The tocopherol transfer protein mediates vitamin E trafficking between cerebellar astrocytes and neurons.

Alpha-tocopherol (vitamin E) is an essential nutrient that functions as a major lipid-soluble antioxidant in humans. The alpha-tocopherol transfer protein (TTP) binds α-tocopherol with high affinity and selectivity and regulates whole-body distribution of the vitamin. Heritable mutations in the TTPA gene result in familial vitamin E deficiency, elevated indices of oxidative stress, and progressive neurodegeneration that manifest primarily in spinocerebellar ataxia. Although the essential role of vitamin E in neurological health has been recognized for over 50 years, the mechanisms by which this essential nutrient is transported in the central nervous system are poorly understood. Here we found that, in the murine cerebellum, TTP is selectively expressed in glial fibrillary acidic protein-positive astrocytes, where it facilitates efflux of vitamin E to neighboring neurons. We also show that induction of oxidative stress enhances the transcription of the TtpA gene in cultured cerebellar astrocytes. Furthermore, secretion of vitamin E from astrocytes is mediated by an ABC-type transporter, and uptake of the vitamin into neurons involves the low-density lipoprotein receptor-related protein 1. Taken together, our data indicate that TTP-expressing astrocytes control the delivery of vitamin E from astrocytes to neurons, and that this process is homeostatically responsive to oxidative stress. These are the first observations that address the detailed molecular mechanisms of vitamin E transport in the central nervous system, and these results have important implications for understanding the molecular underpinnings of oxidative stress-related neurodegenerative diseases.

Vitamin E is essential for Purkinje neuron integrity.

α-Tocopherol (vitamin E) is an essential dietary antioxidant with important neuroprotective functions. α-Tocopherol deficiency manifests primarily in neurological pathologies, notably cerebellar dysfunctions such as spinocerebellar ataxia. To study the roles of α-tocopherol in the cerebellum, we used the α-tocopherol transfer protein for the murine version (Ttpa(-/)(-)) mice which lack the α-tocopherol transfer protein (TTP) and are a faithful model of vitamin E deficiency and oxidative stress. When fed vitamin E-deficient diet, Ttpa(-/)(-) mice had un-detectable levels of α-tocopherol in plasma and several brain regions. Dietary supplementation with α-tocopherol normalized plasma levels of the vitamin, but only modestly increased its levels in the cerebellum and prefrontal cortex, indicating a critical function of brain TTP. Vitamin E deficiency caused an increase in cerebellar oxidative stress evidenced by increased protein nitrosylation, which was prevented by dietary supplementation with the vitamin. Concomitantly, vitamin E deficiency precipitated cellular atrophy and diminished dendritic branching of Purkinje neurons, the predominant output regulator of the cerebellar cortex. The anatomic decline induced by vitamin E deficiency was paralleled by behavioral deficits in motor coordination and cognitive functions that were normalized upon vitamin E supplementation. These observations underscore the essential role of vitamin E and TTP in maintaining CNS function, and support the notion that α-tocopherol supplementation may comprise an effective intervention in oxidative stress-related neurological disorders.

Altered vitamin E status in Niemann-Pick type C disease.

Vitamin E (α-tocopherol) is the major lipid-soluble antioxidant in many species. Niemann-Pick type C (NPC) disease is a lysosomal storage disorder caused by mutations in the NPC1 or NPC2 gene, which regulates lipid transport through the endocytic pathway. NPC disease is characterized by massive intracellular accumulation of unesterified cholesterol and other lipids in lysosomal vesicles. We examined the roles that NPC1/2 proteins play in the intracellular trafficking of tocopherol. Reduction of NPC1 or NPC2 expression or function in cultured cells caused a marked lysosomal accumulation of vitamin E in cultured cells. In vivo, tocopherol significantly accumulated in murine Npc1-null and Npc2-null livers, Npc2-null cerebella, and Npc1-null cerebral cortices. Plasma tocopherol levels were within the normal range in Npc1-null and Npc2-null mice, and in plasma samples from human NPC patients. The binding affinity of tocopherol to the purified sterol-binding domain of NPC1 and to purified NPC2 was significantly weaker than that of cholesterol (measurements kindly performed by R. Infante, University of Texas Southwestern Medical Center, Dallas, TX). Taken together, our observations indicate that functionality of NPC1/2 proteins is necessary for proper bioavailability of vitamin E and that the NPC pathology might involve tissue-specific perturbations of vitamin E status.

