Effects of temporal lobe epilepsy on retrograde memory

PURPOSE: In a previous investigation (Lah et al., 2004), we found deficits in retrograde memory in patients who had undergone temporal lobectomy (TL). In this study, we set out to determine whether such deficits are present before surgery in patients with temporal lobe epilepsy (TLE). METHODS: Memory for public and autobiographic facts and events was assessed in patients with focal left-sided (n=15) or right-sided (n=14) TLE and healthy control subjects (n=15). The impact of epilepsy and underlying cognitive deficits on retrograde memory also was examined. RESULTS: Patients with left TLE demonstrated retrograde memory deficits across domains. Patients with right TLE showed defective recall only in the autobiographic domain. Young age at onset (younger than 14 years) was associated with greater difficulties in recall of famous events, and patients receiving polytherapy had significantly reduced recall of autobiographic events compared with those receiving monotherapy. In most cases, deficient memory for the past was associated with impairments in other cognitive skills, especially language abilities. CONCLUSIONS: In unoperated-on patients with TLE, we found deficits in retrograde memory that were similar to those seen after TL, with the pattern of deficits being influenced by side of lesion, anticonvulsant medication, and word-finding deficits. Unlike patients tested after right TL, patients with right TLE did not have difficulty recalling details of famous events, which raises the possibility that right TL results in a decline in this aspect of retrograde memory.     

Longitudinal evaluation of the concordance and prognostic value of lymphovascular invasion in transurethral resection and radical cystectomy specimens

THIS IS A COMMENT MODERATED PAPER
available at http://www.bjui.org/commentary Study Type – Therapy (case series)
Level of Evidence 4 What’s known on the subject? and What does the study add? Lymphovascular invasion (LVI) is a prognostic marker for biologically aggressive disease in numerous tumour types. Indeed, numerous studies have documented the negative prognostic value of LVI in bladder cancer patients who have undergone radical cystectomy, however few studies have evaluated the prognostic value of LVI at TURBT. The current study examines both the concordance between the presence of LVI at TURBT and radical cystectomy specimens and furthermore examines the survival implications of the presence of LVI at both TURBT and radical cystectomy.

OBJECTIVE

To evaluate the concordance transurethral resection of bladder tumour (TURBT) and radical cystectomy (RC) specimens with regard to the presence of lymphovascular invasion (LVI). Additionally, to evaluate the prognostic value of LVI in the prediction of lymph node metastases, overall survival, disease‐specific survival and recurrence‐free survival following RC.

PATIENTS AND METHODS

The records of 487 patients who underwent RC at our institution between 1987 and 2008 were retrospectively reviewed and evaluated for the presence or absence of LVI as determined by pathological evaluation. The presence or absence of LVI was then evaluated on previous transrectal resection specimens of this cohort of patients undergoing RC. Cox regression and Kaplan–Meier analysis were undertaken to evaluate the contribution of LVI to various outcomes.

RESULTS

Of 474 patients with complete LVI data, 60 (12.3%) were found to have LVI at TURBT compared to 161 (33.1%) at RC. Although the presence of LVI at TURBT was more significantly associated with the presence of LVI at RC, only 42.9% of patients in whom LVI was documented at TURBT were found to harbour LVI at RC. The risk of nodal disease was higher in those patients with LVI at TURBT than in those with no evidence of LVI at TURBT (48.3% vs 25.0%, P < 0.001). Additionally, LVI at TURBT was associated with an increasing risk of pathological upstaging and the receipt of adjuvant chemotherapy. Survival analysis showed a significant decrement in overall and recurrence‐free survival among those with LVI at TURBT compared to those with no evidence of LVI.

CONCLUSIONS

Lymphovascular invasion at TURBT provides useful prognostic information that should be incorporated into clinical decision‐making, particularly with regard to cystectomy for nonmuscle‐invasive carcinoma and the administration of neoadjuvant chemotherapy.     

Are Tri‐Ethnic Low‐Income Women with Breast Cancer Effective Teachers of the Importance of Breast Cancer Screening to Their First‐Degree Relatives? Results from a Randomized Clinical Trial

