Claudins: unlocking the code to tight junction function during embryogenesis and in disease

Gupta IR, Ryan AK. Claudins: unlocking the code to tight junction function during embryogenesis and in disease. Claudins are the structural and molecular building blocks of tight junctions. Individual cells express more than one claudin family member, which suggests that a combinatorial claudin code that imparts flexibility and dynamic regulation of tight junction function could exist. Although we have learned much from manipulating claudin expression and function in cell lines, loss‐of‐function and gain‐of‐function experiments in animal model systems are essential for understanding how claudin‐based boundaries function in the context of a living embryo and/or tissue. These in vivo manipulations have pointed to roles for claudins in maintaining the epithelial integrity of cell layers, establishing micro‐environments and contributing to the overall shape of an embryo or tissue. In addition, loss‐of‐function mutations in combination with the characterization of mutations in human disease have demonstrated the importance of claudins in regulating paracellular transport of solutes and water during normal physiological states. In this review, we will discuss specific examples of in vivo studies that illustrate the function of claudin family members during development and in disease.     

Concomitant choroid plexus papillomas involving the third and fourth ventricles: A case report and review of the literature

Choroid plexus papillomas (CPP) are histopathologically benign and rare central nervous system (CNS) neoplasms arising from the epithelium of the choroid plexus. The most common site of presentation of these lesions is in the fourth ventricle in adults and lateral ventricles in children. Third ventricular CPP are uncommon. In this study, we present a case of a 66-year-old woman with complaints of progressive confusion, lethargy, and weakness who was found to have concomitant third and fourth ventricular masses on imaging studies. The patient underwent a biopsy of the third ventricular mass. The biopsy was followed by staged resections of the fourth and third ventricular masses, respectively. Pathology from the biopsy and both resections was benign CPP. Multifocal concomitant CPP is rare. Concomitant CPPs may be secondary to mere coincidental tumor occurrence or to biologic seeding of cerebrospinal fluid (CSF) from a primary CPP despite otherwise benign histopathology. The primary treatment for CPP is surgical resection. Post-operative chemotherapy or radiation for CPP is of controversial benefit.     

Survival trends in elderly patients with glioblastoma multiforme: resective surgery, radiation, and chemotherapy

BACKGROUND: It is appropriate to investigate and to determine survival trends following glioblastoma multiforme treatment using resective surgery, radiation therapy, and/or chemotherapy in patients aged 59 years and higher. METHODS: We retrospectively reviewed 30 elderly patients (> or =59 years old) who were treated for histopathologically confirmed glioblastoma multiforme at our tertiary care institution from 1990 through 2002. All patients were treated with steroids. In addition, 22 patients underwent resective surgery (RS), 17 patients underwent radiation therapy (RT), and 10 patients underwent chemotherapy (C). Many patients underwent these treatments in various combinations: 6 underwent biopsy only, 7 RS only, 6 RS+RT only, and 9 RS+RT+C. For each case, pre-treatment Karnofsky performance scores (KPS), tumor location, presenting symptoms and signs, associated surgical morbidity, and pre-existing medical conditions were also recorded. Patients were categorized into one of four treatment subgroups: Biopsy only, RS only, RS+RT, and RT+RS+C. For each of these subgroups, pretreatment KPS and post-treatment survival were compared. RESULTS: Post-treatment survival following biopsy only was 3.2 +/- 0.8 months (mean +/- SE); RS 2.2 +/- 0.5; RS+RT 5.5 +/- 1.2; RS+RT+C 13.6 +/- 2.1. A longer survival trend was noted for the RS+RT versus RS group (two-tailed unpaired t test, p = 0.02;), as well as the RS+RT+C group, which showed consistently higher survival in comparison to most of the other groups (p = 0.0021, 0.00039, 0.013 vs. the biopsy only, RS only, and RS+RT groups, respectively). No significant difference was found in KPS, comparing all individual groups versus each other (p > or = 0.06). Remarkably, 6 patients survived over 14 months (range, 14.1-22.7 months), all of which received RS+RT+C. CONCLUSIONS: This study suggests a significant improvement in elderly patients treated with the combination of resective surgery, radiation therapy, and chemotherapy, rather than either treatment alone or other combination. This significant improvement does not appear to be biased by pretreatment KPS, as mean KPS values did not significantly differ between any of these groups. However, a greater number of patients in each group must be considered to achieve the power to make more definitive treatment guidelines.     

