Deleterious effects of minocycline in animal models of Parkinson's disease and Huntington's disease

Minocycline has been shown to exert anti-inflammatory effects underlying its putative neuroprotective properties in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease and in the R6/2 mouse model of Huntington's disease (HD). However, contradictory results have recently been reported. We report deleterious effects of minocycline in two phenotypic (toxic) models of Parkinson's disease and HD in monkey and mouse. Of seven MPTP-intoxicated female cynomolgus monkeys (0.2 mg/kg, i.v. until day 15), three received minocycline (200 mg b.i.d.). While placebo-MPTP-treated animals displayed mild parkinsonism at day 15, the minocycline/MPTP-treated animals tended to be more affected (P = 0.057) and showed a greater loss of putaminal dopaminergic nerve endings (P < 0.0001). In the 3-nitropropionic acid (3-NP) mouse model of HD, minocycline (45 mg/kg i.p.) was administered 30 min before each i.p. injection of 3-NP (b.i.d., cumulated dose, 360 mg/kg in 5 days). Mice receiving minocycline exhibited a worsening of the mean motor score with a slower recovery slope, more impaired general activity and significantly deteriorated performances on the rotarod, pole test and beam-traversing tasks. The histopathological outcome demonstrated that minocycline-treated mice presented significantly more severe neuronal cell loss in the dorsal striatum. The effect of minocycline vs. 3-NP was also investigated on hippocampal and cortical cell cultures. minocycline blocked 3-NP-induced neurotoxicity at certain doses (1 mm cortical neurons) but not at higher doses (10 mm). Thus, minocycline may have variable and even deleterious effects in different species and models according to the mode of administration and dose.     

Neuroprotective strategies for Parkinson's disease: conceptual limits of animal models and clinical trials

Parkinson's disease (PD) is a progressive neurodegenerative disorder. Although therapies that treat the symptoms of the disease have proven efficacy, strategies that slow or stop the neurodegenerative process are currently not available. Recently, the National Institute of Neurological Disorders and Stroke (NINDS) conducted a systematic assessment of candidate pharmacological agents with putative neuroprotective properties. Twelve agents have been selected as potential candidates for upcoming clinical trials. However, the data resulting from the use of these agents in animal models of PD using a clinically driven design have not been published. Furthermore, the selection of interesting candidates should be based on the soundest clinically driven preclinical validation. This lack of published data, associated with the conceptual limits of the current way of testing drugs in clinical trials, prompts us to argue for further preclinical validation of the 12 candidates.     

Temperature sensitivity of glycolysis during sepsis

OBJECTIVE: To investigate the temperature sensitivity of glycolysis during sepsis. DESIGN: A prospective, randomized, controlled animal study. SETTING: The Physiological Department of a University Hospital. SUBJECTS: Ten male Sprague-Dawley rats, weighing 400-500 g. INTERVENTIONS: The rats were assigned to either a septic (n = 5) or a sham-control group (n = 5). After anesthesia (H0), experimental sepsis was induced by a cecal ligation and perforation, and the left lateral gastrocnemius was sampled. Four hours later (H4), a second anesthesia was performed to sample the contralateral muscle. The sham-control group underwent the same procedures, but the cecum was neither ligated nor incised. MEASUREMENTS AND MAIN RESULTS: Glycolytic flux (J(B), the rate at which glycogen can be used in muscle) and the transition time (t99 : the time required for the transition from aerobic to anaerobic metabolism) were measured by using spectrophotometry. The measurements were performed at seven different temperature levels, ranging from 32 to 42 degrees C. For each measured variable, the temperature sensitivity of glycolysis was assessed by computing the Q10 values, which is the variation ratio of the measured variable, attributed to a 10 degrees C temperature increase. In control rats, anesthesia and surgical procedures induced a J(B) increase (7.9 +/- 1.6 at H0 vs. 11.9 +/- 2.1 micromol x min-1 x g(tissue) at H4, p<.05) without any t99 variation. Whatever the group (control or septic), the same temperature variation induced an effect that was approximately three times higher in the hypothermia (<37 degrees C) than in the hyperthermia range (>37 degrees C; p<.05). However, a loss in thermal sensitivity was observed in septic rats in the hyperthermia range (Q10 = 1.2 +/- 0.1 for septic animals vs. 2.3 +/- 0.4 for control animals; p<.05). CONCLUSIONS: This study demonstrates that glycolysis is more sensitive to temperature in the hypothermia range than in the hyperthermia range. The loss in thermal sensitivity at >37 degrees C in septic rats suggests that sepsis may induce a dysregulation of glycolysis. From an energetic point of view, this signifies that hyperthermia may by itself impair energy metabolism without improving energy production and thus must be treated during sepsis.     