Human disease-causing NOG missense mutations: effects on noggin secretion, dimer formation, and bone morphogenetic protein binding.

Secreted noggin protein regulates bone morphogenetic protein activity during development. In mice, a complete loss of noggin protein leads to multiple malformations including joint fusion, whereas mice heterozygous for Nog loss-of-function mutations are normal. In humans, heterozygous NOG missense mutations have been found in patients with two autosomal dominant disorders of joint development, multiple synostosis syndrome (SYNS1) and a milder disorder proximal symphalangism (SYM1). This study investigated the effect of one SYNS1 and two SYM1 disease-causing missense mutations on the structure and function of noggin. The SYNS1 mutation abolished, and the SYM1 mutations reduced, the secretion of functional noggin dimers in transiently transfected COS-7 cells. Coexpression of mutant noggin with wild-type noggin, to resemble the heterozygous state, did not interfere with wild-type noggin secretion. These data indicate that the human disease-causing mutations are hypomorphic alleles that reduce secretion of functional dimeric noggin. Therefore, we conclude that noggin has both species-specific and joint-specific dosage-dependent roles during joint formation. Surprisingly, in contrast to the COS-7 cell studies, the SYNS1 mutant was able to form dimers in Xenopus laevis oocytes. This finding indicates that there also exist species-specific differences in the ability to process mutant noggin polypeptides.

Relationship between defective mouse mammary tumor virus envelope glycoprotein synthesis and GRP78 synthesis in glucocorticoid-treated mouse lymphoma cells. Evidence for translational control of GRP78 synthesis.

We have found that synthesis of the 78-kDa glucose-regulated protein, GRP78, was increased following glucocorticoid treatment of S49 and W7MG1 mouse lymphoma cell lines. These lines synthesized a 74-kDa mouse mammary tumor virus envelope glycoprotein precursor, Pr74, both constitutively and in response to glucocorticoid treatment. In these cell lines, nascent Pr74 was not processed normally but was retained within the endoplasmic reticulum where it was bound stably by GRP78. GRP78 synthesis was not increased following glucocorticoid treatment of the W7.2 mouse lymphoma cell line, which does not synthesize Pr74, suggesting that the increase in GRP78 synthesis following glucocorticoid treatment of S49 and W7MG1 cells was secondary to the glucocorticoid-induced increase in Pr74 synthesis. Consistent with this hypothesis, the glucocorticoid-induced increase in Pr74 synthesis preceded the increase in GRP78 synthesis. Also, there was a direct correlation between the level of GRP78 synthesis and the level of Pr74 synthesis among multiple subclones of the W7-ENV/N line. This line was derived from the W7.2 line by retroviral mediated transfer of a constitutively expressed sequence encoding a defective form of Pr74 that was bound stably by GRP78 within the endoplasmic reticulum. An elevation in the steady state level of GRP78 mRNA was not detected either in glucocorticoid-treated S49 cells and W7MG1 cells or in subclones of the W7-ENV/N line that have an increased level of GRP78 synthesis. Therefore, it appears that the binding of Pr74 to GRP78 induces an increase in GRP78 synthesis that is regulated at a translational level, rather than at a transcriptional level.

[Does retroperitonealization of anastomoses in left-sided large intestine resections lower postoperative mortality?]. / Senkt die Retroperitonealisierung der Anastomosen bei linksseitigen Dickdarmresektionen die postoperative Letalität?

601 low anterior anastomoses of the rectum are analysed concerning suture techniques, leakage rate and operative mortality. None of the patients who developed a dehiscence (9.3%) died due to the extraperitoneal position of the anastomosis and the continuous sump-suction drainage of the retroperitoneum. The operative mortality was 1.5%.

