We used existing and customized bibliometric and scientometric methods to analyze publication trends in neuroimaging research of minimally conscious states and describe the domain in terms of its geographic, contributor, and content features. We considered publication rates for the years 2002–2011, author interconnections, the rate at which new authors are added, and the domains that inform the work of author contributors. We also provided a content analysis of clinical and ethical themes within the relevant literature. We found a 27% growth in the number of papers over the period of study, professional diversity among a wide range of peripheral author contributors but only few authors who dominate the field, and few new technical paradigms and clinical themes that would fundamentally expand the landscape. The results inform both the science of consciousness as well as parallel ethics and policy studies of the potential for translational challenges of neuroimaging in research and health care of people with disordered states of consciousness.
Minimally conscious states; Persistent vegetative state; Clinical research; Neuroimaging; Bioethics; Altmetrics
To determine the health and economic burdens of post-partum Staphylococcus aureus breast abscess.
We conducted a matched cohort study (N = 216) in a population of pregnant women (N = 32,770) who delivered at our center during the study period from 10/1/03–9/30/10. Data were extracted from hospital databases, or via chart review if unavailable electronically. We compared cases of S. aureus breast abscess to controls matched by delivery date to compare health services utilization and mean attributable medical costs in 2012 United States dollars using Medicare and hospital-based estimates. We also evaluated whether resource utilization and health care costs differed between cases with methicillin-resistant and -susceptible S. aureus isolates.
Fifty-four cases of culture-confirmed post-partum S. aureus breast abscess were identified. Breastfeeding cessation (41%), milk fistula (11.1%) and hospital readmission (50%) occurred frequently among case patients. Breast abscess case patients had high rates of health services utilization compared to controls, including high rates of imaging and drainage procedures. The mean attributable cost of post-partum S. aureus breast abscess ranged from $2,340–$4,012, depending on the methods and data sources used. Mean attributable costs were not significantly higher among methicillin-resistant vs. –susceptible S. aureus cases.
Post-partum S. aureus breast abscess is associated with worse health and economic outcomes for women and their infants, including high rates of breastfeeding cessation. Future study is needed to determine the optimal treatment and prevention of these infections.
Antibiotic use rates have declined dramatically since the 1990s. We aimed to determine if, when, and at what level the decline in antibiotic-dispensing rates ended and which diagnoses contributed to the trends.
Antibiotic dispensings and diagnoses were obtained from 2 health insurers for 3- to <72-month-olds in 16 Massachusetts communities from 2000 to 2009. Population-based antibiotic-dispensing rates per person-year (p-y) were determined according to year (September–August) for 3 age groups. Fit statistics were used to identify the most likely year for a change in trend. Rates for the first and last years were compared according to antibiotic category and associated diagnosis.
From 2000–2001 to 2008–2009, the antibiotic-dispensing rate for 3- to <24-month-olds decreased 24% (2.3–1.8 antibiotic dispensings per p-y); for 24- to <48-month-olds, it decreased 18% (1.6–1.3 antibiotic dispensings per p-y); and for 48- to <72-month-olds, it decreased 20% (1.4–1.1 antibiotic dispensings per p-y). For 3- to <48-month-olds, rates declined until 2004–2005 and remained stable thereafter; the downward trend for 48- to <72-month-olds ended earlier in 2001–2002. Among 3- to <24-month-olds, first-line penicillin use declined 26%. For otitis media, the dispensing rate decreased 14% and the diagnosis rate declined 9%, whereas the treatment fraction was stable at 63%.
The downward trend in antibiotic dispensings to young children in these communities ended by 2004–2005. This trend was driven by a declining otitis media diagnosis rate. Continued monitoring of population-based dispensing rates will support efforts to avoid returning to previous levels of antibiotic overuse.
antibiotic use; managed care programs; otitis media
Guillain-Barré Syndrome (GBS) can be triggered by gastrointestinal or respiratory infections, including influenza. During the 2009 influenza A (H1N1) pandemic in the United States, monovalent inactivated influenza vaccine (MIV) availability coincided with high rates of wildtype influenza infections. Several prior studies suggested an elevated GBS risk following MIV, but adjustment for antecedent infection was limited.
We identified patients enrolled in health plans participating in the Vaccine Safety Datalink and diagnosed with GBS from July 2009 through June 2011. Medical records of GBS cases with 2009–10 MIV, 2010–11 trivalent inactivated influenza vaccine (TIV), and/or a medically-attended respiratory or gastrointestinal infection in the 1 through 141 days prior to GBS diagnosis were reviewed and classified according to Brighton Collaboration criteria for diagnostic certainty. Using a case-centered design, logistic regression models adjusted for patient-level time-varying sources of confounding, including seasonal vaccinations and infections in GBS cases and population-level controls.
