Editor's Choice-- A Systematic Review of Endovenous Stenting in Chronic Venous Disease Secondary to Iliac Vein Obstruction.

OBJECTIVES: Deep endovenous stenting to relieve chronic venous disease (CVD) secondary to post-thrombotic or non-thrombotic iliac vein obstruction is becoming increasingly well described. However, current and adequately reported systematic reviews on the topic are lacking. This report aimed to produce a systematic review and meta-analysis of the available data, reported to the Preferred Reporting Items for Systematic reviews and Meta-Analyses guideline. METHODS: MEDLINE, EMBASE, and the Cochrane Central Register for Controlled Trials databases and key references were searched. RESULTS: Sixteen studies were included (14 before-and-after studies, 1 controlled before-and-after study, and 1 case series) encompassing successful deep venous stenting in 2,373 and 2,586 post-thrombotic or non-thrombotic limbs and patients respectively. The data were too heterogeneous to perform a meta-analysis. There were significant improvements in validated measures of the severity of CVD and venous disease-specific quality of life. Persistent ulcer healing rates ranged from 56% to 100% in limbs that had often already failed conservative management. Primary and secondary stent patency ranged from 32% to 98.7% and 66%-96% respectively. The major complication rate ranged from 0 to 8.7% per stented limb. A GRADE assessment demonstrated the quality of the evidence for five outcomes to be "Very Low" and one to be "Low" (ulcer healing). CONCLUSIONS: The quality of evidence to support the use of deep venous stenting to treat obstructive CVD is currently weak. The treatment does however appear promising and is safe and should therefore be considered as a treatment option while the evidence base is improved.

X-linked dominant protoporphyria: a new porphyria.

X-linked dominant protoporphyria (XLDPP) was first reported in the genetics literature in 2008. It has a phenotype very similar to erythropoietic protoporphyria (EPP), but is distinguished from EPP by higher concentrations of erythrocyte protoporphyrin (of which a high proportion is zinc-chelated), its apparently higher incidence of liver disease, and an X-linked dominant pattern of inheritance. Dermatologists should understand how XLDPP differs from EPP, in order to advise newly diagnosed patients correctly about the genetic implications and the long-term management strategy. We present a case series of XLDPP to introduce this condition to the dermatology literature.

Shared medical appointments for bariatric surgery follow-up: a patient satisfaction questionnaire.

BACKGROUND: Shared medical appointments (SMAs) are group clinics where practitioners see several patients, with common health needs, at once. There is a great financial strain on the National Health Service (NHS) to provide bariatric surgery. The aim of this study was to review patient satisfaction with the SMA that is the default means of following up patients after bariatric surgery at one particular NHS trust. METHODS: A patient-validated questionnaire was designed and handed out at the end of the SMAs. Patients who attended an SMA earlier in 2011 were also retrospectively sent questionnaires via post. RESULTS: A total of 47 patients completed the questionnaire from seven different SMAs covering the period from January to July 2011. All patients underwent laparoscopic adjustable gastric banding. After attending an SMA, patients gave an overall mean satisfaction rating of 4.13 ± 0.163 (on a scale of 1 to 5, 1 = very poor and 5 = excellent) which represented an increase (p < 0.01) compared to preconceptions before the clinic (3.59 ± 0.175). A cost analysis estimated a yearly saving of £4,617 or 65.1% made by the SMAs compared to 1:1 appointments. CONCLUSIONS: The bariatric surgery SMA demonstrates high levels of patient satisfaction and is cost-effective.

Ovarian VEGF(165)b expression regulates follicular development, corpus luteum function and fertility.

Angiogenesis and vascular regression are critical for the female ovulatory cycle. They enable progression and regression of follicular development, and corpora lutea formation and regression. Angiogenesis in the ovary occurs under the control of the vascular endothelial growth factor-A (VEGFA) family of proteins, which are generated as both pro-(VEGF(165)) and anti(VEGF(165)b)-angiogenic isoforms by alternative splicing. To determine the role of the VEGF(165)b isoforms in the ovulatory cycle, we measured VEGF(165)b expression in marmoset ovaries by immunohistochemistry and ELISA, and used transgenic mice over-expressing VEGF(165)b in the ovary. VEGF(165)b was expressed in the marmoset ovaries in granulosa cells and theca, and the balance of VEGF(165)b:VEGF(165) was regulated during luteogenesis. Mice over-expressing VEGF(165)b in the ovary were less fertile than wild-type littermates, had reduced secondary and tertiary follicles after mating, increased atretic follicles, fewer corpora lutea and generated fewer embryos in the oviduct after mating, and these were more likely not to retain the corona radiata. These results indicate that the balance of VEGFA isoforms controls follicle progression and luteogenesis, and that control of isoform expression may regulate fertility in mammals, including in primates.