Influence of diets containing high and low risk factors for colon cancer on early stages of carcinogenesis in human flora-associated (HFA) rats

Germ-free rats colonised with a human intestinal flora were fed diets containing high risk (HR) or low risk (LR) factors for colorectal cancer, and putative biomarkers were evaluated in the colonic mucosa; (i) proliferation, (ii) 1,2-dimethylhydrazine (DMH)-induced aberrant crypt foci and (iii) DMH-induced DNA damage. The HR diet was high in fat (45% of calories) and low in calcium and fibre, reflecting levels characteristic of typical western diets. The LR diet was low in fat (<5% of calories), and high in calcium and fibre. The nutrient/energy ratio of the two diets were similar. Mucosal crypt cell proliferation, assessed after microdissection, was higher on the LR diet (mean number of mitoses per crypt was 2.65 on the LR diet, and 1.62 on the HR diet; P < 0.05). Aberrant crypt foci (ACF) were assessed in the mucosa 12 weeks after DMH treatment. On the HR diet there were significantly more small ACF with 1 and 2 crypts per focus, but fewer ACF with 3, 5 and 7 or more crypts per focus. There was no significant difference in total ACF or the total number of crypts. The effect of diet on DNA damage in the colon was assessed in vivo by the comet assay. Animals were fed a HR or LR diet for 12 weeks before treatment with DMH or saline. For carcinogen-treated animals, DNA damage was significantly higher in colon cells from animals on the HR diet. On the LR diet both DNA damage and the induction of small ACF were reduced despite an increase in cell proliferation. The increase in large ACF on the LR diet may be attributable to elevated crypt cell proliferation possibly increasing crypt fission rates.      

Acoustic neuromas: Gd-DTPA enhancement in MR imaging

Magnetic resonance (MR) imaging examinations were performed in ten patients with 12 acoustic neuromas before and after intravenous administration of 0.1 mmol/kg body weight gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA). The degree of enhancement was greatest with the inversion recovery sequence 1,500/500/44 (repetition time [TR]/inversion time/echo delay time [TE]), followed by spin-echo (SE) 544/44 (TR/TE) sequences, then by SE 1,500/44 and SE 1,500/80 sequences. After enhancement there was a 50% reduction for measured T1 values, 33% for T2, and no significant change for proton density. There were no toxic effects on patients. Enhanced CT scans failed to demonstrate lesions in six of 12 cases. Air-CT technique improved sensitivity in four of five cases. Enhanced MR imaging added significant clinical information in two small intracanalicular tumors and in one recurrent tumor.     

Laparoscopic dismembered pyeloplasty in children

PURPOSE: Ureteropelvic junction obstruction remains the most common obstructive uropathy in children. Although laparoscopic dismembered pyeloplasty was described in a child in 1993, there have been few reports of laparoscopic Anderson-Hynes dismembered pyeloplasty in children. We report on a series of children who underwent laparoscopic Anderson-Hynes dismembered pyeloplasty. MATERIALS AND METHODS: The diagnosis of ureteropelvic junction obstruction was firmly established in all patients based on history, clinical examination, renal sonography and scintigraphy. Laparoscopic Anderson-Hynes pyeloplasty was performed using either 3 or 4 ports. Children were followed for urinary tract infection, and renogram was repeated at 3 months. RESULTS: A total of 16 children 5 months to 11 years old underwent laparoscopic Anderson-Hynes pyeloplasty between July 2002 and December 2003. No major intraoperative or postoperative complications were noted. One child with horseshoe kidney had development of fever and tenderness on the operated side on postoperative day 4. A percutaneous nephrostomy tube was placed and was removed 2 weeks later. CONCLUSIONS: Laparoscopic Anderson-Hynes pyeloplasty in children is too new to assess long-term outcome adequately. However, our study reveals improved outcome in the short term in the form of improved hydronephrosis and improved glomerular filtration rate on renal scan, and resolution of symptoms in all children.     

