In 2008, a clinical practice guideline (CPG) was developed for the prevention of infections among military personnel with combat-related injuries. Our analysis expands on a prior 6-month evaluation and assesses CPG adherence with respect to antimicrobial prophylaxis for U.S. combat casualties medically evacuated to Landstuhl Regional Medical Center over a 1-year period (June 2009 through May 2010), with an eventual goal of continuously monitoring CPG adherence and measuring outcomes as a function of compliance. We classified adherence to the CPG as receipt of recommended antimicrobials within 48 hours of injury. A total of 1106 military personnel eligible for CPG assessment were identified and 74% received antimicrobial prophylaxis. Overall, CPG compliance within 48 hours of injury was 75%. Lack of antimicrobial prophylaxis contributed 2 to 22% to noncompliance varying by injury category, whereas receipt of antibiotics other than preferred was 11 to 30%. For extremity injuries, antimicrobial prophylaxis adherence was 60 to 83%, whereas it was 80% for closed injuries and 68% for penetrating abdominal injuries. Overall, the results of our analysis suggest an ongoing need to improve adherence, monitor CPG compliance, and assess effectiveness.
clinical practice guidelines; antimicrobial prophylaxis; guideline adherence; combat-related infections
Ajmaline is a pharmaceutical agent now administered globally for a variety of indications, particularly investigation of suspected Brugada syndrome. There have been previous reports suggesting that repetitive use of this agent may cause severe liver injury, but little evidence exists demonstrating the same effect after only a single administration.
A 33-year-old man of Libyan origin with no significant past medical history underwent an ajmaline provocation test for investigation of suspected Brugada syndrome. Three weeks later, he presented with painless cholestatic jaundice which peaked in severity at eleven weeks after the test. Blood tests confirmed no evidence of autoimmune or viral liver disease, whilst imaging confirmed the absence of biliary tract obstruction. A liver biopsy demonstrated centrilobular cholestasis and focal rosetting of hepatocytes, consistent with a cholestatic drug reaction. Over the course of the next few months, he began to improve clinically and biochemically, with complete resolution by one year post-exposure.
Whilst ajmaline-related hepatotoxicity was well-recognised in the era in which the drug was administered as a regular medication, clinicians should be aware that ajmaline may induce severe cholestatic jaundice even after a single dose administration.
Ajmaline; Drug-induced liver injury; Brugada syndrome; Liver; Pathology
We tested the hypothesis that dopamine-dependent motor learning mechanism underlies the long-duration response to levodopa in Parkinson disease (PD) based on our studies in a mouse model. By data-mining the motor task performance in dominant and nondominant hands of the subjects in a double-blind randomized trial of levodopa therapy, the effects of activity and dopamine therapy were examined.
We data-mined the Earlier versus Later Levodopa Therapy in Parkinson's Disease (ELLDOPA) study published in 2005 and performed statistical analysis comparing the effects of levodopa and dominance of handedness over 42 weeks.
The mean change in finger-tapping counts from baseline before the initiation of therapy to predose at 9 weeks and 40 weeks increased more in the dominant compared to nondominant hand in levodopa-treated subjects in a dose-dependent fashion. There was no significant difference in dominant vs nondominant hands in the placebo group. The short-duration response assessed by the difference of postdose performance compared to predose performance at the same visit did not show any significant difference between dominant vs nondominant hands.
Active use of the dominant hand and dopamine replacement therapy produces synergistic effect on long-lasting motor task performance during “off” medication state. Such effect was confined to dopamine-responsive symptoms and not seen in dopamine-resistant symptoms such as gait and balance. We propose that long-lasting motor learning facilitated by activity and dopamine is a form of disease modification that is often seen in trials of medications that have symptomatic effects.
To evaluate the ability of certified retinal imagers to identify presence versus absence of sight-threatening diabetic retinopathy (stDR) (moderate nonproliferative diabetic retinopathy or worse or diabetic macular edema) at the time of retinal imaging in a telemedicine program.
RESEARCH DESIGN AND METHODS
Diabetic patients in a primary care setting or specialty diabetes clinic received Joslin Vision Network protocol retinal imaging as part of their care. Trained nonphysician imagers graded the presence versus absence of stDR at the time of imaging. These gradings were compared with masked gradings of certified readers.
