Noninvasive, transcranial and localized opening of the blood-brain barrier using focused ultrasound in mice

The feasibility of blood-brain barrier (BBB) opening in the hippocampus of wild-type mice using focused ultrasound (FUS) through the intact skull and skin was investigated. Needle hydrophone measurements through ex vivo skulls revealed minimal attenuation ( approximately 18% of the pressure amplitude), a well-focused beam pattern and minute focus displacement through the parietal bone. In experiments in vivo, the brains of three mice were sonicated transcranially. Pulsed ultrasound sonications at 1.5 MHz and acoustic pressures ranging from 0.8 to 2.7 MPa were used at 20% duty cycle. Before sonication, a bolus of 10 microL of an ultrasound contrast agents (Optison) was injected intravenously. Contrast-enhanced high-resolution magnetic resonance imaging (9.4 T) revealed BBB opening and allowed for the monitoring of the slow permeation of gadolinium in the hippocampus. The region of the brain where BBB opening occurred increased with the pressure amplitude. These findings thus demonstrated the feasibility of locally opening the BBB in mice using FUS through intact skull and skin and serve as the first step in determining and assessing feasibility of drug delivery to specific regions in the mouse brain using FUS.     

Biofeedback Training for Partial Weight Bearing in Patients After Total Hip Arthroplasty

Pataky Z, De León Rodriguez D, Golay A, Assal M, Assal J-P, Hauert C-A. Biofeedback training for partial weight bearing in patients after total hip arthroplasty.

Objective

To evaluate a new biofeedback training method based on visual delivery of information in patients after total hip arthroplasty (THA).

Design

Intervention study with prepost design.

Setting

Hospitalized care in a university referral center.

Participants

Patients (N=11) (age 56.1±9.0y) shortly after THA.

Intervention

A mobile system has been used for biofeedback training with the predefined partial weight bearing (PWB) threshold of 20kg. After the learning period, 4 retention tests, consisting of 3 successive walking cycles without feedback, were recorded for each patient: (1) acquisition test, (2) early retention test (after 30min), (3) the day after, and (4) after 2 days.

Main Outcome Measure

The pressure error and the maximum pressure force at each step before and after biofeedback training.

Results

A significant difference of pressure errors between the beginning and the end of the learning period has been measured (42.5±22.5N vs 3.7±11.4N, P<.001). However, there was no difference between the beginning of the learning period and different retention tests (after 30 minutes, after 1 day, after 2 days). In terms of maximal pressure force, there was a difference between the beginning and the end of learning (251N vs 195N, P<.05). The retention tests did not show significant differences compared with the baseline values.

Conclusions

THA patients were able to use the defined PWB during a short period of time and shortly after stopping the training; both the pressure errors and the maximal pressure force attended the values before training. These results confirm the difficulties to achieve PWB in patients after THA.     

Emotional valence contributes to music-induced analgesia

The capacity of music to soothe pain has been used in many traditional forms of medicine. Yet, the mechanisms underlying these effects have not been demonstrated. Here, we examine the possibility that the modulatory effect of music on pain is mediated by the valence (pleasant-unpleasant dimension) of the emotions induced. We report the effects of listening to pleasant and unpleasant music on thermal pain in healthy human volunteers. Eighteen participants evaluated the warmth or pain induced by 40.0, 45.5, 47.0 and 48.5 degrees C thermal stimulations applied to the skin of their forearm while listening to pleasant and unpleasant musical excerpts matched for their high level of arousal (relaxing-stimulating dimension). Compared to a silent control condition, only the pleasant excerpts produced highly significant reductions in both pain intensity and unpleasantness, demonstrating the effect of positive emotions induced by music on pain (Pairwise contrasts with silence: p's<0.001). Correlation analyses in the pleasant music condition further indicated that pain decreased significantly (p's<0.05) with increases in self-reports of music pleasantness. In contrast, the unpleasant excerpts did not modulate pain significantly, and warmth perception was not affected by the presence of pleasant or unpleasant music. Those results support the hypothesis that positive emotional valence contributes to music-induced analgesia. These findings call for the integration of music to current methods of pain control.     