Augmentation of Cheek Bone Contour Using Malar Osteotomy

Patients with a narrow face have often a defect in expansion of the maxillary–malar complex. A malar osteotomy, separating the malar–zygomatic complex from the orbit and the maxilla, allows an anterolateral cheek projection when performing an external rotation. This technique changes facial contour and improves facial aesthetics. During the past 5 years, 18 malar osteotomies have been performed; the external rotation was stabilized with interposed coral graft in six patients and with interposed bone graft fixed by a miniplate or with a stainless steel wire in 12 patients. Simultaneously septoplasty was performed in five patients, rhinoplasty in 13 patients, and genioplasty in two patients. Six patients had a face and neck lift, one patient had a forehead lift, and one patient had onlay iliac crest bone graft to treat atrophic maxillary alveolar ridges prior to implant placement. Stability was defined after 1 year follow-up. The increase in projection was correlated to the size of the graft. At least 5 mm were necessary to have cheek modification. Mucous inflammation, maxillary sinusitis, and relapse were observed with the use of interposed coral graft, but no complications were observed with bone graft. Malar osteotomy is a simple and safe procedure; it allows an anterolateral cheek projection and seems to be effective for treating transverse midface deficiency. Presented at the XVI^th congress of ISAPS, Istanbul, Turkey, 26–29 May 2002     

Training with cognitive sequences improves syntactic comprehension in agrammatic aphasics

A major open question in cognitive neuroscience concerns the modularity of language: does human language rely, in part, on neural processes that are not language specific? Such reliance would predict that learning should transfer between non-linguistic and linguistic domains via this common neural basis. To test this prediction, we studied effects of non-linguistic cognitive sequence training on syntactic comprehension of six left-hemisphere damaged aphasic patients. Syntactic comprehension impairment was quantified before and after 10 weeks of training on a non-linguistic sequence processing task. This task used a transformational rule specifically corresponding to the transformation required for understanding a particular type of sentence referred to as relativised. Non-linguistic sequencing improved significantly with training (day effect: F(9,45)=3.7, <0.005). Moreover, a significant transfer of this improvement was observed for relativised, but not active nor passive sentences (pre-post x type interaction: F(2,10)=4.72, <0.05). The specificity of this transfer indicates that language relies partially on functional and neural processes that are not language specific.     

Compensatory regulation of striatal neuropeptide gene expression occurs before changes in metabolic activity of basal ganglia nuclei

Compensatory mechanisms delay the appearance of parkinsonian symptoms. However, both the order of appearance and potential interactions of compensatory mechanisms acting within the nigrostriatal pathway as well as inside and outside the basal ganglia are not clear. We hypothesize that, after the striatal dopaminergic homeostasis breakdown, a modification in the expression of several striatal markers (neuropeptide precursors and dopamine receptors) may occur before a change in the activity of both globus pallidus (GP) and substantia nigra pars reticulata (SNr) in response to a partial nigrostriatal lesion. The present data show, in MPTP-treated mice, that preproenkephalin-A and preprotachykinin mRNA expression and D(3) receptor binding are modified without changes in cytochrome oxidase metabolic activity in both GP and SNr, respectively. These changes in neuropeptide expression would compensate for the dopamine depletion-induced changes in inhibitory GABAergic input from the striatum to GP and SNr. It also indicates that nondopaminergic compensatory mechanisms inherent to the basal ganglia are activated before those residing outside the basal ganglia.     

