Cutaneous manifestations of small fibre polyneuropathy.

BACKGROUND: Because typical and atypical features of small fibre polyneuropathy (SFN) in the skin have not been fully elucidated, the diagnosis is often made by the exclusion of alternative conditions rather than by its identification as a primary syndrome. OBJECTIVE: The objective of this study was to characterize dermatologic manifestations in patients with SFN. METHODS: Large retrospective series of biopsy-proven SFN cases seen at the Massachusetts General Hospital and Brigham and Women's Hospital (January 2000 to December 2019). RESULTS: The majority of the 301 participants included presented with at least one cutaneous manifestation [292/301 (97%)]. Pain was most common with 254/301 (84.4%) perceiving this as occurring in the skin. It was frequently described as 'burning' [95/254 (37.4%)] and affected distal [174/254 (68.5%)] slightly more than proximal [111/254 (43.7%)] limbs. Numbness [182/301 (60.5%)], edema [61/301 (20.3%)] and skin colour changes [53/301 (17.6%)], which include redness [23/53 (43%)], also had predominant distal distribution. Characteristic loss of distal hair occurred among 17/29 (59%) those reporting hair loss. Other findings with classic limb involvement, Raynaud's phenomenon [33/301 (11%)] and erythromelalgia [26/301 (8.6%)] were seen. Itch [45/301 (15%)], mostly localized [22/45 (49%)] and localized eczematous dermatitis were also found. CONCLUSION: SFN has a wide range of clinical features in which the skin is affected, with characteristic findings affecting the extremities.

Value of constructive interference in steady-state three-dimensional, Fourier transformation magnetic resonance imaging for the neuroendoscopic treatment of hydrocephalus and intracranial cysts.

OBJECTIVE: To assess the value of constructive interference in steady-state, three-dimensional, Fourier transformation (CISS) magnetic resonance imaging in the endoscopic management of hydrocephalus and intracranial cysts. METHODS: CISS imaging and T2-weighted imaging were performed for 14 consecutive patients before and after fenestration procedures, using a flexible endoscope, to treat loculated or multiloculated hydrocephalus (4 patients), aqueductal stenosis or obstruction (4 patients), arachnoid cysts (4 patients), a cyst of the velum interpositum (1 patient), or an ependymal cyst (1 patient). Fifteen fenestration procedures were performed, including one reoperation. RESULTS: Preoperative CISS imaging demonstrated intracystic intraventricular septa not observed with conventional T2-weighted imaging for 11 of 15 procedures and provided better brain tissue/cerebrospinal fluid contrast, allowing better understanding of the cause of hydrocephalus and the nature of the cysts. CISS imaging and T2-weighted imaging were equally useful for monitoring postoperative changes in the sizes of ventricles or cysts and the presence of flow voids after third ventriculostomies. However, only CISS imaging clearly demonstrated the site of fenestration for six of the nine patients who underwent fenestration procedures. CONCLUSION: CISS imaging provides excellent cerebrospinal fluid/brain tissue contrast, allowing detailed study of the anatomic features of the ventricular system and cystic lesions. CISS imaging is valuable for both preoperative decision-making and postoperative evaluation.

Serial follow-up MR imaging after gamma knife radiosurgery for vestibular schwannoma.

BACKGROUND AND PURPOSE: Gamma knife radiosurgery has become an important treatment option for vestibular schwannoma. The effect of treatment can be assessed only by neuroimaging. We analyzed the evolution of follow-up MR imaging findings after gamma knife radiosurgery to provide information for the clinical management of these tumors. METHODS: Changes in tumor volume and enhancement were assessed visually on 341 follow-up MR studies obtained in 78 of 86 consecutive patients with unilateral vestibular schwannoma who underwent gamma knife radiosurgery. RESULTS: Follow-up MR studies were obtained between 10 and 63 months (mean, 34 months) after treatment. Tumor control rate was 81%. Changes in tumor volume were classified as temporary enlargement (41%), no change or sustained regression (34%), alternating enlargement and regression (13%), or continuous enlargement (12%). Temporary enlargement occurred within 2 years after radiosurgery. Changes in tumor enhancement were classified as transient loss of enhancement (84%), continuous increase in enhancement (5%), or no change in enhancement (11%). There was no significant correlation between changes in tumor volume and tumor enhancement. Areas of T2 hyperintensity in adjacent brain tissue appeared in 31% of patients. CONCLUSION: Dynamic changes in vestibular schwannoma are seen on serial follow-up MR studies obtained after gamma knife radiosurgery. An increase in tumor size up to 2 years after radiosurgery is likely to be followed by regression. Changes in contrast enhancement are not predictive of clinical outcome. Neuroimaging follow-up is recommended.

Amelioration of vasospasm after subarachnoid hemorrhage in transgenic mice overexpressing CuZn-superoxide dismutase.