Prophylactic endoscopic sclerotherapy of large esophagogastric varices in infants with biliary atresia

BACKGROUND: Esophageal varices-related GI bleeding occurs frequently and early in life in children with biliary atresia and it may be life threatening. OBJECTIVE: We report the results of prophylactic sclerotherapy in 13 infants with biliary atresia and large varices. PATIENTS: Mean age was 13 months, mean weight was 8.2 kg, mean total serum bilirubin was 258 mumol/L, and mean prothrombin time was 78%. Esophageal varices were grade III (11 patients) or II (2 patients), with red signs in all infants and gastric varices in 12. None had GI bleeding. INTERVENTION: Sclerotherapy was performed with the patient under continuous intravenous octreotide therapy in 7 infants. RESULTS: In 8 children a complete or almost complete eradication of varices was obtained; none of these children bled later, 4 underwent liver transplantation, 3 are alive without liver transplantation, and 1 died of sepsis after 9 months awaiting liver transplantation. In 4 children a partial eradication was obtained and liver transplantation was performed. None of these children bled. One other child bled to death after 2 sessions of sclerotherapy. LIMITATIONS: Four ulcers and 2 stenoses occurred in 6 children with no octreotide versus no ulcer and 1 stenosis in 7 children receiving octreotide. CONCLUSION: These results (1) indicate that primary prevention of GI bleeding by sclerotherapy of esophageal varices is technically feasible and fairly effective in infants with biliary atresia and large varices, even in those with end-stage liver disease, (2) suggest that decreasing the risk of bleeding may allow liver transplantation under better conditions, and (3) further suggest that octreotide associated with sclerotherapy lowers the rate of complications.     

The clinimetric properties of the World Health Organization Disability Assessment Schedule II in early inflammatory arthritis

OBJECTIVE: To assess the clinimetric properties of a new health-related quality of life (HRQOL) instrument, the World Health Organization Disability Assessment Schedule II (WHODAS II), in patients with early inflammatory arthritis. METHODS: Internal consistency as well as criterion, construct, and discriminative validity of the WHODAS II were assessed in 172 patients with early inflammatory arthritis who completed the WHODAS II, the Medical Outcomes Study Short Form 36 (SF-36), and other measures of disease severity, functioning, pain, depression, and resource use. Test-retest reliability of the WHODAS II was assessed by having a subset of 20 patients complete the WHODAS II a second time, 1 week after the first assessment. RESULTS: The WHODAS II had high internal consistency (Cronbach's alpha = 0.96 for patients working or in school and 0.93 for patients not working or in school). Test-retest intraclass correlation coefficients of the WHODAS II total score and subscales ranged from 0.82-0.96. The WHODAS II total score was strongly correlated with the SF-36 physical component score (Kendall's tau-b 0.51, P < 0.001) and moderately correlated with the SF-36 mental component score (tau-b 0.43, P < 0.001). WHODAS II correlations with disease outcomes ranged from Kendall's tau-b 0.15-0.55. The WHODAS II significantly differentiated between every aspect of disease severity assessed with the exception of measures of health resource use. CONCLUSION: The WHODAS II is a valid and reliable measure of HRQOL in cross-sectional studies of patients with early inflammatory arthritis. Research is still required to investigate potential item redundancy and determine its usefulness in longitudinal studies.     

Air Pollution–Related Prothrombotic Changes in Persons with Diabetes

Background

Population studies suggest that persons with diabetes are more sensitive to the effects of particulate matter (PM) air pollution. However, the biological mechanisms of a possible prothrombotic effect underlying this enhanced susceptibility remain largely unknown.

Objective

We hypothesized that exposure to PM causes prothrombotic changes in persons with diabetes, possibly via systemic inflammation.

Methods

Our study included 137 nonsmoking adults with diabetes who were outpatients at the University Hospital Leuven. Recent exposure (2 hr before examination) to ambient PM was measured at the entrance of the hospital. Individual chronic exposure to PM was assessed by measuring the area occupied by carbon in airway macrophages obtained by sputum induction. Platelet function was measured ex vivo with the PFA-100 platelet function analyzer, which simulates a damaged blood vessel; we analyzed the function of platelets in primary hemostasis under high shear conditions. Total and differential blood leukocytes were counted.

