Nature of optokinetic response and zonal organization of climbing fiber afferents in the vestibulocerebellum of the pigmented rabbit

In pigmented rabbits anesthetized with N2O (70%) and halothane (2-4%), Purkinje cells were extracellularly recorded in the flocculus. A large central visual field (60 degrees x 60 degrees) was used to optokinetically stimulate either the ipsi- or contralateral eye, and the direction and velocity selectivities of complex spike responses were examined. For optokinetic stimulation (OKS) delivered to the ipsilateral eye (n = 129), the preferred direction was forward (F, n = 57) or upward (U, n = 37), while the remaining cells (n = 35) showed no response (N). For OKS delivered to the contralateral eye (n = 107), the preferred direction was backward (B, n = 11), downward (D, n = 42) or upward (U, n = 2), and the rest (n = 52) showed N. Cells tested with both eyes (n = 89) fell into five categories based on the preferred direction to ipsi- and contralateral OKS: (1) ipsi-F and contra-B (F/B type, n = 9), (2) ipsi-F but contra-N (F/N type, n = 28), (3) ipsi-U and contra-D (U/D type, n = 13), (4) ipsi-U but contra-N (U/N type, n = 17), and (5) ipsi-N but contra-D (N/D type, n = 22). The optimum velocity was within 0.1-2.0 degrees/s for all cells. On the average, the best response was obtained at 0.2-0.5 degrees/s stimulation. All ipsi-F cells responded to electrical stimulation of the optic tract (OT), while most cells preferring ipsi-U, contra-B and contra-D directions did not respond. No characteristic feature was found in cells innervated with collateralized climbing fiber branches to the nodulus. In the flocculus, cells preferring horizontal orientation (H cells, preferring ipsi-F and/or contra-B directions) were localized in a narrow dorsoventral zone (less than 1.0 mm) along the caudal border of the rostral one third, while those preferring the vertical orientation (V cells, preferring ipsi-U and/or contra-D directions) were in two distinct narrow zones located rostral and caudal to the H cell zone. H and V cells were intermingled in the central portion of the ventral flocculus. These four zones are in good agreement with previously defined H, anterior V, posterior V and R zones, respectively. The results indicate that the subdivision of the flocculus which controls horizontal (vertical) eye movements receives information regarding movements of the visual surround in the horizontal (vertical) orientation through visual climbing fiber afferents, thus being organized in olivo-cortico-nuclear functional units for control of eye movements.     

Myoglobinuria due to enzyme abnormalities in glycolytic pathway--especially lactate dehydrogenase M subunit deficiency]

Glycolysis is an important energy productive system. Enzyme abnormalities the in glycolytic pathway, which cause myoglobinuria, are deficiencies of phosphofructokinase, phosphoglycerate kinase, phosphoglycerate mutase, and lactate dehydrogenase (LDH). Common symptoms of these enzyme abnormalities are muscle cramp, muscle pain, and rhabdomyolysis after strenuous exercise. Acute renal failure owing to myoglobinuria is the most noteworthy symptom. In daily life, symptoms are rarely observed and prognosis is usually good. Correct and fast diagnosis of such latent symptomatic disorders is important to prevent a turn for the worse of these symptoms. LDH M subunit deficiency was first discovered by urinary discoloration and a discrepancy of laboratory data. Since then, only four cases have been reported in the Japanese population. The response to ischemic forearm work is characteristic (an increase of venous lactate concentration after ischemic work is not observed and a marked increase of venous pyruvate is found). The increase of pyruvate concentration is specific in LDH-M subunit deficiency, and is not observed in other abnormalities of the glycolytic pathway. Glycolysis was markedly retarded in the patient's muscle in the glyceraldehyde 3-phosphate dehydrogenase (GA3PD) step, possibly due to the impaired reoxidation of NADH produced by GA3PD activity. Then, the excess NADH is reoxidized by alpha-glycerophosphate dehydrogenase and triose phosphates are drained to alpha-glycerophosphate and glycerol. Therefore ATP production is significantly impaired and muscle tissue is damaged. A genetical study revealed a deletion of 20 base-pairs in exon 6 in LDH-M subunit deficiency. This mutation results in a frame-shift translation and premature termination.     