Eighteen confirmed GBS cases received vaccination in the 6 weeks preceding onset, among 1.27 million 2009–10 MIV recipients and 2.80 million 2010–11 TIV recipients. Forty-four confirmed GBS cases had infection in the 6 weeks preceding onset, among 3.77 million patients diagnosed with medically-attended infection. The observed-versus-expected odds that 2009–10 MIV/2010–11 TIV was received in the 6 weeks preceding GBS onset was odds ratio = 1.54, 95% confidence interval (CI), 0.59–3.99; risk difference = 0.93 per million doses, 95% CI, −0.71–5.16. The association between GBS and medically-attended infection was: odds ratio = 7.73, 95% CI, 3.60–16.61; risk difference = 11.62 per million infected patients, 95% CI, 4.49–26.94. These findings were consistent in sensitivity analyses using alternative infection definitions and risk intervals for prior vaccination shorter than 6 weeks.
After adjusting for antecedent infections, we found no evidence for an elevated GBS risk following 2009–10 MIV/2010–11 TIV influenza vaccines. However, the association between GBS and antecedent infection was strongly elevated.
Improving the situation in older adults with cognitive decline and evidence of cognitive rehabilitation is considered crucial in long-term care of the elderly. The objective of this study was to implement a computerized errorless learning-based memory training program (CELP) for persons with early Alzheimer’s disease, and to compare the training outcomes of a CELP group with those of a therapist-led errorless learning program (TELP) group and a waiting-list control group.
A randomized controlled trial with a single-blind research design was used in the study. Chinese patients with early Alzheimer’s disease screened by the Clinical Dementia Rating (score of 1) were recruited. The subjects were randomly assigned to CELP (n = 6), TELP (n = 6), and waiting-list control (n = 7) groups. Evaluation of subjects before and after testing, and at three-month follow-up was achieved using primary outcomes on the Chinese Mini-Mental State Examination, Chinese Dementia Rating Scale, Hong Kong List Learning Test, and the Brief Assessment of Prospective Memory-Short Form. Secondary outcomes were the Modified Barthel Index, Hong Kong Lawton Instrumental Activities of Daily Living Scale, and Geriatric Depression Scale-Short Form. The data were analyzed using Friedman’s test for time effect and the Kruskal-Wallis test for treatment effect.
Positive treatment effects on cognition were found in two errorless learning-based memory groups (ie, computer-assisted and therapist-led). Remarkable changes were shown in cognitive function for subjects receiving CELP and emotional/daily functions in those receiving TELP.
Positive changes in the cognitive function of Chinese patients with early Alzheimer’s disease were initially found after errorless training through CELP. Further enhancement of the training program is recommended.
Alzheimer’s disease; memory training; errorless learning; computerized; early dementia
This study explored the cross sectional association between adverse life events and gambling in a sample of 515 urban adolescents (average age 17, 55% male, 88% African American). Approximately half of the sample had gambled in the past year (51%); 78% of the gamblers gambled monthly and 39% had a gambling-related problem. On the other hand, 88% of the sample had experienced at least one life event in the past year, and those experiencing events tended to live in more disadvantaged neighborhoods. The mere acknowledgement of experiencing a stressful life event in the past year (yes/no) was not associated with an increase in odds of being a gambler, with gambling more frequently, or with having a gambling problem. However, when the context of the event was considered, an association was found between directly experiencing threatening and deviant/violent types of events and frequent gambling (OR > 2). Additionally, the probability of being a gambler increased as the number of events experienced increased (aOR = 1.07, 95% CI = 1.01, 1.13, P = 0.013), but problems among gamblers were not associated with the number of events experienced (aOR = 1.01, 95% CI = 0.92, 1.11, P = 0.876). During adolescence, life events appear to be connected more with the frequency of gambling rather than with problems related to gambling.
Gambling; Life events; Adolescence
Depression has been associated with higher conversion rates from mild cognitive impairment (MCI) to Alzheimer’s disease (AD) and may be a potential clinical marker of prodromal AD that can be used to identify individuals with MCI who are most likely to progress to AD. Using tensor-based morphometry (TBM), we examined the longitudinal neuroanatomical changes associated with depressive symptoms in MCI.