BACKGROUND AND PURPOSE: To clarify the effect of superoxide dismutase (SOD) on vasospasm after subarachnoid hemorrhage (SAH), we investigated sequential changes in arterial diameter after SAH in transgenic mice overexpressing CuZn-SOD (SOD-1). METHODS: SOD-transgenic mice and nontransgenic littermates (35 to 40 g) were subjected to SAH produced by endovascular perforation of left anterior cerebral artery. At 4 hours and 1, 3, 7, and 14 days after SAH, the mice were perfused with 10% formalin and consequently with a mixture of carbon black and 10% gelatin to cast all vessels. Vasospasm was evaluated by measuring the diameter of the left middle cerebral artery (MCA) with a microscope. RESULTS: In nontransgenic mice, the diameter of the MCA on day 3 after SAH (110.5+/-20.5 microm [mean+/-SD]; n=16) was significantly reduced compared with that without SAH (138.5+/-14.5 microm; n=12) (P<0.01). Moreover, on day 3 after SAH, the diameter of the MCA in SOD-transgenic mice (127. 9+/-20.2 microm; n=20) was significantly larger than that in nontransgenic mice (110.5+/-20.5 microm; n=16) (P<0.05). CONCLUSIONS: These results suggest that SOD is effective on the amelioration of vasospasm after SAH and that oxygen free radicals, particularly superoxide, play an important role in the pathogenesis of vasospasm after SAH.

Enhancement of glucose-induced insulin secretion in transgenic mice overexpressing human VIP gene in pancreatic beta cells.

Using transgenic mice technology, it has now become possible to test directly whether VIP and PHM-27 can enhance glucose-induced insulin secretion and reduce blood glucose in vivo. By microinjecting the entire human VIP gene ligated to the rat insulin II promoter, we have established a mouse model that overproduces VIP and PHM-27 in pancreatic beta cells. VIP was secreted from transgenic islets in a glucose-dependent manner. Analyses of these VIP-transgenic mice indicated that the transgene efficiently enhances glucose-induced insulin secretion and significantly reduces blood glucose as compared with control mice. The transgene also ameliorated glucose intolerance of 70% depancreatized mice. The present results suggest that somatic cell gene therapy directed to diabetic islets by human VIP/PHM-27 gene introduction may provide a means to improve the secretory function of the diabetic islets.

Inducible nitric oxide synthase following hypoxia in rat cultured glial cells.

Nitric oxide (NO) produced by inducible nitric oxide (iNOS) exerts inhibitory and cytotoxic effects on various cells including neuronal cells. In the present study, we examined the ability of rat glial cells to produce NO following hypoxia/reoxygenation in vitro by measuring nitrite. The levels of nitrite produced in the cultured media of glial cells significantly increased after 12-h hypoxia but not after 0- and 6-h hypoxia. The NOS inhibitor, NG-monomethyl-L-arginine, decreased hypoxia-induced nitrite formation. In glial cells after hypoxia/reoxygenation, the iNOS and mRNA and protein expressions were detected by reverse-transcription polymerase chain reaction and by immunocytochemical analysis, respectively. The present study provides the first evidence that hypoxia induces NO production from glial cells. This hypoxia-induced, glial cell-derived NO may play a critical role in the pathogenesis of cerebral ischemia in vivo.

Induction of brain-derived neurotrophic factor (BDNF) and the receptor trk B mRNA following middle cerebral artery occlusion in rat.

Middle cerebral artery (MCA) occlusion in halothane-anesthetized rats induced brain-derived neurotrophic factor (BDNF) and the receptor, trk B mRNA, in brain. In situ hybridization studies showed that BDNF and trk B mRNAs were induced in a widespread region of the ipsilateral cortex outside the infarct at 4 h following MCA occlusion. They were also induced in the bilateral hippocampi which are remote from the ischemic MCA region. These data show that changes in neurotrophic factor and receptor gene expressions can occur in the areas outside the infarct which could survive.

Regulatory role of CD38 (ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase) in insulin secretion by glucose in pancreatic beta cells. Enhanced insulin secretion in CD38-expressing transgenic mice.

Cyclic ADP-ribose (cADPR) serves as a second messenger for Ca2+ mobilization in insulin secretion, and CD38 has both ADP-ribosyl cyclase and cADPR hydrolase activities (Takasawa, S., Tohgo, A., Noguchi, N., Koguma, T., Nata, K., Sugimoto, T., Yonekura, H., and Okamoto, H. (1993) J. Biol. Chem. 268, 26052-26054). Here, we produced transgenic mice overexpressing human CD38 in pancreatic beta cells. The enzymatic activity of CD38 in transgenic islets was greatly increased, and ATP efficiently inhibited the cADPR hydrolase activity. The Ca2+ mobilizing activity of cell extracts from transgenic islets incubated in high glucose was 3-fold higher than that of the control, suggesting that ATP produced by glucose metabolism increased cADPR accumulation in transgenic islets. Glucose- and ketoisocaproate-induced but not tolbutamide- nor KCl-induced insulin secretions from transgenic islets were 1.7-2.3-fold higher than that of control. In glucose-tolerance tests, the transgenic serum insulin level was higher than that of control. The present study provides the first evidence that CD38 has a regulatory role in insulin secretion by glucose in beta cells, suggesting that the Ca2+ release from intracellular cADPR-sensitive Ca2+ stores as well as the Ca2+ influx from extracellular sources play important roles in insulin secretion.

