Recent developments in multiple sclerosis therapeutics

Multiple sclerosis, the most common neurologic disorder of young adults, is traditionally considered to be an inflammatory, autoimmune, demyelinating disease of the central nervous system. Based on this understanding, the initial therapeutic strategies were directed at immune modulation and inflammation control. These approaches, including high-dose corticosteroids for acute relapses and long-term use of parenteral interferon-β, glatiramer acetate or natalizumab for disease modification, are at best moderately effective. Growing evidence supports that, while an inflammatory pathology characterizes the early relapsing stage of multiple sclerosis, neurodegenerative pathology dominates the later progressive stage of the disease. Multiple sclerosis disease-modifying therapies currently in development attempt to specifically target the underlying pathology at each stage of the disease, while avoiding frequent self-injection. These include a variety of oral medications and monoclonal antibodies to reduce inflammation in relapsing multiple sclerosis and agents intended to promote neuroprotection and neurorepair in progressive multiple sclerosis. Although newer therapies for relapsing MS have the potential to be more effective and easier to administer than current therapies, they also carry greater risks. Effective treatments for progressive multiple sclerosis are still being sought.     

The effect of red blood cells on the ADP-induced aggregation of human platelets in flow through tubes

The effect of red blood cells, rbc, and shear rate on the ADP-induced aggregation of platelets in whole blood, WB, flowing through polyethylene tubing was studied using a previously described technique (1). Effluent WB was collected into 0.5% glutaraldehyde and the red blood cells removed by centrifugation through Percoll. At 23 degrees C the rate of single platelet aggregation was upt to 9 x greater in WB than previously found in platelet-rich plasma (2) at mean tube shear rates G = 41.9, 335, and 1,920 s-1, and at both 0.2 and 1.0 microM ADP. At 0.2 microM ADP, the rate of aggregation was greatest at G = 41.9 s-1 over the first 1.7 s mean transit time through the flow tube, t, but decreased steadily with time. At G greater than or equal to 335 s-1 the rate of aggregation increased between t = 1.7 and 8.6 s; however, aggregate size decreased with increasing shear rate. At 1.0 microM ADP, the initial rate of single platelet aggregation was still highest at G = 41.9 s-1 where large aggregates up to several millimeters in diameter containing rbc formed by t = 43 s. At this ADP concentration, aggregate size was still limited at G greater than or equal to 335 s-1 but the rate of single platelet aggregation was markedly greater than at 0.2 microM ADP. By t = 43 s, no single platelets remained and rbc were not incorporated into aggregates. Although aggregate size increased slowly, large aggregates eventually formed. White blood cells were not significantly incorporated into aggregates at any shear rate or ADP concentration. Since the present technique did not induce platelet thromboxane A2 formation or cause cell lysis, these experiments provide evidence for a purely mechanical effect of rbc in augmenting platelet aggregation in WB.     

Generalized dilation of the visceral microvasculature by peritoneal dialysis solutions.

OBJECTIVES: Conventional peritoneal dialysis solutions are vasoactive. This vasoactivity is attributed to hyperosmolality and lactate buffer system. This study was conducted to determine if the vasodilator property of commercial peritoneal dialysis solutions is a global phenomenon across microvascular levels, or if this vasodilation property is localized to certain vessel types in the small intestine. DESIGN: Experimental study in a standard laboratory facility. INTERVENTIONS: Hemodynamics of anesthetized rats were monitored while the terminal ileum was prepared for in vivo intravital microscopy. Vascular reactivity of inflow arterioles (A1), branching (A2), and arcade, as well as pre-mucosal (A3) arterioles was assessed after suffusion of the terminal ileum with a non-vasoactive solution or a commercial 4.25% glucose-based solution (Delflex; Fresenius USA, Ogden, Utah, USA). Vascular reactivity of three different level venules was also assessed. Maximum dilation response was obtained from sequential applications of the endothelial-dependent dilator, acetylcholine (10(-5) mol/L), and the endothelial-independent nitric oxide donor, sodium nitroprusside (NTP; 10(-4) mol/L). RESULTS: Delflex induced an instant and sustained vasodilation that averaged 28.2% +/- 2.4% of baseline diameter in five different-level arterioles, ranging in size between 7 mu and 100 mu. No significant vascular reactivity was observed in three different-level venules. Delflex increased intestinal A1 blood flow from baseline 568 +/- 31 nL/ second to 1,049 +/- 46 nL/sec (F= 24.7, p< 0.001). Similarly, intestinal venous outflow increased to 435 +/- 17 nL/sec from a baseline outflow of 253 +/- 59 nL/sec (F= 4.7, p < 0.05). Adjustment of the initial pH of Delflex from 5.5 to 7.4 resulted in similar microvascular responses before pH adjustment. CONCLUSIONS: Ex vivo exposure of intestinal arterioles to conventional peritoneal dialysis solutions produces a sustained and generalized vasodilation. This vasoactivity is independent of arteriolar level and the pH of the solution. Dialysis solution-mediated vasodilation is associated with doubling of A1 intestinal arteriolar blood flow. Addition of NTP at an apparent clinical dose does not appear to produce any further significant arteriolar dilation than that induced by dialysis solution alone. Experimental data that estimate the exchange vessel surface area per unit volume of tissue will be required to make a correlation with permeability in order to extrapolate our findings to clinical in vivo conditions.     

