Impaired postural control in patients affected by tension-type headache

Sixteen subjects, affected by chronic tension-type headache (TTH) accordingly to the International Headache Society Classification (1988) criteria, in presence of tenderness in pericranial muscles,with a mean age of 37+/-11.8 years, and ten healthy volunteer subjects, age and sex matched, were submitted to postural analysis by Static Posturography (S.Ve.P. Amplaid). Aim of the study was to evaluate whether patients with TTH have disturbed postural control, as compared to normal subjects. Postural analysis considered all posturographic variables but focused on spectral frequency analysis of body sway. In both open (OE) and closed eyes (CE) condition, spectral frequency analysis showed a significantly increased body sway at low (OE= p < or = 0.01; CE= p < or = 0.01) and middle (OE= p < or = 0.01; CE= p < or = 0.01) frequencies on the antero-posterior (y) plane and at low frequencies (OE= p < or = 0.05; CE= p < or = 0.05) on the lateral (x) plane. Statistical analysis was performed using the Student's t test for unpaired data, p value 0.05 defined significant. The proprioceptive input seems to be predominant at middle and high frequencies in maintaining posture, our results seem then to suggest a proprioceptive disturbance in TTH patients. The disturbance is likely related to chronic pericranial muscle contraction and tenderness. Posturography and spectral analysis may help not only in the diagnosis of a postural disturbance but even more in the follow-up of TTH patients, during and after a medical and/or a rehabilitative treatment.     

Membrane Transporters in Drug Disposition

Many clinically used drugs and their metabolites as well as a variety of environmental toxins are organic cations at physiologic pH. Secretion in the renal proximal tubule constitutes a major pathway in the elimination of organic cations. In this report, the results of studies recently performed in this laboratory are presented. First, the molecular cloning of a novel splice variant of organic cation transporter from rat kidney (rOCTIA) is described. The functional characteristics of the transporter are discussed along with the implications of RNA splicing in enhancing transporter diversity. Second, the molecular cloning of the first human organic cation transporter (hOCTI) is described. Distinct interspecies differences in the tissue distribution and function of this transporter is presented. These studies have paved the way for elucidating molecular structure function relationships of organic cation transporters and for determining their physiologic role in drug absorption and elimination. The cloned transporters can be used in mammalian expression systems for screening candidate compounds identified during drug discovery and development and in the in vivo prediction of the pharmacokinetics of therapeutic agents.     

Medical Necessity in Canadian Health Policy: Four Meanings and . . . a Funeral?

Four meanings of medical necessity have emerged, evolved, and dominated past and current health policy debates about the appropriate level of service coverage under Canada's health insurance program. To explore the shift in definition, provincial government and national health care association position papers responding to federal legislative and policy reviews of Canada's health insurance program from 1957 to 1984 were examined, as were more current reports on medical necessity. Four meanings of medical necessity predominated: "what doctors and hospitals do"; "the maximum we can afford"; "what is scientifically justified"; and "what is consistently funded across all provinces." These meanings changed with time as different stakeholder associations and governments redefined the concept of medical necessity to achieve different policy objectives for health service coverage under Canada's health insurance program.     

Interaction of Nucleoside Analogues with the Sodium–Nucleoside Transport System in Brush Border Membrane Vesicles from Human Kidney

The therapeutic efficacy of nucleosides and nucleoside analogues as antitumor, antiviral, antiparasitic, and antiarrhythmic agents has been well documented. Pharmacokinetic studies suggest that many of these compounds are actively transported in the kidney. The goal of this study was to determine if therapeutically relevant nucleosides or analogues interact with the recently characterized Na⁺-driven nucleoside transport system of the brush border membrane of the human kidney. Brush border membrane vesicles (BBMV) were prepared from human kidney by divalent cation precipitation and differential centrifugation. The initial Na⁺-driven ³H-uridine uptake into vesicles was determined by rapid filtration. The effect of several naturally occurring nucleosides (cytidine, thymidine, adenosine), a pyrimidine base (uracil), a nucleotide (UMP), and several synthetic nucleoside analogues [zidovudine (AZT), cytarabine (Ara-C), and dideoxycytidine (ddC)] on Na⁺–uridine transport was determined. At a concentration of 100 µM the naturally occurring nucleosides, uracil, and UMP significantly inhibited Na+-uridine transport, whereas the three synthetic nucleoside analogues did not. Adenosine competitively inhibited Na+-uridine uptake with a K _i of 26.4 µM (determined by constructing a Dixon plot). These data suggest that naturally occurring nucleosides are substrates of the Na⁺–nucleoside transport system in the renal brush border membrane, whereas synthetic nucleoside analogues with modifications on the ribose ring are not. The K _i of adenosine is higher than clinically observed concentrations and suggests that the system may play a physiologic role in the disposition of this nucleoside.     

