After the first observations of life under the microscope, it took two centuries of research before the 'cell theory', the idea that all living things are composed of cells or their products, was formulated. It proved even harder to accept that individual cells also make up nervous tissue.
The objective of this study was to compare the efficacy and tolerability of gabapentin and amitriptyline monotherapy in painful diabetic neuropathy. This was a 12-week, open-label, prospective, randomized trial. Twenty-five type-II diabetic patients with pain attributed to diabetic neuropathy and a minimum score of 2 on a pain intensity scale ranging from 0 (no pain) to 4 (excruciating pain) were randomized to receive either gabapentin, titrated from 1,200 mg/day to a maximum of 2,400 mg/day, or amitriptyline, titrated from 30 mg/day to a maximum of 90 mg/day. Both drugs were titrated over a 4-week period and maintained at the maximum tolerated dose for 8 weeks. The main outcome measures were weekly pain intensity and paresthesia intensity, measured on two categorical scales. Thirteen patients received gabapentin and 12 received amitriptyline. All 25 patients completed the trial. Gabapentin produced greater pain reductions than amitriptyline (mean final scores were 1.9 vs. 1.3 points below baseline scores; P = 0.026). Decreases in paresthesia scores also were in favor of gabapentin (1.8 vs. 0.9 points; P = 0. 004). Adverse events were more frequent in the amitriptyline group than in the gabapentin group: they were reported by 11/12 (92%) and 4/13 (31%) of patients, respectively (P = 0.003). Side effects were the main limiting factor preventing dose escalation. Gabapentin produced greater improvements than amitriptyline in pain and paresthesia associated with diabetic neuropathy. Additionally, gabapentin was better tolerated than amitriptyline. Further controlled trials are needed to confirm these preliminary results.
Point mutations in the cAMP-responsive element (CRE) of the rat somatostatin gene promoter/enhancer sequence (TGACGTCA) were used as a model for assessing the effect of uracil, deriving either from misincorporation during DNA synthesis (T----U) or cytosine deamination (C----U), on the binding of sequence/specific regulatory proteins. The results show that the T----U conversion in both strands of the CRE palindromic sequence reduces its affinity for the CRE binding factor(s), suggesting the crucial role of the methyl group contributed by T for the correct recognition of the sequence. On the other hand, deamination of C in the CpG central dinucleotide (CpG----UpG) causes an increase of binding affinity which is further enhanced by the contemporary deamination in both strands. Then, both uracil misincorporation and cytosine deamination alter the binding to CRE sequence in vitro, suggesting that uracil, if not removed by uracil DNA-glycosylase, could be dangerous for cellular functions.
When Camillo Golgi invented the black reaction in 1873 and first described the fine anatomical structure of the nervous system, he described a 'big nerve cell' that later took his name, the Golgi cell of cerebellum ('Golgi'schen Zellen', Gustaf Retzius, 1892). The Golgi cell was then proposed as the prototype of type-II interneurons, which form complex connections and exert their actions exclusively within the local network. Santiago Ramón y Cajal (who received the Nobel Prize with Golgi in 1906) proceeded to a detailed description of Golgi cell morphological characteristics, but functional insight remained very limited for many years. The first rediscovery happened in the 1960s, when neurophysiological analysis in vivo revealed that Golgi cells are inhibitory interneurons. This finding promoted the development of two major cerebellar theories, the 'beam theory' of John Eccles and the 'motor learning theory' of David Marr, in which the Golgi cells regulate the spatial organisation and the gain of input signals to be processed and learned by the cerebellar circuit. However, the matter was not set and a series of pioneering observations using single unit recordings and electron microscopy raised new issues that could not be fully explored until the 1990s. Then, the advent of new electrophysiological and imaging techniques in vitro and in vivo demonstrated the cellular and network activities of these neurons. Now we know that Golgi cells, through complex systems of chemical and electrical synapses, effectively control the spatio-temporal organisation of cerebellar responses. The Golgi cells regulate the timing and number of spikes emitted by granule cells and coordinate their coherent activity. Moreover, the Golgi cells regulate the induction of long-term synaptic plasticity along the mossy fibre pathway. Eventually, the Golgi cells transform the granular layer of cerebellum into an adaptable spatio-temporal filter capable of performing several kinds of logical operation. After more than a century, Golgi's intuition that the Golgi cell had to generate under a new perspective complex ensemble effects at the network level has finally been demonstrated.
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