Nicotinamide inhibits IRF-1 mRNA induction and prevents IL-1 beta-induced nitric oxide synthase expression in pancreatic beta cells.

Nitric oxide produced by inducible nitric oxide synthase in islets exerts inhibitory and cytotoxic effects on pancreatic beta cells and is therefore thought to be a potent mediator in the pathogenesis of Type I diabetes mellitus. Here, using isolated rat pancreatic islets, we show that high-concentration nicotinamide (20 mM), but not low-concentration nicotinamide (5 mM), attenuates the interleukin-1 beta-evoked inhibition of glucose-induced insulin secretion by preventing the induction of interferon regulatory factor-1, a transcriptional factor which plays an essential role in inducible nitric oxide synthase gene expression, and the interleukin-1 beta-induced nitric oxide formation. High-concentration nicotinamide also restored an interleukin-1 beta-induced decrease in ATP content in pancreatic beta cells, suggesting that interleukin-1 beta-induced nitric oxide inhibits the mitochondrial function. The present results show the molecular basis of the preventive effect of high-dose nicotinamide on Type I diabetes mellitus.

Monitoring visual evoked potentials during retraction of the canine optic nerve: protective effect of unroofing the optic canal.

To evaluate the effects of unroofing the optic canal during retraction of the optic nerve, the authors monitored changes in visual evoked potentials (VEPs) stimulated by a light-emitting diode in the canine model. At rest, an early VEP wave was reliably observed with an amplitude of 8.2 +/- 0.6 microV and a latency of 51.5 +/- 0.7 msec; this wave was named N50. The intracranial optic nerve was retracted using a weight of 5, 10 or 50 g. The earliest change in VEP noted during retraction was a reduction in N50 wave amplitude. The length of time required until N50 amplitude decreased to 50% of the control group (T50) was 10.7 +/- 1.8 minutes with a weight of 5 g, 4.9 +/- 0.7 minutes with 10 g, and 2.9 +/- 0.4 minutes with 50 g, with statistically significant differences between the groups. Retraction of the optic nerve with all weights finally resulted in the disappearance of the N50 wave. The amplitude of the N50 wave recovered fully to control size when retraction was released immediately after the wave disappeared. The time course of amplitude recovery did not differ significantly between groups. Unroofing the optic canal prolonged the T50 during retraction significantly to 20.7 +/- 2.9 minutes with a weight of 5 g, 18.9 +/- 4.2 with 10 g, and 9.0 +/- 2.4 with 50 g. These results demonstrate that unroofing the optic canal can protect the optic nerve from damage during operations that require optic nerve retraction.

Transgenic mice overexpressing human vasoactive intestinal peptide (VIP) gene in pancreatic beta cells. Evidence for improved glucose tolerance and enhanced insulin secretion by VIP and PHM-27 in vivo.

Vasoactive intestinal peptide (VIP), a 28-amino acid peptide hormone, plays many physiological roles in the peripheral and central nervous systems. It has been proposed that endogenous VIP released from VIP-containing nerves is involved in the regulation of the secretory function of the endocrine pancreas. To test this hypothesis in vivo, we produced transgenic mice carrying the human VIP/peptide histidine methionine 27 (PHM-27) gene under the control of insulin promoter. In immunohistochemical analyses of islets, all the islet beta cells of transgenic mice were intensely stained for both VIP and PHM-27, consistent with the fact that these two peptides are encoded in a single mRNA (Itoh, N., Obata, K., Yanaihara, N., and Okamoto, H. (1983) Nature 304, 547-549). VIP was efficiently secreted from isolated transgenic islets in vitro. The blood glucose assays in free-fed mice indicated that the transgene lowered the blood glucose levels of transgenic mice (128 +/- 4 mg/dl) by about 20% below control levels (155 +/- 6 mg/dl). In the glucose tolerance test, at 60 min after glucose administration, the transgenic blood glucose levels (129 +/- 12 mg/dl) were much lower than control levels (175 +/- 13 mg/dl). The transgenic serum insulin levels at 15 min after glucose administration were 2.5-3.0-fold higher than control levels. The transgene was also effective in ameliorating glucose intolerance of 70% depancreatized mice. These results indicate that VIP and PHM-27 produced from the transgenic beta cells efficiently enhance glucose-induced insulin secretion from beta cells by an autocrine mechanism. These results also suggest that genetic manipulation of islet beta cells by the human VIP/PHM-27 gene or delivery of VIP to beta cells may ultimately provide a valuable approach to enhancing insulin secretion in clinical diabetes.

Primary chronic intrasellar haematoma: a case report.

This report describes a rare case of primary intrasellar haematoma in a 66 year-old man with hypopituitarism. Computerized tomography (CT) and magnetic resonance imaging (MRI) showed an intrasellar cystic lesion with small suprasellar extension. Transsphenoidal surgery revealed that the lesion was a chronic haematoma, without evidence of a tumour or vascular anomaly. Pathological diagnosis confirmed this. This is the first report of a chronic intrasellar haematoma, which is probably primary.