How is an ideal satiating yogurt described? A case study with added-protein yogurts.

Protein is recognized as the macronutrient with the highest satiating ability. Yogurt can be an excellent basis for designing satiating food as it is protein-based food product. Five different set-type yogurts were formulated by adding extra skim milk powder (MP), whey protein concentrate (WPC), calcium caseinate (CAS) or a blend of whey protein concentrate with calcium caseinate (CAS-WPC). A control yogurt without extra protein content was also prepared. Differences in sensory perceptions (through CATA questions) were related to the consumers' expected satiating ability and liking scores (of several modalities). In addition, an "Ideal satiating yogurt" was included in the CATA question to perform a penalty analysis to show potential directions for yogurt reformulation and to relate sensory and non-sensory yogurt characteristics to satiating capacity.

Uso del regenerador dérmico Integra® como material de relleno para el tratamiento de defectos del contorno corporal / Use of Integra® dermal regeneration template in deep tissue planes for contour defects treatment

En el tratamiento de los defectos de contorno corporal se usan múltiples productos biológicos y/o sintéticos. Cuando el volumen no es grande, los autores plantean el uso del regenerador dérmico Integra® eliminando previamente su capa superficial de silicona frente a los inconvenientes que presenta el uso de otros materiales de relleno en Cirugía Plástica (reabsorción variable, intolerancia, infección, granulomas, calcificación, etc). Dicho producto acaba transformándose en neodermis del propio paciente, bien tolerada. Presentamos dos casos con defectos a nivel frontal (postraumático) y en tórax anterior (secuelas de reconstrucción tras mastectomía) respectivamente, en los que se colocó Integra ® en bolsillos profundos y doblado sobre sí mismo para aumentar su volumen. Los resultados son previsibles, con mínima reabsorción y además son duraderos, con seguimiento a los 6 y 12 meses. Los autores recomiendan el uso del regenerador dérmico en volúmenes moderados y/o pequeños, considerando que en grandes volúmenes es preferible el uso del colgajos autólogos y/o colgajos más prótesis (AU)

In the treatment of body contour defects we can use many biological and synthetic products. They have many inconvenient effects as variable reabsortion, intolerance, infection, granulomas, calcification, etc. In moderate defects, the authors propose the use of modificated Integra® dermal regeneration template without the superficial silicone layer. Two patients are reported, one with a traumatic frontal defect and another with a depression in the anterior thorax after postmastectomy breast reconstruction post mastectomy. In both we put Integra ® into a subcutaneous pocket and we bent it to increase lamina volume. Results are predictable, permanent, with minimal reabsortion after 6 and 12 months follow up. Integra ® will be autologous neodermis. The authors recommend the dermal regeneration template for small or medium defects; in large defects they prefer autologous flaps with or without prosthesis (AU)

Tratamiento integral de paciente con quemaduras de 2º GP-3er G en el 95% de uperficie corporal. Cultivo de Queratinocitos / Integral treatment of a patient with 2nd and 3rd degree burns on 95% of the body surface. Keratinocyte culture

Exponemos el tratamiento de un gran quemado destacando sobre todo las distintas etapas que se siguen en el apartado quirúrgico para llegar a una cobertura total. Presentamos el caso de un varón joven que tras accidente laboral sufrió quemaduras en el 95% de la superficie corporal total (S.C.T.) y mostramos la pauta de tratamiento quirúrgico seguida usando cultivo de (..) (AU)

We present the treatment of a serious burn patient, emphasising the different steps followed in surgery, in order to cover all the affected areas. This is the case of a young male, who after a work accident, suffered burns covering 95% of his Total Body Surface (TBS). The presentation explains the surgical procedure followed, using Keratinocyte culture, autografts and homografts and the results obtained. Reanimation of serious burns was carried out and then, surgical treatment in various different stages: First, complete debridement of the burns and then a temporary cover of Biobrane® and a skin biopsy of the scalp to make Keratinocyte culture. Then, the Biobrane was removed and the area was covered with Keratinocyte. Finally, due to the bad results obtained from the cultures, the ‘sandwich’ technique was used. Evolution and healing ‘ad integrum’ was favourable in 12 months. This account descibes our experience with Keratinocytes culture and other alternatives, when the results from this method were unfavourable Patients affected by burns covering more than 90% TBS, present a challenge for the limited donor site available. In these cases, Keratinocyte cultures, as described above, can sometimes be used with good results, but this was not our experience (AU)