Results

Independent of antiplatelet medication, an interquartile range (IQR) increase of 39.2 μg/m³ in PM₁₀ (PM with aerodynamic diameter ≤ 10 μm) concentration measured 2 hr before the clinical examination (recent exposure) was associated with a decrease of 21.1 sec [95% confidence interval (CI), − 35.3 to − 6.8] in the PFA-100 closure time (i.e., increased platelet activation) and an increase in blood leukocytes of 512 per microliter of blood (95% CI, 45.2–979). Each area increase of 0.25 μm² (IQR) in carbon load of airway macrophages (chronic exposure) was associated with an increase of 687 leukocytes per microliter of blood (95% CI, 224–1,150).

Conclusions

A relevant increase in recent PM exposure was associated with a change in platelet function toward a greater prothrombotic tendency. The magnitude of the change was about two-thirds (in the opposite direction) of the average effect of antiplatelet medication. Diabetic patients showed evidence of proinflammatory response to both recent and chronic exposure to PM air pollution.     

How Many Have Died from Undiagnosed Human Immunodeficiency Virus–Associated Histoplasmosis,A Treatable Disease? Time to Act

Human immunodeficiency virus (HIV)–associated disseminated Histoplasma capsulatum capsulatum infection often mimics tuberculosis. This disease is well know in the United States but is dramatically underdiagnosed in Central and South America. In the Amazon region, given the available incidence data and the regional HIV prevalence, it is expected that, every year, 1,500 cases of histoplasmosis affect HIV patients in that region alone. Given the mortality in undiagnosed patients, at least 600 patients would be expected to die from an undiagnosed but treatable disease. The lack of a simple diagnostic tool and the lack of awareness by clinicians spiral in a vicious cycle and made a major problem invisible for 30 years. The HIV/acquired immunodeficiency syndrome community should tackle this problem now to prevent numerous avoidable deaths from HIV-associated histoplasmosis in the region and elsewhere.In the Guianas and the Amazon Basin, the prevalence of human immunodeficiency virus (HIV) is approximately 1%. There have been some decreases in incidence in some states in this region, but recent increases in incidence in northern states of Brazil have been reported.^1–3 The population of the Amazon basin is estimated to be approximately 10 million persons,⁴ which would imply that approximately 100,000 persons are HIV positive in the Amazon Basin.The Amazonian environment is suitable for the growth of Histoplasma capsulatum.⁵ For immunocompetent patients, this organism causes mostly benign infections, but in severely immunodepressed HIV-infected patients, infection with this organism leads to a fatal disease in the absence of diagnosis and treatment. There lies the problem. Clinical symptoms are unspecific and often mimic those of tuberculosis.^6,7 Diagnosis is difficult and requires invasive procedures (biopsies, bone marrow smears), and trained staff to detect H. capsulatum, often after weeks of culture.⁸ Severe infections are often fatal within days.⁹ However, death often occurs after long delays in which patients are unsuccessfully treated for unconfirmed tuberculosis. Patients die because they are not treated for a treatable disease and because there is no diagnosis test. With no diagnosis, this possibility is not included in the diagnostic and treatment algorithms of clinicians who, despite unknowingly encountering this disease on a regular basis, have never seen a case because it was never diagnosed. In this context, then why give presumptive treatment of a disease that is not present?It is tragic but it makes total sense. It is even frighteningly tragic when one crunches the numbers to estimate what it means that after 30 years of the HIV epidemic, one of the leading causes of acquired immunodeficiency syndrome (AIDS) in the Amazon¹⁰ still goes largely unrecognized and evolves under the radar of national plans and international funding efforts.The only incidence data available for this region suggests that the incidence of histoplasmosis during the highly active antiretroviral therapy era was 1.5 cases/100 person-years.¹⁰ The historical mortality rate of disseminated histoplasmosis was > 30% despite mycology expertise.^7,8 This finding indicates that for 100,000 HIV patients, there would be 1,500 cases of histoplasmosis/year and 600 deaths/year, and probably more if undiagnosed. This finding also indicates that for more than 30 years the cumulated death rate in the region must have been huge, in the tens of thousands.A rational sceptic could rightly doubt this claim from the generalization of data from the smallest South American territory to the entire Amazon and elsewhere. However, when one reviews the literature, it becomes evident that histoplasmosis is present throughout the region, this fact has been known for decades, and that we should have been paying more attention.⁵ The high prevalence of histoplasmin test reactivity in the region was known even before AIDS was identified in 1981.¹¹ Histoplasmosis has been an AIDS-defining illness since 1993. We should have connected the dots earlier.How could something so huge escape the attention of the HIV/AIDS community in the region? One explanation for this dramatic blind spot is that in the region, the diagnostic capacity for mycology has been insufficient. It has been long argued that medical mycology is a neglected area of biology, and that the often low incidence of mycoses is caused by a lack of medical mycologists rather than the absence of the mycoses.¹² Another explanation is that the standard conceptualization of HIV/AIDS, the usual indicators, and the Joint United Nations Programme on HIV/AIDS terminology and framework did not explicitly entail disseminated histoplasmosis or the regional AIDS-defining illnesses. The anesthetic effect of the familiarity of vertical concepts and vertical programs can make it difficult to reframe the problem and see what was always there.For better diagnostic and treatment, we should know what AIDS is to direct diagnostic hypotheses when caring for individual patients. Misdiagnosing histoplasmosis as tuberculosis, not only delays a life-saving treatment of the individual patient, but it can confound tuberculosis statistics (incidence, resistance, mortality) and make it difficult to evaluate tuberculosis program results.The current financial difficulties should not stand in the way of building the diagnostic capacity for detection of histoplasmosis. It does not necessarily cost much to do the diagnosis. Treatment relies on amphotericin B for severe forms and itraconazole for non-severe forms and prophylaxis.⁷ Both drugs are generic drugs that are perfectly affordable. The toxicity of amphotericin B leads industrialized countries to use the costly liposomal version of the drug. However, The Drugs for Neglected Disease Initiative is releasing a cheap alternative that was developed for treatment of cryptococcosis.¹³ This is an opportunity for resource-limited countries in disease-endemic areas for treatment of histoplasmosis. We should not wait any longer. Every year wasted to build capacity for diagnosis and treatment of histoplasmosis in the Amazon Basin and elsewhere leads to hundreds of deaths that could have been avoided. This is not acceptable.     

