Characterization of the CXCR4 Signaling in Pancreatic Cancer Cells

CXCL12 and its receptor, CXCR4, are emerging as promising targets for modulating growth, angiogenesis, and metastasis in several human cancers. Indeed, blocking the receptor is sufficient to prevent metastasis and angiogenesis in experimental breast cancer xenografts. Recently, the biological effect of the CXCR4 in pancreatic cancer, one of the most deadly neoplastic diseases, has been reported. However, the molecular mechanism by which CXCR4 contributes to these properties is not completely understood. In this paper, we characterize the signaling pathways activated by CXCR4 in pancreatic cancer. We show that after CXCR4 activation, EGFR becomes tyrosine phosphorylated, and the kinase activity of this receptor, together with the activation of MMPs, Src, and PI3-Kinase, is required for CXCR4-mediated ERK activation. Analysis of this cascade in pancreatic cancer cells revealed that the ERK-mediated pathway regulates genes involved in angiogenesis, such as VEGF, CD44, HIF1α, and IL-8. Furthermore, ERK blockage inhibits the migration and tube formation of endothelial cells induced by CXCL12. Considering that inhibitors for several components of this pathway, including CXCR4 itself, are at different stages of clinical trials, this study provides theoretical justification for the clinical testing of these drugs in pancreatic cancer, thus extending the list of potential targets for treating this dismal disease.     

Neonatal renal failure due to obstructive candidal bezoars

Acute renal failure (ARF) developed in a 7-week-old infant due to bilateral candidal bezoars (fungal balls) causing obstruction at the pelviureteric junction. The baby was born at term with an appropriate birthweight, and had been treated with broad-spectrum antibiotics for respiratory distress and septicemia during the 1st week of life. Recovery from ARF followed renal decompression with bilateral nephrostomy tube placement and parenteral administration of amphotericin B and 5-flucytosine. Received August 21, 1996; received in revised form and accepted January 3, 1997     

An unusual cause of adult onset cerebellar ataxia with hypogonadism

We report an unusual case of sporadic adult onset cerebellar ataxia with hypogonadism. A 40-year-old unmarried man presented with progressive ataxia and dysarthria along with complaints of non-development of secondary sexual characteristics and erectile dysfunction. There were complaints of intermittent diarrhea. Clinical examination revealed a pan-cerebellar syndrome with features of hypoandrogenism. No eye movement abnormalities were evident. There were signs of malabsorption. Investigations confirmed the presence of auto-antibodies found in celiac disease, and a duodenal biopsy confirmed the same. Hypoandrogenism was postulated to be due to hypergonadotropic hypogonadism which has been mentioned in a few patients of celiac disease. However, the pattern seen in our patient was of a hypogonadotropic hypogonadism. This is probably secondary to an autoimmune hypophysitis seen in some patients in the absence of other clinical manifestations. Autoantibody testing should be a diagnostic necessity in any adult with a sporadic cerebellar ataxia.     

Dopa-responsive parkinsonism secondary to right temporal lobe haemorrahage.

A 46-year-old man developed a symmetrical parkinsonian syndrome 7 weeks after large right temporal intracerebral haemorrhage resulting from a ruptured arteriovenous malformation. His signs included bradykinesia, rigidity, start hesitation, and poor postural reflexes, without a resting tremor. He also had signs of a Parinaud's syndrome. Computed tomography and magnetic resonance imaging of the brain demonstrated changes in the right temporal lobe associated with the haemorrhage but no abnormality of the basal ganglia or midbrain. Levodopa therapy produced a dramatic improvement within a few days of commencement. We postulate that the parkinsonism resulted from midbrain compression secondary to transtentorial herniation. Although parkinsonism is a rare complication of lobar intracerebral haemorrhage, it is important to recognise as it may be potentially treatable.     

Activity-induced weakness in recessive myotonia congenita with a novel (696+1G>A) mutation.