Actualización epidemiológica y mortalidad de quemados adultos en Cataluña (España) / Adult burn epidemiology and mortality rate update in Catalonia (Spain)

La Unidad de Quemados del Hospital Universitario de la Vall d’Hebron de Barcelona (España) ha realizado un segundo estudio epidemiológico y de mortalidad en quemados adultos que complementa y actualiza el publicado por Barretet al en 1998. La revisión epidemiológica comprende cinco años, desde enero de 1997 a diciembre de 2001. En dicho período se atendieron 1430 urgencias/año con una media de424 ingresos/año hasta un total de 2120 pacientes ingresados vía urgencias. Con una mortalidad global del 3,25 %, se observa una disminución aparente respecto a la obtenida en la primera mitad de la década de los 90 (3,49 %). La causa principal de quemaduras es el accidente casual por llama, destacándola ignición de material altamente inflamable, siendo la mortalidad en mujeres más elevada que en hombres: 3,43 versus3,14 % (p<0,05). Varios son los factores que determinan un peor pronóstico evolutivo de los pacientes como son la edad, la superficie corporal total quemada (SCTQ), la inhalación de humos, el ingreso en la Unidad de Cuidados Intensivos(UCI) y los antecedentes personales previos. La Dosis Letal 50 (DL50) obtenida en este período de 83,2 % de superficie corporal total quemada (SCTQ) conjuntamente con la baja mortalidad, sitúan a la Unidad de Quemados de la Vall d’Hebron en el grupo de centros desarrollados con mejores índices de supervivencia en quemados (AU)

The Val d’Hebron University Hospital Burns Unit in Barcelona (Spain) has carried out a second study of epidemiology and mortality rate in adult burns cases, which complements and updates the one published by Barret et al in 1998 (1). The epidemiology consists of five years between January 1997 and December 2001. In this period , 1430 urgent cases were treated per year, with an average of 424 admissions per year, thus making a total of 2120 patients admitted through emergencies. The average mortality rate (3,25%) shows an apparent decrease compared with the results obtained during the first half of the 90s decade, ( 3,49%). The main cause of burns are accidents with involving fire, which subsequently cause the ignition of highly flammable material. The death rate in women is higher than that in men: 3,43% compared with 3,14%. There are various factors which determine the worst evolutional prognosis: age, TBAB (total body area burned), smoke inhalation, admittance into Intensive Care Unit (ICU), personal antecedents. The Lethal Dose 50 (LD50) (83,2%) and the low mortality rate seen during this period places the Burns Unit of the Val d’Hebron amongs the best developed centres with the highest survival rates of burns cases (AU)

Histological and immunohistochemical study of clinically normal skin of Leishmania infantum-infected dogs.

Skin lesions are the most usual manifestation of canine leishmaniosis. The aim of this study was to investigate the histological pattern and parasite load in clinically normal skin of Leishmania-infected dogs. Two groups of Leishmania-infected dogs were studied. Group A consisted of 15 symptomless animals which, although seronegative or only mildly seropositive, gave a positive polymerase chain reaction (PCR) for Leishmania in the skin. Group B consisted of 20 clinically affected dogs which were highly seropositive and PCR-positive. Biopsies of normal skin from all dogs were processed for routine histology and Leishmania immunohistochemistry. The study demonstrated microscopical lesions and the presence of parasites in the skin from dogs of group B, but not group A. The results cast doubt on the relevance of infected but symptomless dogs in the epidemiology of canine leishmaniosis. In contrast, however, the clinically normal skin of sick dogs harbours the parasite and probably plays a role in the transmission of leishmaniosis.