243 MCI subjects from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) who had brain MRI scans at baseline and 2-year follow-up were classified into depressed (DEP, n=44), non-depressed with other neuropsychiatric symptoms (OTHER, n=93), and no-symptom (NOSYMP, n=106) groups based on the Neuropsychiatric Inventory Questionnaire (NPI-Q). TBM was used to create individual 3D-maps of 2-year brain changes that were compared between groups.
DEP subjects had more frontal (p=0.024), parietal (p=0.030), and temporal (p=0.038) white matter atrophy than NOSYMP subjects. A subset of DEP subjects whose depressive symptoms persisted over 2-years also had higher conversion to AD and more decline on measures of global cognition, language abilities, and executive functioning compared to stable NOSYMP subjects. OTHER and NOSYMP groups exhibited no differences in rates of atrophy.
Depressive symptoms in MCI subjects were associated with greater atrophy in AD-affected regions, increased cognitive decline, and higher rates of conversion to AD. Depression in individuals with MCI may be associated with underlying neuropathological changes including prodromal AD. Thus, assessment of depressive symptoms may be a potentially useful clinical marker in identifying MCI patients who are most likely to progress to AD.
Depression; Mild Cognitive Impairment; Alzheimer’s Disease; Neuropsychiatric Symptoms; Tensor-Based Morphometry; White Matter
Anticoagulation is essential for maintaining the fluidity of extravascular blood on the apheresis circuit. Although both citrate and heparin are used as an anticoagulant during apheresis, citrate is preferred for the majority of exchange procedures because of its safety and effectiveness. Complications of citrate are primarily due to physiologic effects of hypocalcemia. Symptoms of hypocalcemia and other citrate-induced metabolic abnormalities affect neuromuscular and cardiac function and range in severity from mild dysesthesias (most common) to tetany, seizures and cardiac arrhythmias. Oral or intravenous calcium supplementation is advised for decreased ionized calcium levels and/or symptomatic management of hypocalcemia. Heparin-based anticoagulation is limited to certain apheresis procedures (membrane-based plasma exchange, LDL apheresis, or photopheresis) or is used in combination with citrate to reduce citrate load. While effective, heparin anticoagulation is associated with an increased frequency of bleeding complications and heparin-induced thrombocytopenia.
apheresis; citrate; heparin; anticoagulation; hypocalcemia
The clinical syndromes of frontotemporal lobar degeneration include behavioral variant frontotemporal dementia (bvFTD) and semantic (SV-PPA) and nonfluent variants (NF-PPA) of primary progressive aphasia. Using magnetic resonance imaging (MRI), tensor-based morphometry (TBM) was used to determine distinct patterns of atrophy between these three clinical groups.
Twenty-seven participants diagnosed with bvFTD, 16 with SV-PPA, and 19 with NF-PPA received baseline and follow-up MRI scans approximately 1 year apart. TBM was used to create three-dimensional Jacobian maps of local brain atrophy rates for individual subjects.
Regional analyses were performed on the three-dimensional maps and direct comparisons between groups (corrected for multiple comparisons using permutation tests) revealed significantly greater frontal lobe and frontal white matter atrophy in the bvFTD relative to the SV-PPA group (p < 0.005). The SV-PPA subjects exhibited significantly greater atrophy than the bvFTD in the fusiform gyrus (p = 0.007). The NF-PPA group showed significantly more atrophy in the parietal lobes relative to both bvFTD and SV-PPA groups (p < 0.05). Percent volume change in ventromedial prefrontal cortex was significantly associated with baseline behavioral symptomatology.
The bvFTD, SV-PPA, and NF-PPA groups displayed distinct patterns of progressive atrophy over a 1-year period that correspond well to the behavioral disturbances characteristic of the clinical syndromes. More specifically, the bvFTD group showed significant white matter contraction and presence of behavioral symptoms at baseline predicted significant volume loss of the ventromedial prefrontal cortex.