Identification of a mutation in synapsin I, a synaptic vesicle protein, in a family with epilepsy.

A four generation family is described in which some men of normal intelligence have epilepsy and others have various combinations of epilepsy, learning difficulties, macrocephaly, and aggressive behaviour. As the phenotype in this family is distinct from other X linked recessive disorders linkage studies were carried out. Linkage analysis was done using X chromosome microsatellite polymorphisms to define the interval containing the causative gene. Genes from within the region were considered possible candidates and one of these, SYN1, was screened for mutations by direct DNA sequencing of amplified products. Microsatellite analysis showed that the region between MAOB (Xp11.3) and DXS1275 (Xq12) segregated with the disease. Two point linkage analysis demonstrated linkage with DXS1039, lod score 4.06 at theta = 0, and DXS991, 3.63 at theta = 0. Candidate gene analysis led to identification of a nonsense mutation in the gene encoding synapsin I that was present in all affected family members and female carriers and was not present in 287 control chromosomes. Synapsin I is a synaptic vesicle associated protein involved in the regulation of synaptogenesis and neurotransmitter release. The SYN1 nonsense mutation that was identified is the likely cause of the phenotype in this family.

Hippocampal theta oscillations and classical conditioning.

Studies are reviewed that support a hypothesized role for hippocampal theta oscillations in the neural plasticity underlying behavioral learning. Begun in Richard F. Thompson's laboratory in the 1970s, these experiments have documented a relationship between free-running 3- to 7-Hz hippocampal slow waves (theta) and rates of acquisition in rabbit classical nictitating membrane (NM) conditioning. Lesion and drug manipulations of septohippocampal projections have affected NM and jaw movement conditioning in ways consistent with a theta-related brain state being an important modulator of behavioral acquisition. These findings provide essential empirical support for the recently developed neurobiological and computational models that posit an important role for rhythmic oscillations (such as theta) in cellular plasticity and behavioral learning.

Conditioning-specific reflex modification of the rabbit (Oryctolagus cuniculus) nictitating membrane response: generality and nature of the phenomenon.

Conditioning-specific reflex modification (CRM) occurs when classical conditioning modifies responding to an unconditioned stimulus in the absence of a conditioned stimulus. This form of reflex modification suggests that learning modifies the unconditioned reflex pathway. Rabbit (Oryctolagus cuniculus) nictitating membrane responses to 5 intensities and 3 durations of airpuff (AP) or periorbital electrical stimulation (ES) were monitored before and after conditioning. AP tests detected strong CRM after conditioning with ES and modest levels of CRM after conditioning with AP. After conditioning with AP, ES tests failed to detect CRM. After conditioning with a stronger AP, CRM was again detected by AP tests. CRM is a general phenomenon but is more readily detected after training with a relatively aversive stimulus; thus, it may be a function of level of arousal.

Medial septal microinfusion of scopolamine disrupts hippocampal activity and trace jaw movement conditioning.

This study investigated the effects of microinfusion of scopolamine into the medial septum (MS Scp) on hippocampal neurophysiology and learning of the rabbit's classically conditioned jaw movement response. The percentage of hippocampal theta slow waves (2-8 Hz) decreased after drug infusion in the MS Scp group but did not change in control groups that received infusion of saline into the MS or scopolamine into the cortex. Unit recordings from the MS Scp group showed significantly smaller conditioning-related hippocampal neural responses than seen in controls, and during conditioning, rabbits in the MS Scp group took significantly longer to reach learning criterion than either control group. Thus, the neural and behavioral impairments previously reported for systemic muscarinic blockade were reproduced by microinfusions restricted to the medial septal nucleus.

Scopolamine disruption of behavioral and hippocampal responses in appetitive trace classical conditioning.

Twelve young rabbits (3-6 months; Oryctolagus cuniculus) were classically conditioned in a trace jaw movement paradigm (300 ms tone, 450 ms trace, 200 ms intraoral water) after implantation of electrodes into area CA1 of dorsal hippocampus. Rabbits were divided into two groups and administered either 0.5 mg/kg scopolamine hydrobromide (HBr) or 0.5 mg/kg scopolamine methylbromide (MBr) subcutaneously before daily training sessions. Rabbits given HBr took significantly more trials to reach a behavioral criterion of eight conditioned responses in any nine consecutive trials than rabbits given MBr (P = 0.03). Conditioned, but not unconditioned, rhythmic jaw movement responses of the HBr group were of a lower frequency (Hz) than those of MBr rabbits (P = 0.02). The magnitude of hippocampal conditioning-related responses across the first 3 days of training was significantly smaller for HBr rabbits than for MBr rabbits (P = 0.02). These effects of central cholinergic blockade are similar to those reported for undrugged aging rabbits trained in the same paradigm (Seager MA, Borgnis RL, Berry SD. Neurobiol. Aging 1997;18(6):631 639).