Of 158 patients (316 eyes) imaged, all cases of stDR (42 eyes [13%]) were identified by the imagers at the time of imaging. Six eyes with mild nonproliferative diabetic retinopathy were graded by the imagers to have stDR (sensitivity 1.00, 95% CI 0.90–1.00; specificity 0.97, 0.94–0.99).
Appropriately trained imagers can accurately identify stDR at the time of imaging.
Mycobacterium tuberculosis arabinogalactan (AG) is an essential cell wall component. It provides a molecular framework serving to connect peptidoglycan to the outer mycolic acid layer. The biosynthesis of the arabinan domains of AG and lipoarabinomannan (LAM) occurs via a combination of membrane bound arabinofuranosyltransferases, all of which utilize decaprenol-1-monophosphorabinose as a substrate. The source of arabinose ultimately destined for deposition into cell wall AG or LAM originates exclusively from phosphoribosyl-1-pyrophosphate (pRpp), a central metabolite which is also required for other essential metabolic processes, such as de novo purine and pyrimidine biosyntheses. In M. tuberculosis, a single pRpp synthetase enzyme (Mt-PrsA) is solely responsible for the generation of pRpp, by catalyzing the transfer of pyrophosphate from ATP to the C1 hydroxyl position of ribose-5-phosphate. Here, we report a detailed biochemical and biophysical study of Mt-PrsA, which exhibits the most rapid enzyme kinetics reported for a pRpp synthetase.
arabinan; cell wall; Mycobacteria; phosphoribosylpyrophosphate; polysaccharides
Chromosome 9 is highly structurally polymorphic. It contains the largest autosomal block of heterochromatin, which is heteromorphic in 6–8% of humans, whereas pericentric inversions occur in more than 1% of the population. The finished euchromatic sequence of chromosome 9 comprises 109,044,351 base pairs and represents >99.6% of the region. Analysis of the sequence reveals many intra- and interchromosomal duplications, including segmental duplications adjacent to both the centromere and the large heterochromatic block. We have annotated 1,149 genes, including genes implicated in male-to-female sex reversal, cancer and neurodegenerative disease, and 426 pseudogenes. The chromosome contains the largest interferon gene cluster in the human genome. There is also a region of exceptionally high gene and G + C content including genes paralogous to those in the major histocompatibility complex. We have also detected recently duplicated genes that exhibit different rates of sequence divergence, presumably reflecting natural selection.
Chromosome 13 is the largest acrocentric human chromosome. It carries genes involved in cancer including the breast cancer type 2 (BRCA2) and retinoblastoma (RB1) genes, is frequently rearranged in B-cell chronic lymphocytic leukaemia, and contains the DAOA locus associated with bipolar disorder and schizophrenia. We describe completion and analysis of 95.5 megabases (Mb) of sequence from chromosome 13, which contains 633 genes and 296 pseudogenes. We estimate that more than 95.4% of the protein-coding genes of this chromosome have been identified, on the basis of comparison with other vertebrate genome sequences. Additionally, 105 putative non-coding RNA genes were found. Chromosome 13 has one of the lowest gene densities (6.5 genes per Mb) among human chromosomes, and contains a central region of 38 Mb where the gene density drops to only 3.1 genes per Mb.
The human X chromosome has a unique biology that was shaped by its evolution as the sex chromosome shared by males and females. We have determined 99.3% of the euchromatic sequence of the X chromosome. Our analysis illustrates the autosomal origin of the mammalian sex chromosomes, the stepwise process that led to the progressive loss of recombination between X and Y, and the extent of subsequent degradation of the Y chromosome. LINE1 repeat elements cover one-third of the X chromosome, with a distribution that is consistent with their proposed role as way stations in the process of X-chromosome inactivation. We found 1,098 genes in the sequence, of which 99 encode proteins expressed in testis and in various tumour types. A disproportionately high number of mendelian diseases are documented for the X chromosome. Of this number, 168 have been explained by mutations in 113 X-linked genes, which in many cases were characterized with the aid of the DNA sequence.
