Testing the vestibular-ocular reflexes: abnormalities of the otolith contribution in patients with neuro-otological disease.

Conventional vestibular rotation testing with the head centered on the axis stimulates the semicircular canals evoking compensatory eye movements. If the head is placed forwards of the axis in an eccentric position the otoliths are also stimulated by a tangential linear acceleration acting laterally to the skull. In normal subjects the additional otolithic stimulus evokes compensatory eye movements with a higher gain than with head centred, particularly for high frequency (greater than 0.1 Hz) stimuli. The responses with head centred and eccentric in various patients with known/suspected neuro-otological abnormalities have been compared. Patients with vestibular neurinectomies who have asymmetrical head centred responses showed greater asymmetry with head eccentric at higher stimulus frequencies. Some patients with cerebellar lesions showed abnormally enhanced or depressed and asymmetrical responses with head eccentric in comparison with head centred responses, which could be normal. The enhancing effects could be specific to low frequency stimuli. All patients who showed abnormal responses with head eccentric also had positional nystagmus provoked by the gravity acceleration vector when the head was tilted laterally. The direction of the positional nystagmus with respect to the gravity vector was not necessarily the same as the direction of the effect on eye movements of lateral acceleration during eccentric oscillation. Patients with benign paroxysmal vertigo or chronic linear vertigo in whom otolithic abnormalities are suspected were not found to have abnormal responses with head eccentric. We conclude that this method of testing may be useful in elucidating pathophysiology but is not a decisive clinical test for the presence of disordered otolith function.     

Staged bilateral pallidotomy for treatment of Parkinson disease

OBJECT: Several investigators have described the motor benefits derived from performing unilateral stereotactic pallidotomy for the treatment of Parkinson disease (PD), but little is known about the efficacy and complication rates of bilateral procedures. The goal of this study was to assess both these factors in 12 patients. METHODS: Eleven patients with medically intractable PD underwent staged bilateral pallidotomy and one patient underwent a simultaneous bilateral procedure. Unilateral pallidotomy resulted in an improvement in the patients' Unified Parkinson Disease Rating Scale (UPDRS) total scores and motor subscores, Hoehn and Yahr stages, and Schwab and England Activities of Daily Living scores. There were no complications. The second procedures were performed 5 to 25 months after the first, and nearly complete 3-month follow-up data are available for eight of these patients. Staged bilateral pallidotomy did result in further improvements in some symptoms, but the patients proved to be less responsive to levodopa. In contrast to outcomes of the initial unilateral pallidotomy, there were significant complications. One patient suffered an acute stroke, two patients suffered delayed infarctions of the internal capsule, four patients had mild-to-moderate worsening of speech and increased drooling, and one patient complained of worsening memory. CONCLUSIONS: Bilateral pallidotomy results in modest benefits but is associated with an increased risk of complications.     

Involvement of OSP/claudin-11 in oligodendrocyte membrane interactions: role in biology and disease

Oligodendrocyte-specific protein (OSP/claudin-11) is a four transmembrane protein concentrated in central nervous system myelin. Recent evidence has emerged suggesting that OSP/claudin-11 is involved in membrane interactions at tight junctions and with the extracellular matrix. OSP/claudin-11 seems to modulate proliferation and migration of oligodendrocytes presumably through these interactions. Furthermore, evidence is presented implicating OSP/claudin-11 as an autoantigen in the development of autoimmune demyelinating disease.     

Tumor immunity within the central nervous system stimulated by recombinant Listeria monocytogenes vaccination

Tumors arising within the central nervous system (CNS) present the immune system with a challenging target, given the heterogeneous nature of these neoplasms and their location within an "immunologically privileged" site. We used the lymphocytic choriomeningitis virus nucleoprotein (LCMV-NP) as a pseudotumor antigen to investigate recombinant Listeria monocytogenes as a tumor vaccine against s.c. and intracerebral challenges with a NP-expressing glioma, 9L-NP. Using Fischer 344 rats, we demonstrate that vaccination with recombinant L. monocytogenes-NP stimulates protection against s.c., but not intracerebral, 9L-NP tumor challenge in an antigen-specific, CD8(+) T-cell-dependent manner. After s.c. tumor rejection, enhanced antitumor immunity is achieved via epitope spreading that permits complete resistance against lethal intracerebral challenge with 9L-NP and with the untransfected parental 9L tumor. Unlike the CD8(+)-dependent immune responses against s.c. 9L-NP tumors, this expanded intracerebral immunity against endogenous tumor-associated antigens is dependent on both CD4(+) and CD8(+) T cells. Taken together, these results demonstrate that the mechanisms of tumor immunity within the brain are different from those elicited against non-CNS tumors. Furthermore, vaccination approaches exploiting the concept of epitope spreading may enhance the efficacy of antitumor immune responses within the immunologically privileged CNS, potentially mediating tumor cell killing through both CD4(+)- and CD8(+)-dependent effector pathways.     

Dose Dependency of Pharmacokinetics and Therapeutic Efficacy of Pegylated Liposomal Doxorubicin (DOXIL) in Murine Models

Stealth (pegylated) liposomal doxorubicin (Doxil) has been extensively studied at the pre-clinical and clinical level in recent years. However, one issue not yet addressed is the effect of dose on tumor localization and therapeutic efficacy of Doxil. Although it has been reported that the pharmacokinetics of drug-free Stealth liposomes is independent of dose within a certain range, clinical pharmacokinetic analysis of Doxil suggests a dose-dependent clearance saturation phenomenon when a broad dose range is examined. In addition, liposome-encapsulated doxorubicin can exert toxic effects on the liver macrophage population in the form of impairment of the phagocytic function and reduced ability of colloid particle clearance. In studies with tumor-bearing mice in which the dose of Doxil was escalated from 2.5 to 20 mg/kg, we demonstrate that dose escalation results in a saturation of Doxil clearance and a disproportional increase of the amount of liposomal drug accumulating in tumor. Experiments with radiolabeled highly negatively-charged liposomes injected into mice previously treated with Doxil are consistent with a partial blockade of the reticulo-endothelial system with relative reduction of liver uptake and greater prolongation of liposome circulation time. The clearance saturation effect is seen after Doxil in a dose-dependent fashion, and not after a similar free doxorubicin dose or similar phospholipid dose in drug-free liposomes. A trend to superior therapeutic efficacy for treatments based on larger doses as compared to smaller split doses, while maintaining an equivalent dose intensity, was also observed. These observations may be relevant to the choice of dose-schedule of Doxil to ensure optimal anti-tumor activity. Therefore, dose-dependent liposomal doxorubicin blockade of the reticulo-endothelial system may prolong liposome circulation time and enhance significantly drug delivery to tumors.     

Arkansas Medicaid Family Planning Waiver services: what physicians should know

The development of family planning services is considered one of the ten greatest achievements in public health in the United States (US) during the 20th century, enabling women to improve birth spacing and control family size. Arkansas Medicaid has expanded eligibility for family planning services to women of childbearing age with income at or below 200% of the federal poverty level (FPL). This paper describes the impact the family planning waiver has had on birth-related and economic outcomes. It also provides information that every physician should know regarding scope of services, client eligibility and provider enrollment.