Tropheryma whipplei infective endocarditis as the only manifestation of Whipple's disease

Here we describe a case of infective endocarditis caused by Tropheryma whipplei in a patient with no other symptoms of Whipple's disease. The case was diagnosed using broad-range PCR and confirmed by specific PCRs. We review the cases of infective endocarditis presenting as the only manifestation of Whipple's disease reported in the literature.     

Physical education and physical activity: results from the School Health Policies and Programs Study 2006

BACKGROUND: Comprehensive school-based physical activity programs consist of physical education and other physical activity opportunities including recess and other physical activity breaks, intramurals, interscholastic sports, and walk and bike to school initiatives. This article describes the characteristics of school physical education and physical activity policies and programs in the United States at the state, district, school, and classroom levels. METHODS: The Centers for Disease Control and Prevention conducts the School Health Policies and Programs Study every 6 years. In 2006, computer-assisted telephone interviews or self-administered mail questionnaires were completed by state education agency personnel in all 50 states plus the District of Columbia and among a nationally representative sample of districts (n=453). Computer-assisted personal interviews were conducted with personnel in a nationally representative sample of elementary, middle, and high schools (n=988) and with a nationally representative sample of teachers of required physical education classes and courses (n=1194). RESULTS: Most states and districts had adopted a policy stating that schools will teach physical education; however, few schools provided daily physical education. Additionally, many states, districts, and schools allowed students to be exempt from participating in physical education. Most schools provided some opportunities for students to be physically active outside physical education. Staff development for physical education was offered by states and districts, but physical education teachers generally did not receive staff development on a variety of important topics. CONCLUSIONS: To enhance physical education and physical activity in schools, a comprehensive approach at the state, district, school, and classroom levels is necessary. Policies, practices, and comprehensive staff development at the state and district levels might enable schools to improve opportunities for students to become physically active adults.     

Breast cancer patients with a negative axillary ultrasound may have clinically significant nodal metastasis

Breast Cancer Research and Treatment - The non-invasive nature of the preoperative axillary ultrasound (AUS) fits the current trend of increasingly conservative axillary management. Recent...     

Cardiac troponins and renal function in nondialysis patients with chronic kidney disease

BACKGROUND: Serum cardiac troponin concentrations are commonly increased in end-stage renal disease (ESRD) in the absence of an acute coronary syndrome (ACS). The data on cardiac troponin I (cTnI) are more variable than those for cardiac troponin T (cTnT). There is little information on cardiac troponin concentrations in patients with chronic kidney disease (CKD) who have not commenced dialysis. METHODS: We studied 222 patients: 56 had stage 3 (moderate CKD); 70 stage 4 (severe CKD); and 96 stage 5 (kidney failure). Patients underwent echocardiography and were followed prospectively for a median of 19 months; all-cause mortality was recorded. RESULTS: Overall, serum cTnT was increased above the 99th percentile reference limit in 43% of all CKD patients studied, compared with 18% for cTnI. Serum cTnT and cTnI concentrations were more commonly increased in the presence of more severe CKD (11 and 6 patients in stage 3, 27 and 8 in stage 4, and 57 and 24 in stage 5 (P < 0.0001 and <0.02, respectively). Among 38 patients with detectable cTnI, 32 had detectable cTnT (r(s) = 0.67; P < 0.0001). There was evidence that decreasing estimated glomerular filtration rate increased the odds of having detectable cTnT (P < 0.001) but not cTnI (P = 0.128). There was no evidence to support an adjusted association of detectable cardiac troponins with increasing left ventricular mass index. Increased cTnT (P = 0.0097), but not cTnI, was associated with decreased survival. CONCLUSIONS: Increased cTnT and cTnI concentrations are relatively common in predialysis CKD patients, in the absence of an ACS, including among those with stage 3 disease. The presence of left ventricular hypertrophy alone does not explain these data. Detectable cTnT was a marker of decreased survival.     

Sublingual immunotherapy in children. Immunotherapy Committee of the Spanish Society for Clinical Immunology and Pediatric Allergology

Sublingual immunotherapy is currently attracting growing interest because of its ease of administration and, according to previous studies, its infrequent and mild adverse effects. However, at least in children, the efficacy of this therapy has not been completely demonstrated. In addition, the mechanisms of action remain to be elucidated since few studies have been published and the results have been contradictory and sometimes inconclusive. For this reason, we performed a literature review through the MEDLINE database, selecting double-blind studies carried out in children. Only 10 studies meeting these requirements were retrieved. All the studies were performed by European researchers and nine were published in European journals. Efficacy was evaluated by clinical parameters and by reduction in medication use. The results on efficacy are not homogeneous, although most support the utility of this route of administration. Moreover, reports of allergens other than those used in these studies dust mites and grass pollens are lacking. In conclusion, further studies evaluating the efficacy of this therapy in children are required. Among the general population, if the efficacy of sublingual immunotherapy in the treatment of sensitization to hymenoptera venoms were demonstrated, as has been the case with subcutaneous immunotherapy, the utility of this route of administration would be definitively confirmed. Finally, sublingual immunotherapy could be used in children who have shown systemic reactions to subcutaneous immunotherapy or who refuse to undergo injections.