Risk–benefit and cost–benefit ratio in headache treatment

The cost–benefit and the risk–benefit ratios are two of the most relevant items in ongoing health organisation procedures. The choice of a new or an old therapeutic treatment depends on a number of factors and the evaluation of the cost, in terms of economics, but also in terms of quality of life and type of facilities necessary for one treatment are crucial criteria. Therefore, we have to consider in evaluating treatment strategies not only the activity of a drug in reaching the main end–points, (i.e., pain free or headache relief) but also the safety and perception of safety by patients, and the cost effectiveness, including indirect costs compared with personal and social benefits. Because it is reasonable that a subgroup of migraine patients may have a clinically progressive disorder, studies should be necessary to assess strategies for migraine treatments.     

Chitinase 3–like–1 and its receptors in Hermansky-Pudlak syndrome–associated lung disease

Hermansky-Pudlak syndrome (HPS) comprises a group of inherited disorders caused by mutations that alter the function of lysosome-related organelles. Pulmonary fibrosis is the major cause of morbidity and mortality in patients with subtypes HPS-1 and HPS-4, which both result from defects in biogenesis of lysosome-related organelle complex 3 (BLOC-3). The prototypic chitinase-like protein chitinase 3–like–1 (CHI3L1) plays a protective role in the lung by ameliorating cell death and stimulating fibroproliferative repair. Here, we demonstrated that circulating CHI3L1 levels are higher in HPS patients with pulmonary fibrosis compared with those who remain fibrosis free, and that these levels associate with disease severity. Using murine HPS models, we also determined that these animals have a defect in the ability of CHI3L1 to inhibit epithelial apoptosis but exhibit exaggerated CHI3L1-driven fibroproliferation, which together promote HPS fibrosis. These divergent responses resulted from differences in the trafficking and effector functions of two CHI3L1 receptors. Specifically, the enhanced sensitivity to apoptosis was due to abnormal localization of IL-13Rα2 as a consequence of dysfunctional BLOC-3–dependent membrane trafficking. In contrast, the fibrosis was due to interactions between CHI3L1 and the receptor CRTH2, which trafficked normally in BLOC-3 mutant HPS. These data demonstrate that CHI3L1-dependent pathways exacerbate pulmonary fibrosis and suggest CHI3L1 as a potential biomarker for pulmonary fibrosis progression and severity in HPS.     

Phentermine and Coronary Vasospasm–Induced Myocardial Infarction

Women presenting to the cardiac catheterization laboratory with normal coronary arteries without significant atherosclerotic disease is a common presentation. In such patients, it is important to maintain a wide differential and consider alternate diagnoses. We present two cases of women presenting with chest pain found to have severe coronary vasospasm in the setting of recent initiation of phentermine. Phentermine may have vasospastic proprieties which are important to consider when prescribing to patients.     

E-Bike–Related Trauma in Children and Adults

Background

Electric bike (e-bike) usage is growing worldwide, and so is the e-bike–related injury rate.

Endothelium and NOTCH specify and amplify aorta-gonad-mesonephros–derived hematopoietic stem cells

Hematopoietic stem cells (HSCs) first emerge during embryonic development within vessels such as the dorsal aorta of the aorta-gonad-mesonephros (AGM) region, suggesting that signals from the vascular microenvironment are critical for HSC development. Here, we demonstrated that AGM-derived endothelial cells (ECs) engineered to constitutively express AKT (AGM AKT-ECs) can provide an in vitro niche that recapitulates embryonic HSC specification and amplification. Specifically, nonengrafting embryonic precursors, including the VE-cadherin–expressing population that lacks hematopoietic surface markers, cocultured with AGM AKT-ECs specified into long-term, adult-engrafting HSCs, establishing that a vascular niche is sufficient to induce the endothelial-to-HSC transition in vitro. Subsequent to hematopoietic induction, coculture with AGM AKT-ECs also substantially increased the numbers of HSCs derived from VE-cadherin⁺CD45⁺ AGM hematopoietic cells, consistent with a role in supporting further HSC maturation and self-renewal. We also identified conditions that included NOTCH activation with an immobilized NOTCH ligand that were sufficient to amplify AGM-derived HSCs following their specification in the absence of AGM AKT-ECs. Together, these studies begin to define the critical niche components and resident signals required for HSC induction and self-renewal ex vivo, and thus provide insight for development of defined in vitro systems targeted toward HSC generation for therapeutic applications.     