[Sonographically guided and intraoperative alcohol block of the celiac ganglia in conservatively uncontrollable cancer-induced epigastric pain]. / Sonographisch gezielte und intraoperative Alkoholblockade der Zöliakalganglien bei konservativ nicht beherrschbaren malignombedingten Oberbauchschmerzen.

Preliminary results of sonographically controlled alcohol injection into the region of the coeliacal ganglion for treatment of medically intractable pain in inoperable pancreas carcinoma (6 patients) are compared with results of a similar treatment using a surgical approach (10 patients). Both procedures resulted in up to total pain relief and marked reduction of consumption of analgetics. Neurolysis of the coeliacal ganglion by means of sonographically guided alcohol injection seems to be a useful treatment to reduce pain in inoperable pancreas carcinoma.

[The disinsertion of Vater's papilla in stomach resection. Causes, diagnosis and therapy]. / Die Desinsertion der Papilla Vateri bei der Magenresektion. Uraschen, Diagnose und Therapie.

Based on the experiences of our own with two papillary disconnections during partial gastric resection and 105 reports of the world literature (1916-1980), the cause, diagnosis and management of the injury is described. The most important factor favouring the operative accident is the foreshortening of the duodenum caused by the scarring of a chronic postbulbar ulcer. The ampulla of Vater may, therefore, be brought closer to the pylorus. The prognosis of the injury is not determined by the time of discovery, but it depends on the complete diagnosis of both severed ducts and adequate treatment. On delayed recognition the lesion may masquerade leaking of the duodenal stump. Successful repair can be achieved by reimplantation or invagination of the transsected common bile and pancreatic duct into the duodenal stump or an isolated Roux-en-Y-loop.

[Mechanical esophago-jejunostomy: a modern trend or progress?]. / Maschinelle Oesophago-Jejunostomie: Moderner Trend oder fortschritt?

After comparing our own experience with previous publications in using the American EEA suture gun for esophagojejunostomies it has to be discussed, whether the use of such suturing apparatus in this type of anastomosis is really valuable. After performing 29 mechanical esophagojejunostomies we observed a low suture insufficiency rate: 3.5% (an average rate of 12,6% is found in the available literature). We try to explain this significant difference by the use of special technical procedures, respecting the anatomy of this area.

[Effect of a fibrin-antibiotic compound in bone and soft tissue infections]. / Zur Wirkung eines Fibrin-Antibiotikum-Verbundes bei Knochen- und Weichteil-Infektionen.

It is reported on experimental experiences in the use of a biological adhesive system--highly concentrated native fibrinogen, thrombin and clotting factor XIII--in conjunction with local antibiotics. The results in animals are: Antibiotics in conjunction with the mentioned adhesive system give a high local concentration for a short time. The activity of the antibiotics decreases quickly within some activity of the antibiotics decreases quickly within some hours, there is no more antibiotic effect after 36 hours.

Liposarcoma of the mediastinum. Case report and review of the literature.

A case of liposarcoma of the mediastinum in reported and a review of the literature is given. To our knowledge 53 cases have been described in the literature. The most common symptoms are dyspnea, chest-pain, a cough and loss of weight. There is no relation between operability, the duration of clinical symptoms and the size of the tumor. The final diagnosis was made by histological examination in all cases. A clinical classification of the tumor is not possible, because there are no characteristic clinical findings. The prognosis in general depends on the histological type of the malignant. Although recurrence of the tumor appears in more than 40% of cases, radical surgical resection is the only method of successful treatment. The significance of the five-year survival rate is doubtful, because recurrent tumors were reported up to 14 years after the initial surgical procedure.

[Diffuse polypoid lipomatosis coli with hypertrophy of the appendices epiploicae in congenital lipomatosis (author's transl)]. / Polypoide Lipomatosis diffusa coli mit Hypertrophie der Appendices epiploicae bei kongenitaler Lipomatose.

In a 62-year-old patient diffuse polypoid lipomatosis of the colon and hypertrophy of the appendices epiploicae was found together with subcutaneous lipomata and bone changes. Out of the five cases of diffuse lipomatosis coli published so far certain parallels can be drawn in only one case. The clinical picture and course indicate that it is either a pathogenetically uniform form of mesenchymal dysplasia or a syndrome.