Hippocampal age differences reoccur after modification of stimulus configurations in rabbit jaw movement conditioning.

Rabbits of two age groups, young (3-7 months; n = 7) and aging (40-49 months; n = 7), were implanted with chronic recording electrodes in area CA1 of dorsal hippocampus and trained in a delay conditioned jaw movement (CJM) paradigm (after previously reaching criterion in a trace CJM paradigm with the same conditioned stimulus and unconditioned stimulus). Unlike results from the trace experiment, there was no significant difference in trials to behavioral criterion between the two age groups. There were large, but temporary, differences in the magnitude of conditioning-related hippocampal neural responses early in delay training. Aging rabbits' hippocampal responses were significantly smaller on Day 2 of delay training than corresponding responses of young rabbits (p = 0.0008). It is important to note that neural differences were not observed on Days 1 and 3 of delay training or at criterion performance in the prior trace conditioning. These results are interpreted in terms of age-related differences in hippocampal responsiveness to changes in biologically significant stimulus configurations.

Delayed acquisition of behavioral and hippocampal responses during jaw movement conditioning in aging rabbits.

Young (3-7 months; n = 7) and aging (40-49 months; n = 7) rabbits (Oryctolagus cuniculus) were classically conditioned in a trace jaw movement paradigm (300 ms tone, 450 ms trace, 200 ms intraoral water) after implantation of electrodes into area CAI of dorsal hippocampus. Aging rabbits took significantly more trials to reach a behavioral criterion of 8 conditioned responses in any 9 consecutive trials than young rabbits (p = 0.04), and their conditioned, but not unconditioned, jaw movement responses were of a lower frequency than those of young rabbits (p = 0.02). Early in training, aging rabbits' hippocampal responses were significantly smaller just before water onset than corresponding responses of young rabbits (p = .03). The magnitude of this response was negatively correlated with trials to criterion (r = -0.60, p = 0.03). These results are interpreted in terms of age-related differences in the hippocampal contribution to jaw movement learning.

Reoperation for recurrent glioblastoma and anaplastic astrocytoma.

The advisability of a second operation for recurrent glioblastoma multiforme or anaplastic astrocytoma depends on the expected duration and quality of subsequent survival. We reviewed the results in 70 consecutive patients who underwent reoperation for supratentorial glioblastoma multiforme (n = 39) or anaplastic astrocytoma (n = 31) between 1975 and 1984. The operative morbidity rate was 5.7% (4 of 70 patients); the 6-week postoperative mortality rate was 4.3% (3 of 70 patients). The median duration of survival after reoperation was 36 weeks in patients with glioblastoma multiforme and 88 weeks in those with anaplastic astrocytoma. The median duration of high quality survival (defined as the period during which the patient had a Karnofsky performance score of at least 70) after reoperation was 10 weeks for patients with glioblastoma multiforme and 83 weeks for patients with anaplastic astrocytoma. Age and preoperative Karnofsky score in patients with glioblastoma multiforme and age in patients with anaplastic astrocytoma had statistically significant effects on the duration of high quality survival after reoperation, but not on postoperative survival independent of quality. Although age and functional status do not significantly affect the duration of survival after reoperation, they do have a significant effect on the quality of life after reoperation. Frequently, a patient can expect to spend a greater portion of his life at a higher level of function than he would have without reoperation. As adjunctive forms of therapy improve, reoperation will play an increasingly prominent role in the management of recurrent malignant astrocytic tumors.

Phase I-II study of eflornithine and mitoguazone combined in the treatment of recurrent primary brain tumors.

Eflornithine (DFMO), an irreversible inhibitor of ornithine decarboxylase, and mitoguazone (MGBG), a competitive inhibitor of S-adenosylmethionine decarboxylase, were evaluated in a phase I-II study for patients with primary recurrent malignant brain tumors. All patients had failed prior radiation therapy and most had also failed prior chemotherapy. Two dose schedules were used, with the second schedule (Group II) a modification of the first schedule (Group I). The Group II schedule, with different dose levels, was better tolerated than the Group I schedule. Gastrointestinal and myelotoxicity were dose-limiting in most patients, and tinnitus was dose-limiting in two patients. Nineteen of 33 evaluable patients had anaplastic gliomas, in whom response was observed in 21%, stable disease in 53%, and immediate progression after one course of therapy in 26%. Of six patients with glioblastoma multiforme, two had brief stabilization of disease. An additional patient with brainstem glioma and ependymoma also had disease stabilization. Four patients with medulloblastoma, a spinal cord mixed glioma, and one with oligodendroglioma failed DFMO-MGBG. Based on this study, we believe that a combination of DFMO and MGBG is well-tolerated and deserves further evaluation for patients with anaplastic gliomas, particularly those that appear to be biologically slow growing.