Anger and emotional distress in patients with migraine and tension–type headache

The objective was to evaluate the prevalence and the characteristics of anger and emotional distress in migraine and tension– type headache patients. Two hundred and one headache patients attending the Headache Center of the University of Turin were selected for the study and divided into 5 groups: (1) migraine, (2) episodic tension–type headache, (3) chronic tension–type headache, (4) migraine associated with episodic tension–type headache and (5) migraine associated with chronic tension–type headache. A group of 45 healthy subjects served as controls. All the subjects completed the State–Trait Anger Expression Inventory, the Beck's Depression Inventory and the Cognitive Behavioral Assessment. Anger control was significantly lower in all headache patients (p<0.05) except in migraineurs. Patients with migraine and tension–type headache showed a significantly higher level of angry temperament and angry reaction (p<0.05). In addition, chronic tension–type headache and migraine associated with tension–type headache patients reported a higher level of anxiety (p<0.05), depression (p<0.001), phobias (p<0.001) and obsessive–compulsive symptoms (p<0.01), emotional liability (p<0.001) and psychophysiological disorders (p<0.001). Our study shows that chronic tension–type headache and migraine associated with tension–type headache patients present a significant impairment of anger control and suggests a connection between anger and the duration of headache experience.     

Pharmacokinetics of Ketamine and Xylazine in Young and Old Sprague–Dawley Rats

To compare the pharmacokinetics of coadministered intraperitoneal ketamine and xylazine in young (8 to 10 wk; n = 6) and old rats (2 to 2.4 y; n = 6), blood samples obtained at 15 and 30 min and 1, 2, and 4 h after drug administration were analyzed by HPLC–tandem mass spectrometry. In both groups, the withdrawal reflex was absent during anesthesia and was present at 1.1 (± 0.2) and 2.6 (± 0.7) h after drug administration in young and old rats, respectively, with the first voluntary movement at 1.5 ± 0.2 and 4.9 ± 1.0 h. Drug availability of ketamine and xylazine was 6.0 and 6.7 times greater, respectively, in old than young rats. The rate constant of elimination of both drugs was greatly decreased and the elimination half-life was significantly greater in old compared with young rats. In conclusion, age and associated factors affect the availability of ketamine and xylazine when coadministered to attain clinical anesthesia, changing the pharmacokinetics of these drugs and prolonging anesthesia duration and recovery times with aging. Compared with their young counterparts, aged rats required much higher doses to attain a similar level of anesthesia. Finally, the long half-life of both ketamine and xylazine, when coadministered to old rats, may be a factor in research protocols because residual plasma concentrations could still be present for as long as 3 and 5 d, respectively, after administration.Abbreviations: C_last, last measurable plasma concentration; K_el, terminal elimination rate constantKetamine, an N-methyl d-aspartate antagonist with anesthetic properties, and xylazine, an α2-adrenoreceptor agonist with sedative and antinociceptive effects, are often used in combination to anesthetize rodents. They are administrated intramuscularly, intraperitoneally, or intravenously to provide relief of pain and distress.²⁷ Ketamine combinations are considered to be a first choice in rodents when injectable anesthetics are used.^6,20 Ketamine and xylazine are metabolized mainly by liver cytochromes P450 enzymes and excreted by the kidney.¹¹ Both drugs are rapidly absorbed and well distributed to the CNS.²⁴ However little is known about their pharmacokinetics in aged animals. Commercial ketamine preparations are composed of 2 enantiomers (the S-enantiomer is more active and produces fewer side effects),¹⁹ and cytochrome metabolism is different across different animal species;¹⁸ therefore findings in rats may not extrapolate to other species.The main objective of the current study was to compare the pharmacokinetics of ketamine and xylazine in young and old rats when coadministered at anesthetic doses to determine a safer, more appropriate combination of injectable drugs for anesthesia of aged rats.     

Oral Delivery of Bioencapsulated Proteins Across Blood–Brain and Blood–Retinal Barriers

Delivering neurotherapeutics to target brain-associated diseases is a major challenge. Therefore, we investigated oral delivery of green fluorescence protein (GFP) or myelin basic protein (MBP) fused with the transmucosal carrier cholera toxin B subunit (CTB), expressed in chloroplasts (bioencapsulated within plant cells) to the brain and retinae of triple transgenic Alzheimer''s disease (3×TgAD) mice, across the blood–brain barriers (BBB) and blood–retinal barriers (BRB). Human neuroblastoma cells internalized GFP when incubated with CTB-GFP but not with GFP alone. Oral delivery of CTB-MBP in healthy and 3×TgAD mice shows increased MBP levels in different regions of the brain, crossing intact BBB. Thioflavin S–stained amyloid plaque intensity was reduced up to 60% by CTB-MBP incubation with human AD and 3×TgAD mice brain sections ex vivo. Amyloid loads were reduced in vivo by 70% in hippocampus and cortex brain regions of 3×TgAD mice fed with bioencapsulated CTB-MBP, along with reduction in the ratio of insoluble amyloid β 42 (Aβ₄₂) to soluble fractions. CTB-MBP oral delivery reduced Aβ₄₂ accumulation in retinae and prevented loss of retinal ganglion cells in 3×TgAD mice. Lyophilization of leaves increased CTB-MBP concentration by 17-fold and stabilized it during long-term storage in capsules, facilitating low-cost oral delivery of therapeutic proteins across the BBB and BRB.     