Tratamiento de las Quemaduras en el Siglo XXI desde la Cirugía / Surgical Burns Treatment in the XXI Century

Los autores valoran desde su propia perspectiva personal y profesional lo que ha sido el tratamiento quirúrgico de los pacientes quemados en los últimos años y lo que puede ser en años venideros en función del gran número de productos biológicos de los que da la impresión vamos a poder disponer como armamento terapeútico en el futuro (AU)

Cerebroside synthesis as a measure of the rate of remyelination following cuprizone-induced demyelination in brain.

We studied markers of myelin content and of the rate of myelination in brains of mice between 8 and 20 weeks of age. During the 12-week time-course, control animals showed slight increases in the content of oligodendroglial-specific cerebroside, as well as cholesterol (enriched in, but not specific to, myelin). In contrast, synthesis of these lipids, as assayed by in vivo incorporation of (3)H(2)O, was substantial, indicating turnover of 0.4% and 0.7% of total brain cerebroside and cholesterol, respectively, each day. We also studied mice exposed to a diet containing 0.2% of the copper chelator, cuprizone. After 6 weeks 20%, and by 12 weeks, over 30% of brain cerebroside was gone. Demyelination was accompanied by down-regulation of mRNA expression for enzymes controlling myelin lipid synthesis (ceramide galactosyl transferase for cerebroside; hydroxymethylglutaryl-CoA reductase for cholesterol), and for myelin basic protein. Synthesis of myelin lipids was also greatly depressed. The 20% cerebroside deficit consequent to 6 weeks of cuprizone exposure was restored 6 weeks after return to a control diet. During remyelination, expression of myelin-related mRNA species, as well as cerebroside and cholesterol synthesis were restored to normal. However, in contrast to the steady state metabolic turnover in the control situation, all the cerebroside and cholesterol made were accumulated. To the extent that accumulating cerebroside is targeted for eventual inclusion in myelin (discussed) the rate of its synthesis is proportional to remyelination. With our assay, in vivo rates of cerebroside synthesis can be determined for a time window of the order of hours. This offers greater temporal resolution and accuracy relative to classical methods assaying accumulation of myelin components at time intervals of several days. We propose this experimental design, and the reproducible cuprizone model, as appropriate for studies of how to promote remyelination.

Episodic demyelination and subsequent remyelination within the murine central nervous system: changes in axonal calibre.

Exposure of young adult C57BL/6 mice to cuprizone in the diet initiated profound and synchronous demyelination of the corpus callosum, which was virtually complete by 4 weeks of exposure. Interestingly, even in the face of a continued exposure to cuprizone, there was spontaneous remyelination 2 weeks later. This remyelination preferentially involved smaller calibre axons. There was a suggestion of yet another cycle of demyelination (at 10 weeks) and remyelination (at 12 weeks), but by 16 weeks of exposure, the regenerative capacity was exhausted and the animals were near death. The relapsing-remitting pattern suggests this may be a useful model for certain human demyelinating disorders. In contrast to the above chronic model, the corpus callosum from mice exposed to cuprizone for only 6 weeks continued to remyelinate, with 67% of the axons being myelinated or remyelinated at 10 weeks. Interestingly, a significant reduction in the mean value for axonal diameter was observed during acute demyelination. Upon remyelination, however, the axonal calibre distribution returned to near-normal. In contrast, when mice were maintained on a cuprizone diet for 16 weeks, the mean value for axonal diameter was reduced to 60% of normal. These results provide further evidence that the interactions between oligodendrocytes and axons alter axonal calibre.

Prevalence of Leishmania infantum infection in dogs living in an area of canine leishmaniasis endemicity using PCR on several tissues and serology.

