Loss-of-function and residual channel activity of connexin26 mutations associated with non-syndromic deafness.

Connexins are the protein subunits of gap junction channels that allow a direct signaling pathway between networks of cells. The specific role of connexin channels in the homeostasis of different organs has been validated by the association of mutations in several human connexins with a variety of genetic diseases. Several connexins are present in the mammalian cochlea and at least four of them have been proposed as genes causing sensorineural hearing loss. We have started our functional analysis by selecting nine mutations in Cx26 that are associated with non-syndromic recessive deafness (DFNB1). We have observed that both human Cx26 wild-type (HCx26wt) and the F83L polymorphism, found in unaffected controls, generated electrical conductance between paired Xenopus oocytes, which was several orders of magnitude greater than that measured in water-injected controls. In contrast, most recessive Cx26 mutations (identified in DFNB1 patients) resulted in a simple loss of channel activity. In addition, the V37I mutation, originally identified as a polymorphism in heterozygous unaffected individuals, was devoid of function and thus may be pathologically significant. Unexpectedly, we have found that the recessive mutation V84L retained functional activity in both paired Xenopus oocytes and transfected HeLa cells. Furthermore, both the magnitude of macroscopic junctional conductance and its voltage-gating properties were indistinguishable from those of HCx26wt. The identification of functional differences of disease causing mutations may lead to define which permeation or gating properties of Cx26 are necessary for normal auditory function in humans and will be instrumental in identifying the molecular steps leading to DFNB1.

Acute posttraumatic paraplegia caused by epidural hematoma at the vertex.

Vertex epidural hematomas (VEDHs) are well known but uncommon. Their clinical presentation may be misleading and missed by routine CT axial scanning; thus, diagnosis may be delayed, with possibly fatal consequences. We report a case of acute posttraumatic paraplegia caused by a VEDH, which was evident at CT and for which the patient underwent successful surgery.

Extracellular NAD(+) induces calcium signaling and apoptosis in human osteoblastic cells.

ADP-ribosyl cyclase/CD38 is a bifunctional enzyme that catalyzes at its ectocellular domain the synthesis from NAD(+) (cyclase) and the hydrolysis (hydrolase) of the calcium-mobilizing second messenger cyclic ADP ribose (cADPR). Furthermore, CD38 mediates cADPR influx inside a number of cells, thereby inducing Ca(2+) mobilization. Intracellularly, cADPR releases Ca(2+) from ryanodine-sensitive pools, thus activating several Ca(2+)-dependent functions. Among these, the inhibition of osteoclastic-mediated bone resorption has been demonstrated. We found that HOBIT human osteoblastic cells display ADP-ribosyl cyclase activity and we examined the effects of CD38 stimulation on osteoblasts function. Extracellular NAD(+) induced elevation of cytosolic calcium due to both Ca(2+) influx from the extracellular medium and Ca(2+) release from ryanodine-sensitive intracellular stores. Culturing these cells in the presence of NAD(+) caused a complete growth arrest with a time-dependent decrease of cell number and the appearance of apoptotic nuclei. The first changes could be observed after 24 h of treatment and became fully evident after 72-96 h. We propose a role of extracellular NAD(+) in bone homeostatic control.

Isolated hemangioblastoma of the filum terminale. Case report.

The filum terminale is an exceptional location for isolated hemangioblastoma. Only five cases are reported in literature, prior to the magnetic resonance imaging era. A 57-year-old man was referred to our Department with a prolonged history of progressive back pain, particularly severe when recumbent, and recurrent unilateral sciatalgia. Computed tomography demonstrated a non-homogeneous mass at L4 level. Magnetic resonance imaging displayed earliness and homogeneous enhancement of the mass with tortuous vessels above the rostral pole of the tumour, suggesting the diagnosis of a vascular tumour. The tumour was totally removed. Histological examination confirmed the hemangioblastoma diagnosis. The case indicates that hemangioblastoma, although uncommon, must be taken into consideration in cauda equina tumour diagnosis, and also emphasises the specificity of magnetic resonance features.

Spontaneous cerebrospinal fluid rhinorrhoea in anteromedial temporal occult encephalocele.

A 75-year-old man was admitted because of a spontaneous rhinorrhoea without a previous history of head injury. Computed tomography showed bone rarefaction of the floor of the middle cranial fossa and magnetic resonance imaging demonstrated a right temporal encephalocele. This was treated via extradural approach, and the bone defects were plugged with temporalis fascia, muscle and the fibrin glue. No recurrence of rhinorrhoea was observed at the follow-up (1 year).

Functional analysis of a dominant mutation of human connexin26 associated with nonsyndromic deafness.