Frontotemporal dementia; Primary progressive aphasia; Longitudinal study; Magnetic resonance imaging; Tensor-based morphometry; White matter
Growth of the remaining lung after pneumonectomy has been observed in many mammalian species; nonetheless, the pattern and morphology of alveolar angiogenesis during compensatory growth is unknown. Here, we investigated alveolar angiogenesis in a murine model of post-pneumonectomy lung growth. As expected, the volume and weight of the remaining lung returned to near-baseline levels within 21 days of pneumonectomy. The percentage increase in lobar weight was greatest in the cardiac lobe (p<.001). Cell cycle flow cytometry demonstrated a peak of lung cell proliferation (12.02±1.48%) 6 days after pneumonectomy. Spatial autocorrelation analysis of the cardiac lobe demonstrated clustering of similar vascular densities (positive autocorrelation) that consistently mapped to subpleural regions of the cardiac lobe. Immunohistochemical staining demonstrated increased cell density and enhanced expression of angiogenesis-related factors VEGFA, and GLUT1 in these subpleural regions. Corrosion casting and scanning electron microscopy 3-6 days after pneumonectomy demonstrated subpleural vessels with angiogenic sprouts. The monopodial sprouts appeared to be randomly oriented along the vessel axis with interbranch distances of 11.4±4.8 um in the regions of active angiogenesis. Also present within the regions of increased vascular density were frequent “holes” or “pillars” consistent with active intussusceptive angiogenesis. The mean pillar diameter was 4.2±3.8 um and the pillars were observed in all regions of active angiogenesis. These findings indicate that the process of alveolar construction involves discrete regions of regenerative growth, particularly in the subpleural regions of the cardiac lobe, characterized by both sprouting and intussusceptive angiogenesis.
scanning electron microscopy; corrosion casting; neoalveolarization; intussusceptive angiogenesis; microCT
We sought to measure trends in Streptococcus pneumoniae (SP) carriage and antibiotic resistance in young children in Massachusetts communities after widespread adoption of heptavalent pneumococcal conjugate vaccine (PCV7) and before the introduction of the 13-valent pneumococcal conjugate vaccine (PCV13).
We conducted a cross-sectional study including collection of questionnaire data and nasopharyngeal specimens among children <7 years in primary care practices from 8 Massachusetts communities during the winter season of 2008–9 and compared with to similar studies performed in 2001, 2003–4, and 2006–7. Antimicrobial susceptibility testing and serotyping were performed on pneumococcal isolates, and risk factors for colonization in recent seasons (2006–07 and 2008–09) were evaluated.
We collected nasopharyngeal specimens from 1,011 children, 290 (29%) of whom were colonized with pneumococcus. Non-PCV7 serotypes accounted for 98% of pneumococcal isolates, most commonly 19A (14%), 6C (11%), and 15B/C (11%). In 2008–09, newly-targeted PCV13 serotypes accounted for 20% of carriage isolates and 41% of penicillin non-susceptible S. pneumoniae (PNSP). In multivariate models, younger age, child care, young siblings, and upper respiratory illness remained predictors of pneumococcal carriage, despite near-complete serotype replacement. Only young age and child care were significantly associated with PNSP carriage.
Serotype replacement post-PCV7 is essentially complete and has been sustained in young children, with the relatively virulent 19A being the most common serotype. Predictors of carriage remained similar despite serotype replacement. PCV13 may reduce 19A and decrease antibiotic-resistant strains, but monitoring for new serotype replacement is warranted.
Streptococcus pneumoniae; pneumococcal conjugate vaccine; antibiotic resistance; serotype; colonization
In many species, pneumonectomy triggers compensatory lung growth that results in an increase not only in lung volume, but also in alveolar number. Whether the associated alveolar angiogenesis involves the contribution of blood-borne progenitor cells is unknown. To identify and characterize blood-borne progenitor cells contributing to lung growth after pneumonectomy in mice, we studied wild-type and wild-type/green fluorescence protein (GFP) parabiotic mice after left pneumonectomy. Within 21 days of pneumonectomy, a 3.2-fold increase occurred in the number of lung endothelial cells. This increase in total endothelial cells was temporally associated with a 7.3-fold increase in the number of CD34+ endothelial cells. Seventeen percent of the CD34+ endothelial cells were actively proliferating, compared with only 4.2% of CD34− endothelial cells. Using wild-type/GFP parabiotic mice, we demonstrated that 73.4% of CD34+ cells were derived from the peripheral blood. Furthermore, lectin perfusion studies demonstrated that CD34+ cells derived from peripheral blood were almost uniformly incorporated into the lung vasculature. Finally, CD34+ endothelial cells demonstrated a similar profile, but had enhanced transcriptional activity relative to CD34− endothelial cells. We conclude that blood-borne CD34+ endothelial progenitor cells, characterized by active cell division and an amplified transcriptional signature, transition into resident endothelial cells during compensatory lung growth.