We studied and compared the prevalence of Leishmania infection and the seroprevalence and the prevalence of canine leishmaniasis in an area where canine leishmaniasis is endemic. One hundred dogs living on the island of Mallorca (Spain) were studied. In this study, we clinically examined each dog for the presence of symptoms compatible with leishmaniasis, determined the titer of anti-Leishmania antibodies, and investigated the presence of Leishmania DNA by PCR in skin, conjunctiva, and bone marrow samples of each dog. The prevalence of the disease and the seroprevalence were 13 and 26%, respectively. In 63% of the dogs, Leishmania DNA could be detected by PCR in at least one of the tissues studied. The results of positive PCR in the bone marrow, the conjunctiva, and the skin were 17.8, 32, and 51%, respectively. The prevalence of the infection, 67%, was calculated using all animals that were seropositive and/or positive by PCR with any tissue. The results showed that the majority of dogs living in an area where canine leishmaniasis is endemic are infected by Leishmania and that the prevalence of infection is much greater than the prevalence of overt Leishmania-related disease.

Parameters related to lipid metabolism as markers of myelination in mouse brain.

Myelination, during both normal development and with respect to disorders of myelination, is commonly studied by morphological and/or biochemical techniques that assay as their end-points the extent of myelination. The rate of myelination is potentially a more useful parameter, but it is difficult and time-consuming to establish, requiring a complete developmental study with labor-intensive methodology. We report herein development of methodology to assay the absolute rate of myelination at any desired time during development. This involves intraperitoneal injection of (3)H(2)O to label body water pools, followed by determination of label in the myelin-specific lipid, cerebroside. The absolute amount of cerebroside synthesized can then be calculated from the specific radioactivity of body water and knowledge of the number of hydrogens from water incorporated into cerebroside. During development, the rate of cerebroside synthesis correlated well with the rate of accumulation of the myelin-specific components, myelin basic protein and cerebroside. For purposes of control, we also tested other putative, albeit less quantitative, indices of the rate of myelination. Levels of mRNA for ceramide galactosyltransferase (rate-limiting enzyme in cerebroside synthesis) and for myelin basic protein did not closely correlate with myelination at all times. Cholesterol synthesis closely matched the rate of cholesterol accumulation but did not track well with myelination. Synthesis of fatty acids did not correlate well with accumulation of either fatty acids (phospholipids) or myelin markers. We conclude that measurement of cerebroside synthesis rates provides a good measure of the rate of myelination. This approach may be useful as an additional parameter for examining the effects of environmental or genetic alterations on the rate of myelination.

The neurotoxicant, cuprizone, as a model to study demyelination and remyelination in the central nervous system.

Myelin of the adult CNS is vulnerable to a variety of metabolic, toxic, and autoimmune insults. That remyelination can ensue, following demyelinating insult, has been well demonstrated. Details of the process of remyelination are, however difficult to ascertain since in most experimental models of demyelination/remyelination the severity, localization of lesion site, or time course of the pathophysiology is variable from animal to animal. In contrast, an experimental model in which massive demyelination can be reproducibly induced in large areas of mouse brain is exposure to the copper chelator, cuprizone, in the diet. We review work from several laboratories over the past 3 decades, with emphasis on our own recent studies, which suggest an overall picture of cellular events involved in demyelination/remyelination. When 8 week old C57BL/6 mice are fed 0.2% cuprizone in the diet, mature olidgodendroglia are specifically insulted (cannot fulfill the metabolic demand of support of vast amounts of myelin) and go through apoptosis. This is closely followed by recruitment of microglia and phagoctytosis of myelin. Studies of myelin gene expression, coordinated with morphological studies, indicate that even in the face of continued metabolic challenge, oligodendroglial progenitor cells proliferate and invade demyelinated areas. If the cuprizone challenge is terminated, an almost complete remyelination takes place in a matter of weeks. Communication between different cell types by soluble factors may be inferred. This material is presented in the context of a model compatible with present data -- and which can be tested more rigorously with the cuprizone model. The reproducibility of the model indicates that it may allow for testing of manipulations (e.g. available knockouts or transgenics on the common genetic background, or pharmacological treatments) which may accelerate or repress the process of demyelination and or remyelination.

Mature oligodendrocyte apoptosis precedes IGF-1 production and oligodendrocyte progenitor accumulation and differentiation during demyelination/remyelination.