Presymptomatic diagnosis of experimental Parkinsonism with 123I-PE2I SPECT

Presymptomatic diagnosis of the loss of nigrostriatal neurons that characterises Parkinson's disease, is a crucial issue for future neuroprotective therapies as degeneration exceeds 70 to 80% when symptoms appear. Here we propose an early diagnosis method that utilises single photon emission computerized tomography (SPECT) coupled to the iodine-123-labelled selective dopamine transporter ligand N-(3-ioprop-2E-enyl)-2-beta-(4-methylphenyl)nortropane ((123)I-PE2I), applying Logan's graphical method for quantification. Sequential (123)I-PE2I SPECT acquisitions were performed in nonhuman primates chronically treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine according to a regimen that consistently produces a progressive Parkinsonian state. While classical neurological examination only allows detection of Parkinsonian signs at Day 12 of the protocol of intoxication, the mean distribution volume ratio calculated according to Logan's graphical method is significantly decreased from Day 6 onward, i.e., when animals are clinically normal. (123)I-PE2I SPECT is a very sensitive method to detect presymptomatic lesions of nigrostriatal neurons and the first to be experimentally validated. It could now be used clinically for early diagnosis and follow-up of neuroprotective treatment.     

Room tilt illusion as a manifestation of peripheral vestibular disorders

Room tilt illusion is a subjective distortion of verticality with transient paradoxical rotation of the visual field, usually in the frontal plane. It might result from dysfunction of the vestibular pathways with subsequent contradictory vestibular, visual, and proprioceptive inputs and erroneous cortical integration. It has already been described in association with brain stem and cortical lesions, but reports of cases of peripheral origin are scarce. We report here 23 cases of room tilt illusion, all but 2 occurring in patients with either vestibular peripheral abnormalities or normal assessment findings. A review of the literature is presented, as well as a hypothesis addressing this phenomenon.     

Apple pectin and a polyphenol-rich apple concentrate are more effective together than separately on cecal fermentations and plasma lipids in rats

To evaluate the effect of apple components on cecal fermentations and lipid metabolism, rats were fed diets containing 5 g/100 g apple pectin (PEC), 10 g/100 g high polyphenol freeze-dried apple (PL) or both (PEC + PL). The cecal pH was slightly acidic (6.49) only in rats fed the PEC + PL diet (controls, 7.02). The cecal short-chain fatty acid pool was enlarged by all the apple fractions, with a peak of 560 micromol in rats fed the PEC + PL diet compared with 189 micromol in controls. Butyrate concentrations were 2-fold greater in rats fed the PL diet than in controls. Substantial concentrations of galacturonate and succinate (approximately 40 mmol/L) were found in the cecum of rats fed the PEC diet and, to a lesser extent, the PEC + PL diet. The PEC + PL diet significantly lowered plasma cholesterol, whereas both the PL and PEC + PL diets lowered plasma triglycerides. Liver cholesterol and triglyceride concentrations were lower in rats fed the PEC and PEC + PL diets. Fecal bile acid excretion was markedly reduced, whereas sterol excretion was significantly increased by dietary PEC. Rats fed the PEC and PEC + PL diets also had lower apparent cholesterol absorption than controls (30 compared with 43%). In conclusion, apple pectin and the polyphenol-rich fraction were more effective when fed combined together than when fed separately on large intestine fermentations and lipid metabolism, suggesting interactions between fibers and polyphenols of apple.     

Complications of nasal obstruction in children

The author reviews the morphogenetic and functional consequences of oral breathing in childhood.