Cx26 has been implicated in dominant (DFNA3) and recessive (DFNB1) forms of nonsyndromic sensorineural deafness. While most homozygous DFNB1 Cx26 mutations result in a simple loss of channel activity, it is less clear how heterozygous mutations in Cx26 linked to DFNA3 cause hearing loss. We have tested the ability of one dominant mutation (W44C) to interfere with wild-type human Cx26 (HCx26wt). HCx26wt induced robust electrical conductance between paired oocytes, and facilitated dye transfer between transfected HeLa cells. In contrast, oocyte pairs injected with only W44C were not electrically coupled above background levels, and W44C failed to dye couple transfected HeLa cells. Moreover, W44C dramatically inhibited intercellular conductance of HCx26wt when co-expressed in an equal ratio, and the low levels of residual conductance displayed altered gating properties. A nonfunctional recessive mutation (W77R) did not inhibit the ability of HCx26wt to form functional channels when co-injected in the same oocyte pairs, nor did it alter HCx26wt gating. These results provide evidence for a functional dominant negative effect of the W44C mutant on HCx26wt and explain how heterozygous Cx26 mutations could contribute to autosomal dominant deafness, by resulting in a net loss, and/or alteration, of Cx26 function.

Prematurely detected traumatic carotid-cavernous sinus fistula, by means of unintentional contralateral inferior petrosal sinus catheterization: bilateral jugular bulb oxygen saturation findings.

A traumatic carotid-cavernous sinus fistula (CCSF) was prematurely suspected following the detection of arterial-like hemoglobin oxygen saturation values, sampled from a catheter placed for cerebrovenous monitoring. A high-resolution scan of jugular foramina revealed that the catheter tip had been unintentionally placed in the inferior petrosal sinus, contralateral to the CCSF, instead of in the superior jugular bulb. Jugular bulb hemoglobin oxygen saturation (SjO2), ipsilateral to CCSF, later approached arterial hemoglobin oxygen saturation (SaO2) values.The possibility and consequences of unintentional catheterization of the inferior petrosal sinus, and of extracerebral contamination of blood in the jugular bulb due to blood in the inferior petrosal sinus, are discussed. We also discuss the reliability of SjO2 monitoring in the present CCSF case.

Two-level thoracic disc herniation.

STUDY DESIGN: A double, contiguous disc herniation in the thoracic spine (T7-T8, T8-T9) in a 44-year-old man is reported. The patient complained of intermittent episodes of weakness and numbness in the lower extremities, paraesthesias radiating to the anterior and medial surfaces of the thigh and the leg (mostly on the left side), and mild sexual and urinary dysfunction. OBJECTIVE: The treatment must achieve complete spinal cord decompression, prevent further herniation, and prevent iatrogenic vascular damage to the cord. A transthoracic approach seems to offer the largest surgical view. SUMMARY OF BACKGROUND DATA: Twenty-six other cases of two-level thoracic disc herniation were found in the literature, only five of which were treated with a transthoracic approach. METHODS: Treatment consisted of complete disc excision (T7-T8 and T8-T9) with a right anterior transthoracic approach. Complete and safe removal of the discs required hemicorporectomy of T8 and subsequent grafting and plating. Spinal cord angiography, showing the Adamkiewicz artery originating from the left T10, was performed before surgery. Computed tomography-guided methylene blue injection in the retropleural interspace of T7-T8 was done for intraoperative level localization. RESULTS: At 1 year follow-up, complete relief of neurologic symptoms was observed, as was solid interbody fusion. CONCLUSION: In this case, a transthoracic approach was safe and effective for disc excision and cord decompression via hemicorporectomy.

Intracranial gliomas in Ferrara, Italy, 1976 to 1991.

INTRODUCTION: We planned a descriptive study on the incidence of intracranial gliomas spanning a 16-year period (1976-1991) in the Local Health Service 31 of Ferrara, Northern Italy. MATERIAL AND METHODS: We used a complete enumeration approach by reviewing all the possible sources of case collection available in the study area. RESULTS: The mean annual incidence rate was 5.8 new cases per 100,000 population (6.96 for men and 4.78 for women; p < 0.05), resulting in 4.7 per 100,000 when directly adjusted to the Italian population. The age-specific incidences showed a small peak in childhood, an increase with age, reaching a maximum in the age group 60 to 64 and then a decline in the elderly. This pattern is similar for both sexes. The adjusted rates increased from 3.94 per 100,000 population in the first five-year period to 5.6 per 100,000 in the third (a nonsignificant difference). The distribution of cases within the study area was substantially uniform. CONCLUSION: The incidence rates of Ferrara fell into the middle-high values so far reported and confirmed the male preponderance found in previous studies. The age-related pattern is similar to that observed, with few exceptions, in other surveys. Like other authors we did not find a significant temporal trend, although the incidence rates tended to increase with time. The data encourage further, wider epidemiological studies of a prospective nature.