We have documented changes in the oligodendrocyte population during demyelinating insult to the adult CNS. Feeding of cuprizone to adult mice led to apoptotic death of mature oligodendrocytes followed by profound demyelination of the corpus callosum. A regenerative response was initiated even during active demyelination. Oligodendrocyte progenitors have begun to proliferate and then accumulate within the lesion. Many of these cells may have migrated from the sub-ventricular zone and fornix before their accumulation in the demyelinating corpus callosum. The accumulation of differentiating oligodendrocyte progenitors was followed closely by the reappearance of mature oligodendrocytes and remyelination. Interestingly, an increase in IGF-1 mRNA was detected at Week 3 through Week 7, suggesting potential involvement in remyelination. Other factors, however, such as PDGF, NT3, FGF, jagged, and notch remained unchanged. These results suggest that the mature oligodendroglial population depleted by apoptosis is replaced by a newly formed oligodendroglial population derived from progenitors; these accumulate and seem to differentiate during remyelination.

Diurnal and dietary-induced changes in cholesterol synthesis correlate with levels of mRNA for HMG-CoA reductase.

We determined the extent to which diurnal variation in cholesterol synthesis in liver is controlled by steady-state mRNA levels for the rate-limiting enzyme in the pathway, hydroxymethylglutaryl (HMG)-CoA reductase. Rats 30 days of age and maintained on a low-cholesterol diet since weaning were injected intraperitoneally with (3)H(2)O. The specific radioactivity of the whole-body water pool soon became constant, allowing for expression of values for incorporation of label into cholesterol as absolute rates of cholesterol synthesis. In liver, there was a peak of cholesterol synthesis from 8 pm to midnight, a 4-fold increase over synthesis rates from 8 am to noon. Increases in synthesis were quantitatively in lock step with increases in mRNA levels for HMG-CoA reductase occurring 4 h earlier. In a parallel experiment, rats received 1% cholesterol in the diet from weaning to 30 days of age. Basal levels of hepatic cholesterol synthesis were greatly diminished and there was little diurnal variation of cholesterol synthesis or of levels of mRNA for HMG-CoA reductase. Levels of mRNA for the low density lipoprotein receptor and scavenger receptor-B1 (putative high density lipoprotein receptor) showed little diurnal variation, regardless of diet. This suggests that diurnal variation of hepatic cholesterol synthesis is driven primarily by varying the steady-state mRNA levels for HMG-CoA reductase. Other tissues were also examined. Adrenal gland also showed a 4-fold diurnal increase in accumulation of recently synthesized cholesterol. In contrast to liver, however, there was little corresponding change in mRNA expression for HMG-CoA reductase. Much of this newly synthesized cholesterol may be of hepatic origin, imported into adrenal by SR-B1, whose mRNA was up-regulated 2-fold. In brain, there was no diurnal variation in either cholesterol synthesis or mRNA expression, and no influence of high- or low-cholesterol diets on synthesis rates or HMG-CoA reductase mRNA levels.

Electric burns: high- and low-tension injuries.

From January 1993 to December 1997, 179 patients with electrical injuries were admitted to our burn unit. There were 55 patients with high-tension injuries and 124 patients with low-tension injuries. A high incidence of amputation (42%) is one of the characteristic sequelae of high-tension injuries, but no patients in this group of burns died. Early and serial debridement of necrotic tissue is our treatment of preference. The patient needs extensive rehabilitation and psychiatric support.

Gene expression in brain during cuprizone-induced demyelination and remyelination.

When C57BL/6J mice, 8 weeks of age, received 0.2% Cuprizone in their diet, extensive demyelination in corpus callosum was detectable after 3 weeks, and there was massive demyelination by 4 weeks. As expected, the accumulation of phagocytically active microglia/macrophages correlated closely with demyelination. When Cuprizone was removed from the diet, remyelination was soon initiated; after 6 weeks of recovery, myelin levels were near-normal and phagocytic cells were no longer prominent. Steady-state levels of mRNA for myelin-associated glycoprotein, myelin basic protein, and ceramide galactosyltransferase were already profoundly depressed after 1 week of Cuprizone exposure and were only 10-20% of control values after 2 weeks. Unexpectedly, upregulation of mRNA for these myelin genes did not correlate with initiation of remyelination but rather with accumulation of microglia/macrophages. After 6 weeks of exposure to Cuprizone, mRNA levels were at control levels or higher-in the face of massive demyelination. This suggests that in addition to effecting myelin removal, microglia/macrophages may simultaneously push surviving oligodendroglia or their progenitors toward myelination.