Selective vulnerability of pallidal neurons in the early phases of manganese intoxication

Prolonged exposure to manganese in mammals may cause an extrapyramidal disorder characterized by dystonia and rigidity. Gliosis in the pallidal segments underlies the well-established phase of the intoxication. The early phase of the intoxication may be characterized by psychic, nonmotor signs, and its morphological and electrophysiological correlates are less defined. In a rat model of manganese intoxication (20 mg/ml in drinking water for 3 months), neither neuronal loss nor gliosis was detected in globus pallidus (GP). However, a striking vulnerability of manganese-treated GP neurons emerged. The majority of GP neurons isolated from manganese-treated rats died following brief incubation in standard dissociation media. In addition, patch-clamp recordings in the whole-cell configuration were not tolerated by surviving GP neurons. Neither coeval but untreated GP neurons nor striatal ones manifested analogous susceptibility. Using the perforated-patch mode of recording we attempted at identifying the functional hallmarks of GP vulnerability: in particular, voltage-gated calcium currents and glutamate-induced currents were examined. Manganese-treated GP neurons exhibited calcium currents similar to control cells aside from a slight reduction in the dihydropyridine-sensitive current facilitation. Strikingly, manganese-treated GP cells--but not striatal ones--manifested peculiar responses to glutamate, since repeated applications of the excitatory amino acid, at concentrations which commonly promote desensitizing responses, produced instead an irreversible cell damage. Possible mechanisms are discussed.     

The concentrative nucleoside transporter family,SLC28

The SLC28 family consists of three subtypes of sodium-dependent, concentrative nucleoside transporters, CNT1, CNT2, and CNT3 (SLC28A1, SLC28A2, and SLC28A3, respectively), that transport both naturally occurring nucleosides and synthetic nucleoside analogs used in the treatment of various diseases. These subtypes differ in their substrate specificities: CNT1 is pyrimidine-nucleoside preferring, CNT2 is purine-nucleoside preferring, and CNT3 transports both pyrimidine and purine nucleosides. Recent studies have identified key amino acid residues that are determinants of pyrimidine and purine specificity of CNT1 and CNT2. The tissue distributions of the CNTs vary: CNT1 is localized primarily in epithelia, whereas CNT2 and CNT3 have more generalized distributions. Nucleoside transporters in the SLC28 and SLC29 families play critical roles in nucleoside salvage pathways where they mediate the first step of nucleotide biosynthesis. In addition, these transporters work in concert to terminate adenosine signaling. SLC28 family members are crucial determinants of response to a variety of anticancer and antiviral nucleoside analogs, as they modulate the entry of these analogs into target tissues. Further, this family is involved in the absorption and disposition of many nucleoside analogs. Several CNT single nucleoside polymorphisms (SNPs) have been identified, but have yet to be characterized.     

HIV-1 Nef protein inhibits the in vitro induction of a specific antibody response to Candida albicans by an early up-regulation of IL-15 production

We have previously demonstrated that exogenous Nef protein induced activation of normal human T cells up-regulating IL-15 production by monocytes. Since HIV-1 infection results in the early impairment of immune functions we decided to evaluate if Nef is able to modulate the induction of a specific antibody response. Human peripheral blood mononuclear cells from healthy donors were induced in vitro to mount a specific antibody response to the Candida albicans antigen. We show that Nef inhibited, in a dose-dependent manner, the induction of the anti-C. albicans antibody response. The ability of an anti-Nef antibody to prevent such inhibition indicates that the effect was indeed Nef-specific. In the Nef-treated cultures an early increase of IL-15 production was observed and the addition of anti-IL-15 antibody abrogated the Nef-induced inhibitory effect. Moreover the addition of IL-15 to the cultures inhibited, as well as Nef, the induction of the specific antibody response. Thus, our results suggest that Nef may inhibit the induction of a specific antibody response by an early up-regulation of IL-15 production. A better comprehension of this phenomenon may be important for unravelling some aspects of the B cell defects in HIV infection.