endothelial progenitor cells; CD31+ CD34+ cell; lung angiogenesis; lung regeneration
Tactile social contact is the most effective form of environmental enrichment for promoting normal behavior in captive primates. For laboratory macaques housed indoors, pair housing is the most common method for socialization. Pairs can be housed either in full contact (FC), or in protected contact (PC). At Washington National Primate Research Center, PC is provided by grooming-contact (GC) cages whereby two partners are housed individually in adjacent cages with access to each other through widely spaced vertical bars. Grooming-contact has been used to accommodate research protocol restrictions and improve the likelihood of compatibility for various pairings, in part by enabling male-female pairs. This study compares the benefits between the two housing types by video recording 14 pairs of adult female Macaca fascicularis in four sequential housing phases following an ABBA design: baseline grooming-contact, full contact shortly after introduction, 1-month-later full contact, and after reversion to grooming-contact. Prior to this study, pairs had been housed compatibly in GC. Twelve of the 14 long-term pairs transitioned successfully to full contact and data presented exclude the two failed pairs. Allogrooming increased significantly when pairs first switched from GC to FC (P = 0.018), but the effect did not last through the on 1-month-later FC phase suggesting that the initial improvement in affiliative behavior was a transitory novelty response that did not persist. Self-grooming significantly decreased between the first GC and first FC phases (P = 0.016), likely due to redirected allogrooming. Non-contact affiliative behavior towards partner or other conspecifics in the room did not differ, nor did agonism towards partner or others in the room. Occurrence of abnormal, tension, manipulation, miscellaneous active, and inactive behaviors did not differ significantly across housing phases. Proximity measurements indicated that pairs were significantly out of arm’s reach more often in protected contact than when in full contact (P ≤ 0.02). Proportion of time spent in physical contact significantly increased between the first GC and first FC phases (P = 0.002), but subsequently declined. For both FC phases, partners chose to spend about 50% of their time in the same cage. Few behavioral improvements were seen after pairs switched to full contact and no negative effects came of reversion to grooming contact. This study suggests that tactile contact provided through widely spaced bars (grooming-contact) is a viable alternative to full contact housing for adult female longtailed macaques. It provides a degree of social housing while allowing both partners choice and control, key concepts in contemporary animal welfare guidelines.
Pair-housing; social housing; abnormal behavior; environmental enrichment; psychological well-being; laboratory macaques
Most KPC-producing organisms have maintained susceptibility to polymyxins; however, development of resistance to polymyxins has been increasingly reported. One potential treatment modality is to optimize the use of combination therapy. Therefore, we evaluated the in vitro activity of doripenem, colistin sulfate, polymyxin B alone and in combination against KPC- producing K. pneumoniae.
In-vitro time-kill assays were performed for four non-duplicate KPC-3 producing K. pneumoniae isolates with the following antibiotics: doripenem, polymyxin B and colistin sulfate alone and in combination. Bacterial densities were determined at 0, 4, 8, 12, 24 and 48 hours. Bactericidal activity was defined as ≥ 3-log10 CFU/mL reduction from the starting inoculum. Synergism was defined as ≥ 2-log10 reduction with the combination when compared to the most active single agent at 24 hours.
Minimum inhibitory concentrations (MICs) for polymyxin B and colistin sulfate ranged from 0.0625 to 0.25 µg/mL, and all isolates were resistant to doripenem (MICs ranged 16 - 32 µg/mL). Monotherapy with colistin sulfate and polymyxin B displayed bacterialcidal activity within 12 hours; however, significant re-growth occurred by 24 hours in all isolates. Monotherapy with doripenem did not show bactericidal activity in any isolate. Synergy occurred with combinations of both colistin sulfate and polymyxin B with doripenem against all isolates and was sustained at 48 hours. Combinations of colistin sulfate or polymyxin B with doripenem demonstrated rapid bactericidal activity by 4 hours in all isolates and was sustained for 24 hours.
Polymyxin B and colistin sulfate in combination with doripenem may be an important treatment modality in treating KPC-producing organisms.