Tuberculosis and Histoplasmosis among Human Immunodeficiency Virus–Infected Patients: A Comparative Study

In disease-endemic areas, histoplasmosis is the main differential diagnosis for tuberculosis among human immunodeficiency virus (HIV)–infected patients. However, no study has compared the two diseases. Thus, the objective of this study was to compare tuberculosis and histoplasmosis in HIV-infected patients. A population of 205 HIV-infected patients (99 with tuberculosis and 106 with histoplasmosis) hospitalized in Cayenne, French Guiana during January 1, 1997–December 31, 2008 were selected retrospectively from the French Hospital Database on HIV. Multivariate analysis showed that tuberculosis was associated with cough (adjusted odds ratio [AOR] = 0.20, 95% confidence interval [CI] = 0.05–0.73) and a C-reactive protein level > 70 mg/L (AOR = 0.98, 95% CI = 0.97–0.99). Variables associated with disseminated histoplasmosis were a γ-glutamyl transferase level > 72 IU/L (AOR = 4.99, 95% CI = 1.31–18.99), origin from French Guiana (AOR = 5.20, 95% CI = 1.30–20.73), disseminated localization (AOR = 6.40, 95% CI = 1.44–28.45), a concomitant opportunistic infection (AOR = 6.71, 95% CI = 1.50–29.96), a neutrophil count < 2,750 cells/mm³ (AOR = 10.54, 95% CI = 2.83–39.24), a CD4 cell count < 60 cells/mm³ (AOR = 11.62, 95% CI = 2.30–58.63), and a platelet count < 150,000/mm³ (AOR = 19.20, 95% CI = 3.35–110.14). Tuberculosis and histoplasmosis have similarities, but some factors show a greater association with one of these diseases. Thus, adapted therapeutic choices can be made by using simple clinical and paraclinical criteria.     

Validity and Reliability of Outcome Measures Assessing Dexterity,Coordination, and Upper Limb Strength in Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay

Objective

To document in adults affected by autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) the intra- and interrater reliability, standard error of measurement, agreement, minimal detectable change, and construct validity of the 9-Hole Peg Test (NHPT), the Standardized Finger-to-Nose Test (SFNT), and grip strength.