Intracranial fungal granuloma: analysis of 40 patients and review of the literature

OBJECTIVE: To describe the characteristics of patients diagnosed with intracranial fungal granuloma (IFG) in the largest reported series to date (to our knowledge). METHODS: A 22-year retrospective, multi-institutional review of 40 patients, aged 16 to 62 years (mean, 40.2 years), was performed in patients with histopathologically confirmed IFG. The variables were symptoms/signs at presentation, predisposing factors, location of granuloma, involvement of paranasal sinuses, diagnostic studies including blood and urine cultures, surgical procedures performed, specific organism identified, treatment, and prognosis. Plain x-rays, computed tomography, and/or magnetic resonance imaging scans were performed. RESULTS: Predominant symptoms included headache (83%), vomiting (65%), proptosis (48%), and visual disturbances (48%). Other symptoms were fever, nasal congestion, and seizures (7 [18%]). Common signs included papilledema (12 [30%]), with cranial neuropathy (I, III/IV/VI, and V in 4, 7, and 2 patients, respectively), hemiparesis (3), and meningismus (3). Predisposing factors were diabetes (16 [40%]), tuberculosis (7 [18%]), and immunocompromise related to renal transplant (2), non-Hodgkin's lymphoma (1), and human immunodeficiency virus (1). Location was primarily frontal (10 [25%]), with anterior cranial fossa involved in 8 (20%) patients; 6 (15%) patients had sellar/parasellar involvement. Eighteen (40%) had paranasal sinus involvement. Twenty-nine patients underwent craniotomy for resection, with 11 undergoing biopsy (of which 3 were transsphenoidally approached). Histopathology revealed aspergilloma (25 [63%]), mucormycosis (7 [18%]), cryptococcoma (3), cladosporidium (3), Bipolaris hawaiiensis (1), and Candida species(1). Microbiological analysis of the specimen was positive in 28 (60%) patients. All patients were treated with amphotericin B, fluconazole, and/or flucytosine. Only 26 patients completed amphotericin B therapy (due to nephrotoxicity). Mortality was 63%, most commonly due to meningoencephalitis (16 [36%]). CONCLUSIONS: High index of suspicion of IFG should exist for the following groups: (1) immunocompromised patients with intracranial lesions and (2) diabetic patients with intracranial and rhinocerebral mass lesions. Early diagnosis, surgical decompression, and a complete course of promptly initiated antifungal therapy are associated with better prognosis.     

Ninth cranial nerve stimulation for epilepsy control. Part 1: efficacy in an animal model

OBJECTIVE: To characterize the effects of stimulation of the nerve of Hering (HN; cranial nerve nine) in controlling seizure activity using a canine model. METHODS: Using penicillin applied topically to a region of the cerebral cortex, 16 seizure-type continuous epileptiform discharges were generated. Ten specimens of HN (five left-sided and five right-sided) were dissected from the cervical region in five dogs and stimulated at varying parameters to determine the effects in controlling epileptiform activity. Electroencephalography (using a multielectrode array), electrocardiography and other vital signs were continuously monitored for side effects. RESULTS: Resolution of continuous epileptiform activity following stimulation was found in 12 of 16 trials (75%); no spontaneous resolution was noted in the absence of stimulation, and stimulation significantly shortened seizure duration (p < 0.05). Mean epileptiform activity duration was 139 s prior to stimulation (range 1-432 s), with a mean poststimulation delay of 17 s until resolution and a mean interictal time of 399 s. Two specimens became free of seizure activity for the duration of our study (p < 0.001). No significant side effects (such as the potentially life-threatening cardiac problems seen with right-sided cervical vagal nerve stimulation) were found with stimulation of either left- or right-sided HN. Stimulation of other regional nerves (e.g. twelfth cranial nerve, nerves of the cervical plexus) failed to yield similar control of epileptiform activity. CONCLUSIONS: The results of this pilot study suggest that stimulation of the HN can successfully control focal seizure activity in the majority of cases. Pending further study, stimulation of the HN may have a role in the management of patients suffering from medically and otherwise surgically refractory epilepsy.