Phase II study of combined carmustine, 5-fluorouracil, hydroxyurea, and 6-mercaptopurine (BFHM) for the treatment of malignant gliomas.

The Neuro-oncology Service of the University of California Brain Tumor Research Center conducted a nonrandomized phase II study to evaluate, in patients with recurrent malignant glioma, the benefit of a four-drug combination (BFHM) consisting of carmustine (1,3-bis (2-chloroethyl)-1-nitrosourea), 5-fluorouracil, hydroxyurea, and 6-mercaptopurine. There were 29 evaluable glioblastoma multiforme patients and 45 nonglioblastoma anaplastic glioma patients available for analysis. Tumor progression was analyzed as the primary study endpoint. Of the glioblastoma patients, 16 of 29 (55%) responded or stabilized on therapy; of the other anaplastic gliomas, 32 of 45 (71%) responded or stabilized. For patients who stabilized or responded to treatment, BFHM achieved a median time to tumor progression of 46 weeks with a 25th percentile time to tumor progression of 68 weeks for anaplastic gliomas and a median time to tumor progression of 23 weeks with a 25th percentile time to tumor progression of 36 weeks for glioblastoma multiforme patients. A Cox multivariate analysis demonstrated that age and Karnofsky score were important prognostic variables for these patients.

Phase II evaluation of dibromodulcitol in the treatment of recurrent medulloblastoma, ependymoma, and malignant astrocytoma.

The authors have conducted a Phase II trial to evaluate orally administered dibromodulcitol in the treatment of 40 evaluable patients with recurrent medulloblastoma, ependymoma, and malignant astrocytoma. Ten of 20 patients harboring medulloblastoma responded to therapy with a median time to tumor progression (MTP) of 40 weeks, and four of 20 patients had no sign of progression of disease 4 years after treatment was begun. The MTP for all 12 patients with ependymoma was 30 weeks. Nine of these 12 patients had stabilization of their disease with an MTP of 67 weeks; three of these 12 patients had no signs of progression for 1 to 3 years after treatment was begun. Of six patients harboring supratentorial gliomas, none responded to dibromodulcitol. Two patients, one with a primitive neuroectodermal tumor and the other with a metastatic carcinoma of the breast, had stabilization of disease for more than 4 and 2 years, respectively.

Cardiac cell damage: a primary myocardial disease in streptozotocin-induced chronic diabetes.

Ultrastructural changes in heart muscle due to chronic diabetes subsequent to a single injection of streptozotocin (65 mg/kg body wt, i.v.) were studied in rats. Presence of diabetes was indicated by hyperglycaemia (plasma glucose, control, 120 +/- 7; diabetic, 448 +/- 21 mg/dl) as well as hypo-insulinaemia (plasma insulin, control, 25.6 +/- 5.2; diabetic, 11.2 +/- 0.5 microU/ml). After 8 weeks of diabetes, the hearts were processed for electron microscopic examination. Cardiac muscle cells in diabetic hearts showed condensation of nuclear chromatin and folding of nuclear membranes. Swelling of mitochondria, clearing of mitochondrial matrix and incorporation of lysosomal membranes into mitochondrial matrix was also noted. A marked increase in both lysosomes and lipid droplets was apparent. Focal areas in diabetic hearts showed contracted sarcomeres, myofibrillar degeneration and separation of the intercalated disc. Atherosclerotic plaque formation as well as structural changes in the smooth muscle or endothelial cells in the small arteries, arterioles or capillaries were not seen to accompany the structural changes in the cardiac muscle cells of the diabetic hearts. This study provides strong evidence for the occurrence of primary myocardial disease in streptozotocin-induced chronic diabetes.

Improvement in survival produced by sequential therapies in the treatment of recurrent medulloblastoma.

Thirty-six patients with recurrent medulloblastoma were treated with various combination chemotherapy protocols after initial treatment (usually irradiation) failed. Use of systemic chemotherapy was limited by depressed bone marrow reserves secondary to previous craniospinal irradiation. Intraventricular and intrathecal therapies included cytosine arabinoside (Ara-C), methotrexate, and thio-tepa given as single agents. Major systemic agents used alone or in combination included CCNU, procarbazine, vincristine, and the hexitol epoxides. Patients were reirradiated with or without misonidazole when there was definite tumor progression after all other therapies failed and/or because myelosuppression was so severe that further chemotherapy was not possible. Sequential systemic or intrathecal chemotherapy and reirradiation produced median survivals of two years and 25% quartile survivals of 2.9 years. The prognosis for patients harboring recurrent medulloblastoma has improved considerably over the years because of the therapeutic approaches reported here.