Klebsiella pneumoniae; KPC; Carbapenemase; Time-kill; Doripenem; Colistin; Polymyxin B; Carbapenem; Synergy
Blood-borne nucleated cells participate not only in inflammation, but in tissue repair and regeneration. Because progenitor and stem cell populations have a low concentration in the blood, the circulation kinetics and tissue distribution of these cells is largely unknown. An important approach to tracking cell lineage is the use of fluorescent tracers and parabiotic models of cross-circulation. Here, we investigated the cross-circulation and cell distribution kinetics of C57/B6 GFP+/wild-type parabionts. Flow cytometry analysis of the peripheral blood after parabiosis demonstrated no evidence for a “parabiotic barrier” based on cell size or surface characterstics; all peripheral blood cell subpopulations in this study reached equilibrium within 14 days. Whole blood fluorescence analysis indicated that the mean exchange flow rate was 16μl/hr or 0.66% of the circulating blood volume per hour. Studies of peripheral lymphoid organs indicated differential cell distribution kinetics. Some subpopulations, such as CD8+ and CD11c+, equilibrated in both lymph nodes and spleen indicating a residence time less than 28 days; in contrast, other lymphocyte subpopulations, such as B220+ and CD4+ cells, had not yet reached equilibrium at 28 days. We conclude that parabiosis can provide important insights into defining tissue distribution, residence times, and recirculating pools using fluorochrome markers of cell lineage.
The emergence of Klebsiella pneumoniae carbapenemases (KPCs) producing bacteria has become a significant global public health challenge while the optimal treatment remains undefined. We performed a systematic review of published studies and reports of treatment outcomes of KPC infections using MEDLINE (2001–2011). Articles or cases were excluded if one of the following was fulfilled: no individual patient data provided, no treatment regimen specified, no treatment outcome specified, report of colonization, or greater than three antibiotics were used to treat the KPC infection. Data extracted included patient demographics, site of infection, organism, KPC subtype, antimicrobial therapy directed at KPC-infection, and treatment outcome. Statistical analysis was performed in an exploratory manner. A total of 38 articles comprising 105 cases were included in the analysis. The majority of infections were due to K. pneumoniae (89%). The most common site of infection was blood (52%), followed by respiratory (30%), and urine (10%). Forty-nine (47%) cases received monotherapy and 56 (53%) cases received combination therapy directed at the KPC-infection. Significantly more treatment failures were seen in cases that received monotherapy compared to cases who received combination therapy (49% vs 25%; p= 0.01). Respiratory infections were associated with higher rates of treatment failure with monotherapy compared to combination therapy (67% vs 29% p= 0.03). Polymyxin monotherapy was associated with higher treatment failure rates compared to polymyxin-based combination therapy (73% vs 29%; p= 0.02); similarly, higher treatment failure rates were seen with carbapenem monotherapy compared to carbapenem-based combination therapy (60% vs 26%; p= 0.03). Overall treatment failure rates were not significantly different in the three most common antibiotic-class combinations: polymyxin plus carbapenem, polymyxin plus tigecycline, polymyxin plus aminoglycoside (30%, 29%, and 25% respectively; p=0.6). In conclusion, combination therapy is recommended for the treatment of KPC infections; however, which combination of antimicrobial agents needs to be established in future prospective clinical trials.
KPC; Treatment outcome; Klebsiella pneumoniae carbapenemases; Carbapenemase; Polymyxin; Carbapenems; Tigecycline; Aminoglycosides
Lopinavir/ritonavir (Kaletra®) is first line therapy for pediatric HIV infection. In clinical practice, Kaletra® tablets are occasionally crushed for pediatric administration. This study compared lopinavir/ritonavir exposure between whole and crushed tablets in HIV-infected children.
This was a randomized, open-label, cross-over study of pediatric patients taking lopinavir/ritonavir as part of their antiretroviral regimen. Each subject had two separate (within 30 days) steady-state 12-hour pharmacokinetic (PK) studies with crushed and whole 200/50 mg lopinavir/ritonavir tablets.
PK blood samples were drawn at 0 (pre-dose), 1, 2, 4, 6, 8, and 12 hours post-dose. Lopinavir and ritonavir plasma concentrations measured by high performance liquid chromatography were used to calculate non-compartmental area under the concentration versus time curve (AUC) and clearance (CL/F). Wilcoxon signed-rank tests compared PK values between crushed and whole tablets.
Twelve children, median age of 13 years (10–16 years), took 550/138 mg/m2/day lopinavir/ritonavir divided every 12 hours. The median lopinavir AUC following crushed and whole tablets were 92 mg*hr/L and 144 mg*hr/L, respectively, with an AUC ratio of 0.55 (p=0.003). Median ritonavir AUC of crushed and whole tablets were 7 mg*hr/L and 13.3 mg*hr/L, respectively, with an AUC ratio of 0.53 (p=0.006).