Control of cholesterol biosynthesis in Schwann cells.

Cholesterol accounts for over one-fourth of total myelin lipids. We found that, during development of the rat sciatic nerve, expression of mRNA for hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in cholesterol biosynthesis, was up-regulated in parallel with mRNA for P0, the major structural protein of PNS myelin, and with ceramide galactosyltransferase (CGT), the rate-limiting enzyme in cerebroside biosynthesis. To help establish the nature of this coordinate regulation of myelin-related genes, we examined their steady-state mRNA levels in cultured primary Schwann cells. We also assayed synthesis of cholesterol and cerebroside to distinguish how much control of synthetic activity for these two myelin lipids involved mRNA levels for HMG-CoA reductase and CGT, and how much involved post-mRNA control mechanisms. Addition of forskolin to cells cultured in media supplemented with normal calf serum resulted in up-regulation of P0 and CGT mRNA expression and cerebroside synthesis, without corresponding increases in HMG-CoA reductase mRNA or cholesterol synthesis. Cholesterol synthesis increased approximately threefold in Schwann cells cultured with lipoprotein-deficient serum, without any increase in HMG-CoA reductase mRNA. Furthermore, addition of either serum lipoproteins or 25-hydroxycholesterol decreased cholesterol synthesis without altering HMG-CoA reductase mRNA levels. We conclude that, as in other tissues, cholesterol synthesis in Schwann cells is regulated primarily by intracellular sterol levels. Much of this regulation occurs at posttranscriptional levels. Thus, the in vivo coordinate up-regulation of HMG-CoA reductase gene expression in myelinating Schwann cells is secondary to intracellular depletion of cholesterol, as it is compartmentalized within the myelin. It is probably not due to coordinate control at the level of mRNA expression.

Monocyte chemoattractant protein 1 is responsible for macrophage recruitment following injury to sciatic nerve.

Following injury to the peripheral nervous system, circulating monocytes/macrophages are recruited to the damaged tissue, where they play vital roles during both nerve degeneration and subsequent regeneration. Monocyte chemoattractant protein-1 (MCP-1), a member of the C-C or beta-chemokine family, is a powerful leukocyte recruitment/activation factor that is relatively specific for monocytes/macrophages. Because these are the predominant leukocyte type recruited by injured nerve, we hypothesized that upregulation of MCP-1 expression is involved in recruitment of these cells. Indeed, assay of steady-state levels of MCP-1 mRNA in rat sciatic nerve during tellurium-induced primary demyelination indicated up-regulation of this chemokine with a peak after 3 days of tellurium exposure, preceding the peak of accumulation of phagocytic macrophages (assayed as lysozyme mRNA levels) by 6 days. Increasing levels of MCP-1 mRNA expression, induced by increasing levels of tellurium exposure, resulted in corresponding increases in subsequent recruitment of macrophages. In situ hybridization suggested that MCP-1 mRNA was localized in Schwann cells. No expression of MIP-2, which is a C-X-C or alpha-chemokine that is specific for recruitment of neutrophils, was detected, consistent with the lack of recruitment of significant numbers of these cells. In addition, we also investigated the response seen following nerve transection (axonal degeneration and secondary demyelination with no subsequent regeneration) and nerve crush (degeneration followed by regeneration). In these latter two nerve injury models, there was also a marked, early up-regulation of MCP-1 mRNA, with a time course that is compatible with a role for this chemokine in macrophage recruitment. We conclude that MCP-1 is involved in recruiting monocytes/macrophages to injured peripheral nerve and that the specificity of leukocyte types recruited results from specificity of chemokine production.