Mouse monoclonal antibody MX35 was developed against
ovarian cancer. The antibody showed homogeneous reactivity with approximately
90% of human ovarian epithelial cancers and with a limited
number of normal tissues by immunohistochemistry. Although mAb MX35
has been used in a number of clinical trials in ovarian cancer,
it has been difficult to define the molecular identity of MX35.
We report here that mAb MX35 recognizes the sodium-dependent phosphate
transport protein 2b (NaPi2b) in human cancer cells. This conclusion
is based on several lines of experimental evidence, including 1)
the identification of SLC34A2, the gene coding for
NaPi2b, by immunoscreening an ovarian cancer cell line cDNA expression
library with mAb MX35; 2) mass spectrometry sequencing of peptides
obtained by fragmentation from mAb MX35 affinity-purified antigen,
which show complete sequence homology to amino acid sequences in
NaPi2b; 3) selective down-regulation of SLC34A2 gene
expression by RNA interference and the resulting loss of mAb MX35
binding to MX35-expressing human cancer cells; and 4) the demonstration
of specific mAb MX35 reactivity with recombinant fusion proteins
and with synthetic peptides of the putative largest extracellular
loop of NaPi2b. We further show that NaPi2b in cancer cells is expressed
on the cell surface as a heavily N-glycosylated
protein, with evidence of additional post-translational modifications
such as palmitoylation and the formation of disulfide bridges in
the major extracellular loop. Membrane transporter molecules, such
as NaPi2b, represent a new family of potential cell surface targets
for the immunotherapy of cancer with monoclonal antibodies.
ovarian cancer; monoclonal
antibody; MX35; protein sequence analysis; NaPi2b; tumor antigen; cancer immunotherapy
The management of bile leaks following laparoscopic cholecystectomy has evolved with increased experience of ERCP and laparoscopy. The purpose of this study was to determine the impact of a minimally invasive management protocol.
PATIENTS AND METHODS
Twenty-four patients with a bile leak following laparoscopic cholecystectomy were recorded consecutively between 1993 and 2003. Between 1993–1998, 10 patients were managed on a case-by-case basis. Between 1998–2003, 14 patients were managed according to a minimally invasive protocol utilising ERC/biliary stenting and re-laparoscopy if indicated.
Bile leaks presented as bile in a drain left in situ post laparoscopic cholecystectomy (8/10 versus 10/14) or biliary peritonitis (2/10 versus 4/14). Prior to 1998, neither ERC nor laparoscopy were utilised routinely. During this period, 4/10 patients recovered with conservative management and 6/10 (60%) underwent laparotomy. There was one postoperative death and median hospital stay post laparoscopic cholecystectomy was 10 days (range, 5–30 days). In the protocol era, ERC ± stenting was performed in 11/14 (P = 0.01 versus pre-protocol) with the main indication being a persistent bile leak. Re-laparoscopy was necessary in 5/14 (P = 0.05 versus preprotocol). No laparotomies were performed (P < 0.01 versus pre-protocol) and there were no postoperative deaths. Median hospital stay was 11 days (range, 5–55 days).
The introduction of a minimally invasive protocol utilising ERC and re-laparoscopy offers an effective modern algorithm for the management of bile leaks after laparoscopic cholecystectomy.
Bile leak; Laparoscopic cholecystectomy
Human populations and animals are often exposed to the airborne pollutants in plumes from incinerators. The incineration of chemical and other waste may release polychlorinated hydrocarbons, some of which have oestrogenic properties. Increased numbers of twins had been reported anecdotally in cattle at risk from plumes from two incinerators near the town of Bonnybridge in central Scotland and also in cattle near a chemical factory in Eire. It was decided to follow up these reports in central Scotland and also to test the hypothesis that the frequency of human twinning might be increased there. Data on human twin and single births in hospitals in central Scotland were obtained for the years 1975-83. The twinning rates in areas exposed to airborne pollution from incinerators were compared with the background rates present in neighbouring areas. Farmers provided information on calving among the herds of two farms close to the incinerators. The frequency of human twinning was increased, particularly after 1979, in the areas most at risk from air pollution from the incinerators. Among the dairy cattle, there was a dramatic increase in twinning at about the same time.