Administration of crushed 200/50 mg lopinavir/ritonavir tablets to children significantly reduced lopinavir and ritonavir exposure with a decrease in AUC by 45% and 47%, respectively. The administration of crushed tablets would require higher doses and therapeutic drug monitoring to ensure adequate lopinavir exposure in patients requiring this practice. The use of crushed lopinavir/ritonavir tablets should be avoided, if possible.
lopinavir; ritonavir; pharmacokinetics; pediatrics
Performance on measures of cognitive processing speed (CPS) slows with age, but the biological basis associated with this cognitive phenomenon remains incompletely understood. We assessed the hypothesis that the age-related slowing in CPS is associated with myelin breakdown in late-myelinating regions in a very healthy elderly population. An in vivo MRI biomarker of myelin integrity was obtained from the prefrontal lobe white matter and the genu of the corpus callosum for 152 healthy elderly adults. These regions myelinate later in brain development and are more vulnerable to breakdown due to the effects of normal aging. To evaluate regional specificity, we also assessed the splenium of the corpus callosum as a comparison region, which myelinates early in development and primarily contains axons involved in visual processing. The measure of myelin integrity was significantly correlated with CPS in highly vulnerable late-myelinating regions but not in the splenium. These results have implications for the neurobiology of the cognitive changes associated with brain aging.
Healthy Aging; Cognition; Information Processing Speed; Myelin; White Matter; Magnetic Resonance Imaging; Alzheimer’s Disease; Dementia
Bipolar disorder (BPD) is a devastating long-term disease for which a significant symptom is mania. Rodent models for mania include psychostimulant-induced hyperactivity and single gene alterations, such as in the CLOCK or DAT gene, but there is still a pressing need for additional models. Recently, our lab isolated a line of mice, termed Madison (MSN), that exhibit behavioral characteristics that may be analogous to symptoms of mania. In this study we quantified possible traits for mania and tested the response to common anti-BPD drugs in altering the behavioral profiles observed in this strain. Relative to other mouse lines, MSN mice showed significant elevations of in-cage hyperactivity levels, significant decreases in daytime sleep, and significant increases in time swimming in the forced swim test. In terms of sexual behavior, the MSN mice showed significantly higher number of mounts and a trend toward higher time mounting. In separate studies, olanzapine and lithium (or respective controls) were administered to MSN mice for at least two weeks and response to treatments was evaluated. Olanzapine (1 mg/kg/day) significantly decreased in-cage hyperactivity and significantly increased time sleeping. Lithium (0.2–0.4% in food) significantly decreased in-cage hyperactivity. Given the behavioral phenotypes and the response to anti-BPD treatments, we propose that MSN mice may provide a possible new model for understanding the neural and genetic basis of phenotypes related to mania and for developing pharmaceutical treatments.
bipolar disorder; mania; lithium; olanzapine; hyperactivity; sleep; mice
To investigate the local mechanical forces associated with intravascular pillars and vessel pruning, we studied the conducting vessels in the extraembryonic circulation of the chick embryo. During the development days 12–16, intravascular pillars and blood flow parameters were identified using fluorescent vascular tracers and digital time-series video reconstructions. The geometry of selected vessels was confirmed by corrosion casting and scanning electron microscopy. Computational simulations of pruning vessels suggested that serial pillars form along pre-existing velocity streamlines; blood pressure demonstrated no obvious spatial relationship with the intravascular pillars. Modeling a Reynolds number of 0.03 produced 4 pillars at approximately 20um intervals matching the observed periodicity. In contrast, a Reynolds number of 0.06 produced only 2 pillars at approximately 63um intervals. Our modeling data indicated that the combination of wall shear stress and gradient of shear predicted the location, direction and periodicity of developing pillars.
Maternal defense (offspring protection) is a critical and highly conserved component of maternal care in mammalian systems that involves dramatic shifts in a female’s behavioral response to social cues. Numerous changes occur in neuronal signaling and connectivity in the postpartum female, including decreases in norepinephrine (NE) signaling in subregions of the CNS. In this study using a strain of mice selected for maternal defense, we examined whether possible changes in NE signaling in the lateral septum (LS) could facilitate expression of maternal aggression. In separate studies that utilized a repeated measures design, mice were tested for maternal defense following intra-LS injections of either the β adrenergic receptor agonist isoproterenol (10 μg or 30 μg) or vehicle (Experiment 1), the β-adrenergic receptor antagonist propranolol (2 μg) or vehicle (Experiment 2), or the β1 receptor antagonist, atenolol (Experiment 3). Mice were also evaluated for light-dark performance and pup retrieval. 30 μg of the agonist isoproterenol significantly decreased number of attacks and time aggressive relative to vehicle without affecting pup retrieval or light/dark box performance. In contrast, the antagonist propranolol significantly increased maternal aggression (lowered latency to attack and increased total attack time) without altering light/dark box test. The β1 specific antagonist, atenolol, significantly decreased latency to attack (1 μg v. vehicle) without altering other measures. Although the findings were identified in a unique strain of mice that may or may not apply to other strains, the results of these studies support the hypothesis that changes in NE signaling in LS during the postpartum period contribute to the expression of offspring protection.