Regenerating sciatic nerve does not utilize circulating cholesterol.

The rapid accumulation of myelin in the peripheral nervous system during the early postnatal period requires large amounts of cholesterol, a major myelin lipid. All of the cholesterol accumulating in the developing rat sciatic nerve is synthesized locally within the nerve, rather than being derived from the supply in lipoproteins in the systemic circulation (Jurevics and Morell, J. Lipid Res. 5:112-120; 1994). Since this lack of utilization of circulating cholesterol may relate to exclusion by the blood-nerve barrier, we examined the sources of cholesterol needed for regeneration following nerve injury, when the blood-nerve barrier is breached. One sciatic nerve was crushed or transected, and at various times later, the rate of cholesterol accumulation was compared with the rate of local in vivo synthesis of cholesterol within the nerve, utilizing intraperitoneally injected 3H2O as precursor. The accumulation of additional cholesterol in nerve during regeneration and remyelination could all be accounted for by that locally synthesized within the nerve. There was also an increase in cholesterol esters in injured nerve segments; in crushed nerves, these levels decreased during regeneration and remyelination, consistent with reutilization of cholesterol originally salvaged by phagocytic macrophages and Schwann cells. Thus, regeneration and remyelination following injury in sciatic nerve utilizes both salvaged cholesterol and cholesterol synthesized locally within the nerve, but not cholesterol from the circulation.

Tellurium causes dose-dependent coordinate down-regulation of myelin gene expression.

Exposure of developing rats to a diet containing elemental tellurium systemically inhibits cholesterol synthesis at the level of squalene epoxidase. At high tellurium exposure levels (> 0.1% in the diet), there is an associated segmental demyelination of the PNS. Low levels of dietary tellurium (0.0001%) led to in vivo inhibition of squalene epoxidase activity in sciatic nerve, and inhibition increased with increasing exposure levels. With increasing dose and increasing exposure times, there was an increasing degree of demyelination and increasing down-regulation of mRNA levels for myelin P0 protein, ceramide galactosyltransferase (rate-limiting enzyme in cerebroside synthesis), and HMG-CoA reductase (rate-limiting enzyme in cholesterol synthesis). Because these were all down-regulated in parallel, we conclude there is coordinate regulation of the entire program for myelin synthesis in Schwann cells. An anomaly was that at early time points and low tellurium levels, mRNA levels for HMG-CoA reductase were slightly elevated, presumably in response to tellurium-induced sterol deficits. We suggest the eventual down-regulation relates to a separate mechanism by which Schwann cells regulate cholesterol synthesis, related to the need for coordinate synthesis of myelin components. Levels of mRNA for the low-affinity nerve growth factor receptor (indicator of alterations in axon-Schwann cell interactions) and for lysozyme (marker for phagocytic macrophages) were both up-regulated in a dose- and time-dependent manner which correlated with the presence of segmental demyelination. Levels of mRNA coding for myelin-related proteins were down-regulated at low tellurium exposure levels, without demyelination or up-regulation of nerve growth factor receptor. This suggests the down-regulation is related to the tellurium-induced cholesterol deficit, and not to the loss of axonal contact associated with early stages of demyelination or to the entry of activated macrophages.

Alterations in gene expression associated with primary demyelination and remyelination in the peripheral nervous system.

Primary demyelination is an important component of a number of human diseases and toxic neuropathies. Animal models of primary demyelination are useful for isolating processes involved in myelin breakdown and remyelination because the complicating events associated with axonal degeneration and regeneration are not present. The tellurium neuropathy model has proven especially useful in this respect. Tellurium specifically blocks synthesis of cholesterol, a major component of PNS myelin. The resulting cholesterol deficit in myelin-producing Schwann cells rapidly leads to sychronous primary demyelination of the sciatic nerve, which is followed by rapid synchronous remyelination when tellurium exposure is discontinued. Known alterations in gene expression for myelin proteins and for other proteins involved in the sequence of events associated with demyelination and subsequent remyelination in the PNS are reviewed, and new data regarding gene expression changes during tellurium neuropathy are presented and discussed.