Treatment with cathepsin L inhibitor potentiates Th2-type immune response in Leishmania major-infected BALB/c mice

Prior to the activation of CD4 (+) T cells, exogenous proteins must be digested by endo/lysosomal enzymes in antigen-presenting cells (APC) to produce antigenic peptides that are able to be presented on class II molecules of the MHC. Studies described here inspect the functional significance of cathepsin L inhibition for antigen processing and T (h) 1/T (h) 2 differentiation in experimental leishmaniasis. We first demonstrated using in vitro systems that cathepsin L is one of the candidate endo/lysosomal enzymes in processing of soluble Leishmania antigen (SLA) and that its specific inhibitor, CLIK148, modulated the processing of SLA. BALB/c mice are known to be susceptible to infection with Leishmania major. Interestingly, treatment of BALB/c mice with CLIK148 exacerbated the infection by enhancing the development of SLA-specific T (h) 2-type response such as production of IL-4 and generation of T (h) 2-dependent specific IgE/IgG1 antibodies. Moreover, addition of CLIK148 in incubation of a SLA-specific CD4 (+) T cell line with APC up-regulated the production of IL-4. However, CLIK148 did not exert any direct influence on the function of T cells themselves. Taken together, these findings suggest that treatment of host mice with CLIK148 affects the processing of SLA in APC, resulting in the potentiation of T (h) 2-type immune responses and thus leading to exacerbation of the infection. Furthermore, endo/lysosomal cathepsin L was found to be functionally distinct from previously described cathepsins B and D.     

Quantification of dentine shape in anthropoid primates

The external shape and thickness of the enamel component of primate molars have been employed extensively in phylogenetic studies of primate relationships. The dentine component of the molar crown also has been suggested to be indicative of phylogenetic relationships, but few studies have quantified dentine morphology in order to evaluate this possibility. To explore the utility of dentine shape as an indicator of phylogenetic affinity, a two-dimensional geometric morphometric analysis (EDMA-II) was performed using nine homologous land-marks on a sample of sectioned maxillary molars of extant ceboid, cercopithecoid, and hominoid primates. Results indicate that dentine shape (the configuration of the enamel-dentine junction, or EDJ) can distinguish taxa at every taxonomic level examined, including superfamilies, subfamilies, and closely related genera and species. This supports the idea that dentine morphology may be useful for phylogenetic studies. It is further suggested that the morphology of the EDJ may be more conservative than enamel morphology, and perhaps better-suited to phylogenetic studies. Among the samples studied, cercopithecoid primates have a unique dentine shape, and it is suggested that the development of bilophodont molars may be related to the distinctive EDJ configuration in cercopithecoids.     

Measurement of intestinal absorption of 57Co vitamin B12 by serum counting

The results of the measurement of vitamin B(12) absorption by counting the radioactivity of 5 ml. serum obtained eight to 10 hours after the ingestion of an oral dose of 0.5 mug. vitamin B(12) labelled with 0.5 muc. (57)Co are compared with those obtained with the urinary excretion (Schilling) test. Inadequate urine collection and impaired renal function were responsible for low results in the Schilling test in four of the 12 control subjects, and an incomplete urine collection in four patients with pernicious anaemia could have led to doubt about the validity of the low result.The measurement of serum radioactivity for 1,000 seconds gave conclusive results, the range in the patients with malabsorption of vitamin B(12) being between 0 and 24 counts per minute, and in the control subjects and other patients with megaloblastic anaemia between 28 and 64 counts per minute. The highest serum radioactivity level in a patient with pernicious anaemia was 19 counts per minute.Serum counting is simpler than the Schilling test and may be done alone when the patient's renal function is known to be poor, when urine collection is expected to be unreliable, or when the flushing dose of vitamin B(12) should be avoided. Otherwise there is an advantage in doing both tests together for confirmation.     

Phase I clinical and pharmacokinetic study ofN 4-behenoyl-1-β-d-arabinofuranosylcytosine

A phase I study ofN ⁴-behenoyl-1-β-d-arabinofuranosylcytosine (BHAC) was conducted in 66 patients, 41 with solid tumors and 25 with hematological malignancies. The patients received either a 2-h single intravenous (i.v.) drip infusion (Schedule 1) or consecutive daily 2-h i.v. infusions (Schedule 2). In Schedule 1 the daily dose was initiated with 1.5 mg kg^?1 which was escalated up to 7 mg kg^?1. Side-effects were mild, and included nausea, vomiting, epilation, and hot flushes. Because of the presence of the solvent vehicle, HCO-60 and in consideration of the mechanism of action of BHAC, the dose escalation was stopped at 7 mg kg^?1. In Schedule 2, the daily dose was started with 1.5 mg kg^?1 which was escalated up to 8 mg kg^?1 and given for 2–16 days. Myelosuppression was found to be dose-limiting toxicity. The maximum tolerated dose (MTD) in patients with non-hematological solid tumors was assumed to be 5 mg kg^?1 daily × 5 days. The plasma disappearance curve of BHAC looked biphasic, and when 4 mg kg^?1 of BHAC were administered the half-lives of the initial phase (t _1/2α) and the second phase (t _1/2β) were calculated as 0.798 and 5.76 h respectively. In Schedule 2 complete remission was observed in 5 out of 21 patients with acute leukemia, one partial remission in Hodgkin’s disease, and one 1-B response (Karnofsky) in thyroid papillary adenocarcinoma.