and therefore provide rational evidence for future novel combination therapies for cancer treatment, we assess the targetable space of natural products using public domain compound-target information. When considering pathways from the Reactome database targeted by natural products, we found an increase in coverage of 61% (725 pathways), relative to pathways covered by FDA approved cancer drugs collected in the Cancer Targetome, a resource for evidence-based drug-target interactions. Not only is the coverage of pathways targeted by compounds increased when we include natural products, but coverage of targets within those pathways is also increased. Furthermore, we examined the distribution of cancer driver genes across pathways to assess relevance of natural products to critical cancer therapeutic space. We found 24 pathways enriched for cancer drivers that had no available cancer drug interactions at a potentially clinically relevant binding affinity threshold of < 100nM that had at least one natural product interaction at that same binding threshold. Assessment of network context highlighted the fact that natural products show target family groupings both distinct from and in common with cancer drugs, strengthening the complementary potential for natural products in the cancer therapeutic space. In conclusion, our study provides a foundation for developing novel cancer treatment with the combination of drugs and natural products.

Electrodermal screening (EDS) is based on three commonly held assumptions: acupuncture points (APs) have lower electrical resistance than non-APs; resistance at APs varies with health and disease; and effective acupuncture treatments are associated with normalization of resistance at APs. Although evidence confirming these assumptions is limited, EDS is frequently practiced worldwide. Researchers are also beginning to assess EDS' utility as an outcome measure in acupuncture trials. Fundamental in developing EDS as a research tool is the need for an accurate and reliable measurement. We developed an automated multichannel prototype system, the Octopus, and recorded electrical resistance and capacitance at eight skin sites in 33 healthy participants over 2 hours. The Octopus accurately measured against known resistors (within 2.5% of the mean value) and capacitors (within 10% of the mean value), and yielded repeatable readings at all eight skin sites: LR 1 (r = 0.79), SP 1 (r = 0.79), toe non-AP (r = 0.77), LU 9 (r = 0.97), PC 6 (r = 0.96), wrist non-APs (r = 0.97), SP 6 (r = 0.96), and leg non-APs (r = 0.97). Resistance at APs was significantly lower than the nearby non-APs in one out of three comparisons.

Background With the growing adoption of the electronic health record (EHR) worldwide over the last decade, new opportunities exist for leveraging EHR data for detection of rare diseases. Rare diseases are often not diagnosed or delayed in diagnosis by clinicians who encounter them infrequently. One such rare disease that may be amenable to EHR-based detection is acute hepatic porphyria (AHP). AHP consists of a family of rare, metabolic diseases characterized by potentially life-threatening acute attacks and chronic debilitating symptoms. The goal of this study was to apply machine learning and knowledge engineering to a large extract of EHR data to determine whether they could be effective in identifying patients not previously tested for AHP who should receive a proper diagnostic workup for AHP.

Objective There are many commercially available instruments for measuring electrical conductance, but there is little information about their reliability. The aim of this study was to quantify measurement variability and assess reliability of the AcuGraph system—a commonly used electrodermal screening device. Methods Four experiments were conducted to measure variability in electrical conductance readings obtained by the AcuGraph system. The fi rst involved measuring known resistors. The second measured non-human organic matter. The third was a test–retest assessment of the Yuan-Source and Jing-Well points in 30 healthy volunteers who were measured by a single operator. The fourth was an interoperator reliability evaluation of seven acupuncturists at the Yuan-Source and Jing-Well acupoints on four individuals at two time points. Results Against known resistors, the AcuGraph had an average coeffi cient of variability (CV) of 1.8% between operators and test–retests. On non-human organic material the AcuGraph had an average CV of 0.9% and 2.8%. When a single operator tested 30 participants, the average reliability for the Yuan-Source points was 0.86 and 0.76 for Jing-Well points with a CV of 23.2% and 25.9% respectively. The average CV for the seven acupuncturists was 24.5% on Yuan-Source points and 23.7% on Jing-Well points. Conclusions The AcuGraph measures known resistors and organic matter accurately and reliably. Skin conductance at acupoints recorded by one operator was also reliable. There was less consistency in electrodermal recordings obtained by seven different operators. Operator training and technical improvements to the AcuGraph may improve consistency among operators.

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Cause-specific mortality was surveyed among 23,180 male (580,000 person-years) and 3,860 female (86,898 person-years) employees with 1 or more years of service from 1940 through 1989 at a large chemical plant. Vital status was ascertained for 99.1% of the males (n = 5,658 deaths) and 98.6% of the females (n = 355 deaths). Comparisons of observed mortality with expected levels based on any of three population comparisons (United States, Texas, or five local counties) showed lower mortality for all causes of death, diseases of the circulatory system, diabetes mellitus, and cirrhosis of the liver. There was an increased risk for lung cancer mortality among male operations employees when compared to the U.S. and Texas populations but not to the local five-county region. Additional evidence suggests this increase was primarily attributable to cigarette smoking. Male operations employees also had an elevated, although not statistically significant, risk for kidney cancer. Prior research had shown an association with work in the cell maintenance area of chlorine production. As a result of a high prevalence of deaths certified by justices of the peace, a mortality excess was observed of cancer of other and unspecified sites and symptoms, senility, and ill-defined conditions. Although specific chemical exposures were not studied, the generally favorable mortality experience suggests that major hazards are unlikely.

Limited evidence suggests that electrodermal activity (EDA) at acupoints and meridians is distinct from EDA in nearby tissue(s) [1,2]. A few studies also suggest that skin conductance (or its reciprocal, resistance) at acupoints correlates with clinical diagnoses [3−8] and with therapeutic outcomes [4,9]. Whereas EDA at palmar sites has been validated and is extensively utilized by psychophysiologists in stress and emotion research [10,11], acupuncturists measure SC at acupoints for a different, as yet unvalidated purpose, based on the 1950s work of Voll [12,13] and Nakatani [14]. Acupuncturists use electrical skin conductance (SC) at acupoints to identify which of 12 classically paired acupuncture meridians are out of balance. These SC measurements then inform the clinician's treatment plans and assist in monitoring therapeutic outcomes. Although SC at acupoints may prove to be a valid diagnostic aid and/or quantifiable outcome measure, more preliminary research is needed to characterize AbstractThe clinical practice of recording skin conductance (SC) at acupuncture points (acupoints), as a diagnostic and/or therapeutic monitoring aid may have scientific merit. However, influences of age, gender and time of day on these recordings are unknown and it is unclear whether SC at acupoints differs from SC levels in general (as reported in psychophysiology research). This paper summarizes SC data obtained with the AcuGraph 3 Digital Meridian Imaging System between June 2005 and March 31, 2010. An initial dataset of 117,725 SC examinations was scrubbed to include only the first SC examination on individual patients and exclude potentially faulty data. The final dataset consists of SC recordings at the 24 Source (Yuan) acupoints in 8637 patients, collected by 311 practitioners. Twelve left/right average conductance measures and an overall average of the 24 acupoints were assessed. Statistical analyses included two sample t tests, three way analyses of variance and linear regression. Results indicate that mean SC at acupoints, similar to SC in general, is higher in males, higher in afternoons and declines with age. Not previously reported, the rate of SC decline with age differs at different acupoints between males and females. These findings have substantial implications for acupuncture research and practice.