adrenergic; isoproterenol; maternal aggression; norepinephrine; propranolol
Dental trauma is frequently unpredictable. The initial assessment and urgent treatment are essential for dentists to save the patient's teeth. Mobile-phone-assisted teleconsultation and telediagnosis for dental trauma could be an aid when a dentist is not available. In the present in-vitro study, we evaluated the success rate and time to transfer images under various conditions.
Materials and Methods
We analyzed the image quality of cameras built into mobile phones based on their resolution, autofocus, white-balance, and anti-movement functions.
The image quality of most built-in cameras was acceptable to perform the initial assessment, with the autofocus function being essential to obtain high-quality images. The transmission failure rate increased markedly when the image size exceeded 500 κB and the additional text messaging did not improve the success rate or the transmission time.
Our optimal protocol could be useful for emergency programs running on the mobile phones.
Cellular Phone; Tooth Injuries; Emergencies; Remote Consultation
Thoracic surgical procedures in mice have been applied to a wide range of investigations, but little is known about the murine physiologic response to pulmonary surgery. Using continuous arterial oximetry monitoring and the FlexiVent murine ventilator, we investigated the effect of anesthesia and pneumonectomy on mouse oxygen saturation and lung mechanics. Sedation resulted in a dose-dependent decline of oxygen saturation that ranged from 55–82%. Oxygen saturation was restored by mechanical ventilation with increased rate and tidal volumes. In the mouse strain studied, optimal ventilatory rates were a rate of 200/minute and a tidal volume of 10ml/kg. Sustained inflation pressures, referred to as a "recruitment maneuver," improved lung volumes, lung compliance and arterial oxygenation. In contrast, positive end expiratory pressure (PEEP) had a detrimental effect on oxygenation; an effect that was ameliorated after pneumonectomy. Our results confirm that lung volumes in the mouse are dynamically determined and suggest a threshold level of mechanical ventilation to maintain perioperative oxygen saturation.
A central feature of intussusceptive angiogenesis is the development of an intravascular pillar that bridges the opposing sides of the microvessel lumen. In this report, we created polydimethyl siloxane (PDMS) microchannels with geometric proportions based on corrosion casts of the colon microcirculation. The structure of the PDMS microchannels was a bifurcated channel with an intraluminal pillar in the geometric center of the bifurcation. The effect of the intraluminal pillar on particle flow paths was investigated using an in vitro perfusion system. The microchannels were perfused with fluorescent particles and the particle movements were recorded using fluorescence videomicroscopy. We found that the presence of an intravascular pillar significantly decreased particle velocity in the bifurcation system (p<.05). In addition, the pillar altered the trajectory of particles in the center line of the flow stream. The particle trajectory resulted in prolonged pillar contact as well as increased residence time within the bifurcation system (p<.001). Our results suggest that the intravascular pillar not only provides a mechanism of increasing resistance to blood flow, but may also participate in spatial redistribution of cells within the flow stream.
Glucagon-like-peptide-1 receptor (GLP-1R) activation within the nucleus tractus solitarius (NTS) suppresses food intake and body weight (BW), but the intracellular signals mediating these effects are unknown. Here, hindbrain (4th icv) GLP-1R activation by Exendin-4 increased PKA and MAPK activity and decreased phosphorylation of AMPK in NTS. PKA and MAPK signaling contribute to food intake and BW suppression by Exendin-4, as inhibitors RpcAMP and U0126 (4th icv), respectively, attenuated Exendin-4's effects. Hindbrain GLP-1R activation inhibited feeding by reducing meal number, not meal size. This effect was attenuated with stimulation of AMPK activity by AICAR (4th icv). The PKA, MAPK and AMPK signaling responses by Ex-4 were present in immortalized GLP-1R-expressing neurons (GT1-7). In conclusion, hindbrain GLP-1R activation suppresses food intake and BW through coordinated PKA-mediated suppression of AMPK and activation of MAPK. Pharmacotherapies targeting these signaling pathways, which mediate intake-suppressive effects of CNS GLP-1R activation, may prove efficacious in treating obesity.