OBJECTIVE: To investigate the cause of the transient weakness that occurs in recessive myotonia congenita (RMC) following sustained muscle contraction. METHODS: Nerve excitability studies were performed on a 35-year-old male with RMC due to a novel 696+1G>A CLCN1 mutation. The median nerve was stimulated at the wrist and compound muscle action potentials (CMAPs) were recorded from abductor pollicis brevis (APB). Stimulus-response behaviour using two stimulus durations, threshold electrotonus to 100-ms polarizing currents, a current threshold relationship and the recovery of excitability following supramaximal stimulation were recorded at rest. Excitability parameters were also recorded before and after maximal voluntary contraction (MVC) of APB against resistance for 60s. Results were compared to data obtained from 12 normal controls. RESULTS: Baseline axonal excitability parameters were all normal, indicating that axonal function was normal at the point of stimulation. Following one minute of MVC, excitability parameters demonstrated a significant increase in threshold when compared to controls (RMC 54.9%; controls 15.5+/-3.1%). In the RMC patient, this increase in threshold was associated with a 39% reduction in the amplitude of the maximal CMAP, which remained unaffected in controls. CONCLUSIONS: The reduction in maximal CMAP is likely to represent muscle activation failure due to depolarization block, with the increase in threshold possibly reflecting a compensatory attempt by motor axons to overcome prolonged contraction-induced changes in the muscle membrane. SIGNIFICANCE: The prolonged recovery of excitability following sustained muscle contraction is likely to be a contributing factor to symptoms of weakness and fatigue experienced by RMC patients.     

Do anterior interbody cages have a potential value in comparison to autogenous rib graft in the surgical management of Scheuermann's kyphosis?

BACKGROUND CONTEXT: Previous studies have analyzed the outcome following posterior correction and combined anterior-posterior correction for Scheuermann's kyphosis. Traditionally interbody fusion has been obtained using morselized rib graft. Recently the use of titanium anterior cages has been suggested for interbody use. There are no long-term studies comparing these two techniques. PURPOSE: To investigate the potential value of titanium anterior interbody cages compared with morselized rib graft for anterior interbody fusion in combination with posterior instrumentation, correction, and fusion for Scheuermann's kyphosis. STUDY DESIGN: Nonrandomized comparison of two surgical techniques in matched subjects. PATIENT SAMPLE: Fifteen patients with identical preoperative radiographic and physical variables (age, gender, height, weight, body mass index) were managed with combined anterior release, interbody fusion, posterior instrumentation, correction, and fusion. Group A (n=8) had morselized rib graft inserted into each intervertebral disc space. Group B (n=7) had titanium interbody cages packed with bone graft inserted at each level. The posterior instrumentation extended from T2 to L2 in both groups. OUTCOME MEASURES: Preoperative and postoperative curve morphometry was studied on plain radiographs by two independent observers. The indices studied included Cobb angle, Ferguson's angle, Voutsinas index, sagittal vertical axis (SVA), sacral inclination (SI), and lumbar lordosis (LL). Interbody fusion was assessed at final follow-up. Each patient was reviewed at 3, 6, 12, 24, 48, and 60 months after surgery with standing radiographs. METHODS: Both surgical groups were compared in terms of radiological parameters and complications. Wilcoxon-matched pairs test and Mann-Whitney test were used. RESULTS: The average follow-up for Group A was 70 months and for Group B 66 months. For the whole group, the preoperative median Cobb angle for thoracic kyphosis was 86 degrees , the median Ferguson angle was 50 degrees , Voutsinas index was 28.7, SVA -3.5 centimeters, lumbar lordosis was 66 degrees , and the median sacral inclination angle was 40 degrees . The median postoperative Cobb angle was 42 degrees , Ferguson angle 28.4 degrees , Voutsinas index 13, SVA -4.0 centimeters, and the median sacral inclination angle was 34 degrees . There were significant differences between preoperative and postoperative measurements for all variables (p<.01), indicating that good correction was achieved. At 4-year follow-up, fusion criteria were satisfied in 12 of 15 cases (80%). Three patients had distal junctional kyphosis. There was no significant difference obtained in the final Cobb angle, Ferguson angle, and Voutsinas index when Group A (rib graft) was compared with Group B (titanium cage) Both Group A and B patients retained the postoperative correction achieved with respect to all the radiographic parameters studied. CONCLUSION: We were unable to demonstrate any significant advantage for the use of anterior titanium interbody cages over the use of morselized rib graft in the surgical management of Scheuermann's kyphosis. Given the not inconsiderable cost and the need for posterior chevron osteotomies when interbody cages are used, we have now reverted to our previous practice of using morselized rib graft at each intervertebral level.