Geographical and temporal associations were shown between high mortality from lung cancer and a high sex ratio of births both in the town of Bathgate (Scotland) and in the area of that town which was most exposed to polluted air from a local steel foundry. These findings constituted a replication of a similar association in an adjacent town.
Fasting blood samples taken from 116 apparently healthy men aged 30-50 years were assayed for selenium, glutathione peroxidase activity, vitamin E, cadmium, lead, glucose, lipids, and albumin. Blood pressure was measured in each subject, and details of height, weight, smoking habits, and alcohol consumption were recorded. Multivariate analysis of the data showed that the decrease in blood and serum concentrations of selenium and the increase in whole blood cadmium concentrations in the cigarette smokers was independent of alcohol consumption. There was no correlation between blood selenium concentrations or glutathione peroxidase activities and the risk factors for cardiovascular disease. Neither alcohol consumption nor smoking had an effect on the vitamin E concentrations. There was a strong association, however, between vitamin E and serum lipid concentrations, although the increase in triglyceride concentrations in the smokers was not matched by a comparable increase in vitamin E. The possible role of selenium in the aetiology of heart disease remains unresolved.
In a study of selenium status in 391 apparently healthy subjects resident in the south of England statistical examination of the data showed a significant effect with regard to age, smoking, alcohol, and oral contraceptives. The most important of these factors seems to be a combination of alcohol and smoking habits in men over 30. Reference ranges have been established for glutathione peroxidase activities and the concentrations of selenium in whole blood plasma and erythrocytes.
Daily electricity consumption of four families was recorded for 106 days. A reversal design, consisting of various experimental conditions interspersed between repeated baseline conditions, was used. During experimental conditions, daily prompts (written conservation slogans attached to front doors) and/or daily feedback (daily kilowatts consumed and daily cost information) were in effect. Maximum consumption occurred during the initial baseline; minimum consumption occurred during different experimental conditions for different families. The mean decrease from the maximum to the minimum for all families was 35%. Reversals in consumption were demonstrated in three families, although successive baselines tended to decrease. No clear differences in effectiveness between prompting and feedback conditions were apparent. The procedures used resulted in considerable dollar savings for the families.
electricity conservation; reversal design; prompts; feedback; cost information; daily kilowatt hour consumption; suburban families
dengue research; dengue burden; dengue vectors; dengue clinical management
To assess pregabalin monotherapy for partial-onset seizures using a historical-controlled conversion-to-monotherapy design.
Adults with inadequately controlled partial-onset seizures while receiving 1 or 2 antiepileptic drugs during an 8-week prospective baseline were randomized to double-blind monotherapy with pregabalin 600 or 150 mg/d (4:1) for 20 weeks (8-week conversion and 12-week monotherapy period). The primary endpoint was the seizure-related exit rate for pregabalin 600 mg/d, based on discontinuations due to predefined criteria. Efficacy was declared if the upper limit of the 95% confidence interval for the exit rate was below a historical-control threshold of 74%, with stepwise evaluation using a threshold of 68%.
The trial was stopped early for positive efficacy after an interim analysis in 125 patients. The full study population included 161 patients, with 148 evaluable for efficacy. The mean time since epilepsy diagnosis was 14 years. Overall, 54.3% (600 mg/d) and 46.9% (150 mg/d) of patients completed 20 weeks of double-blind treatment. Seizure-related exit rate in the 600 mg/d group (27.5%; 95% confidence interval, 17.8%–37.2%) was significantly below the 74% and 68% thresholds (p < 0.001 for both). Eight patients on 600 mg/d and 2 on 150 mg/d were seizure-free throughout pregabalin monotherapy. Pregabalin's overall safety profile was consistent with prior trials.
Pregabalin monotherapy was safe and efficacious for patients with inadequately controlled partial-onset seizures.
Classification of evidence:
This study provides Class III evidence that patients with inadequately controlled partial-onset seizures switched to pregabalin monotherapy have fewer seizure-related exit events compared with historical controls switched to pseudo-placebo monotherapy.