Multidrug–resistant organisms in cystic fibrosis: management and infection–control issues

Chronic infection and inflammation are the hallmarks of cystic fibrosis lung disease. As cystic fibrosis patients are living longer owing to more intense treatment, multidrug-resistant organisms are being isolated increasingly from patients’ respiratory tracts. While the adverse effects of Pseudomonas aeruginosa and Burkholderia cepacia complex are well described, less is known about the clinical significance of other emerging multidrug-resistant organisms, such as methicillin-resistant Staphylococcus aureus and Stenotrophomonas maltophilia. Owing to multiple mechanisms of antimicrobial resistance, these organisms are difficult to treat and often require combination antibiotic therapy. Until more is known about their pathogenicity and effect on clinical outcomes, physicians should be aware of the potential transmissibility of these organisms and implement adequate infection control strategies.     

A Drug–drug Interaction Between Cyclosporine and Nystatin

We present a case of increased cyclosporine concentration and liver function right after the combinational use of cyclosporine and nystatin, which indicated a drug–drug interaction between them. Both the concentration and liver function were decreased after discontinuation of nystatin and remained normal after taking on cyclosporine again. To our knowledge, this is the first case report of the interactions between nystatin and cyclosporine. Enteric P-glycoprotein could play an important role in the pharmacokinetic profile of cyclosporine, which needs further identification by physicians and pharmacists.     

The Sociotropy–Autonomy Scale: Structure and Implications

The Sociotropy Autonomy Scale (SAS), especially the Autonomy Scale, has demonstrated inconsistent results concerning its relationship to depression and psychopathology. We hypothesized that these inconsistent findings may be related to the factor structure of the SAS. Exploratory and confirmatory factor analyses of the SAS were conducted in two separate samples of psychiatric outpatients (n = 1033, n = 1034). The results revealed a two-factor solution for sociotropy: Preference for Affiliation and Fear of Criticism and Rejection. The second factor, Fear of Criticism and Rejection, had a stronger association with psychopathology than the first factor. The results also indicated a two-factor solution for autonomy: Sensitivity to Others' Control and Independent Goal Attainment. Although the Sensitivity to Others' Control factor had a positive correlation with psychopathology, the Independent Goal Attainment factor had a negative correlation with psychopathology. We speculate that Independent Goal Attainment may be associated with resilience or hardiness and functions as a buffer against stress. Implications for revising the SAS as well as employing these factors in future studies are discussed.     

Assessment and Management of Cancer- and Cancer Treatment–Related Cognitive Impairment

Cognitive impairment resulting from cancer and subsequent treatment is one of the most common and troubling sequelae experienced by cancer survivors. Cancer survivors report that cognitive impairment negatively affects their quality of life. Appropriate assessment and management of cognitive impairment is critical to providing optimal care to cancer survivors. The purpose of this article is to briefly describe the state of evidence on incidence, possible mechanisms, and presentation of cancer- and cancer treatment–related cognitive impairment and to provide guidance for its assessment and management. We focus on management with nonpharmacological and pharmacological interventions that may have clinical utility.     

Patient–ventilator synchrony and sleep quality with proportional assist and pressure support ventilation

Objective

To examine patient–ventilator asynchrony and sleep quality in non-sedated critically ill patients ventilated with proportional assist ventilation with load adjustable gain factors (PAV+) and pressure support (PSV).

Methods

This was a randomized crossover physiological study conducted in an adult ICU at a tertiary hospital. Patients who exhibited patient–ventilator asynchrony on PSV were selected. Polysomnography was performed in these patients over 24 h, during which respiratory variables were continuously recorded. During the study period, each patient was randomized to receive alternating 4-h periods of PSV and PAV+ equally distributed during the day and night. Sleep architecture was analyzed manually using predetermined criteria. Patient–ventilator asynchrony was evaluated breath by breath using the flow–time and airway pressure–time waveforms.

Results

Fourteen patients were studied. The majority (85.7 %) had either acute exacerbation of COPD as admission diagnosis or COPD as comorbidity. During sleep, compared to PSV, PAV+ significantly reduced the patient–ventilator asynchrony events per hour of sleep [5 (1–17) vs. 40 (4–443), p = 0.02, median (25–75th interquartile range)]. Compared to PSV, PAV+ was associated with slightly but significantly greater sleep fragmentation [18.8 (13.1–33.1) versus 18.1 (7.0–22.8) events/h, p = 0.01] and less REM sleep [0.0 % (0.0–8.4) vs. 5.8 % (0.0–21.9), p = 0.02).

Conclusions

PAV+ failed to improve sleep in mechanically ventilated patients despite the fact that this mode was associated with better synchrony between the patient and ventilator. These results do not support the hypothesis that patient–ventilator synchrony plays a central role in determining sleep quality in this group of patients.