The purpose of this study was to determine the efficacy of women with breast cancer as teachers of the importance of breast cancer screening to their first-degree female relatives. The sample was restricted to low-income working age women recruited from four hospitals. The study design was a randomized clinical trial. At each hospital, breast cancer patients (probands) were randomized into one of two study groups: (i) intensive, individual educational training on breast cancer screening or (ii) standard clinic education on breast cancer screening. The probands were instructed to teach at least one of their first-degree female relatives (21+ years of age) about breast cancer screening techniques. Three to six months after the enrollment of the probands, their relatives were contacted by telephone to determine breast cancer screening practices. A total of 79 probands and 96 relatives participated in the study. Relatives in the education group when compared with the control group were: 1.25 times more likely to have clinical breast examination (p = 0.005), 2.83 times more likely to have scheduled a clinical breast examination (p = 0.046), and, 1.36 times more likely to have been told about performing breast self-examination (p = 0.05). Additionally, relatives in the education group were more likely to have received a pamphlet on breast cancer screening (RR = 1.58, p = 0.009) and have discussed the importance of breast cancer screening (RR = 1.33, p = 0.020) from the proband. Special education training did not impact mammography utilization of the relatives. From these findings, a tri-ethnic group of low-income women with breast cancer can be effective teachers of breast cancer screening practices, at least for promoting clinical breast examination and transmitting messaging for performance of breast self-examination if given the adequate training.     

Human idiopathic and neurogenic overactive bladders and the role of M2 muscarinic receptors in contraction

OBJECTIVES: This study examines whether M(2) receptors contribute to direct contraction of the detrusor in human neurogenic and idiopathic overactive bladders. METHODS: Control detrusor muscle was obtained from patients undergoing cystectomy for bladder cancer, whilst overactive detrusor muscle was obtained from patients undergoing clam cystoplasty for idiopathic or neurogenic detrusor overactivity. The affinities of a range of subtype selective antagonists (DAMP, darifenacin, methoctramine R0-320-6206, and pirenzepine) were obtained in tissue bath experiments by using carbachol as the agonist. These affinity values were then compared with the known affinities for these antagonists at the muscarinic receptor subtypes. RESULTS: An increased sensitivity to carbachol was observed in both the neurogenic and idiopathic overactive detrusors compared with the control human detrusor. The M(2)-selective antagonists (methoctramine, R0-320-6206) and M(1)-selective antagonist (pirenzepine) had low affinities, whilst the M(3)-selective antagonists (4-DAMP and darifenacin) had high affinities for the human detrusor muscarinic receptor in all three groups of tissues. The affinities (pK(B) values) for the five antagonists were consistent with antagonisms at the M(3) receptor in all three groups; Schild plot analysis indicated an action at this single receptor subtype. CONCLUSIONS: Contraction mediated by muscarinic receptors is enhanced in idiopathic and neurogenic overactive detrusors compared with control detrusor. The direct contractile response to carbachol is mediated by the M(3) receptor in both human normal and overactive bladders, indicating no change in receptor subtype contribution to contraction in the disease state.     

Smaller Hip Circumference is Associated with Dyslipidemia and the Metabolic Syndrome in Obese Women

BACKGROUND: There is great need for simple anthropometric measures that predict risk. The authors explored the relationship between body composition measures and features of the metabolic syndrome (MtS) in women aged between 20 and 50 years with class I obesity. METHODS:This is a cross-sectional study of 49 obese (BMI 30-35) women recruited into a weight management randomized trial. An analysis was conducted of the baseline weight, anthropometric measures, skin-fold thickness, bioelectrical impedance, whole body dual-energy x-ray absorptiometry (DEXA), and their relationships with the features of the MtS. RESULTS: All women but one (n=48) had a population risk waist circumference of >88 cm. 16 of the 49 (33%) fulfilled the criteria of the metabolic syndrome. Simple anthropometric measures provided the strongest correlations with the presence of the MtS. Cut-off values were selected using receiver operator characteristics. Waist circumference of >100 cm and hip circumference <115cm was associated with odds ratios of 5.2 (95% CI, 1.4-20) and 12.3 (95% CI, 3.0-51) respectively for the MtS. Regional DEXA analysis showed that lower leg fat mass rather than fat-free mass was associated with the MtS. The dyslipidemia of the MtS was associated with a lower leg fat mass, while higher HbAlc levels and HOMA, an indirect measure of insulin resistance, were seen with increased trunk fat. Percentage fat as measured by skin-fold thickness and bioelectrical impedance were not related to any features. Women with the metabolic syndrome were found to have lower bone mineral content as measured by DEXA. CONCLUSION: Weight distribution is highly predictive of metabolic risk. Smaller hip and larger waist circumference provided independent effect. BMI adjusted anthropometric measures may be of value.     

Prenatally-counseled congenital diaphragmatic hernia parents exhibit positive well-being before and after surgical repair

Background/Purpose

The purpose of this paper was to examine the effect of prenatal counseling in the Advanced Fetal Care Center (AFCC) on the well-being of parents of infants with congenital diaphragmatic hernia (CDH).

Methods

From 2008 through 2012, 26 mothers and fathers of surgically repaired CDH patients who received prenatal counseling at our institution, and 15 who received no prenatal counseling, each completed the Short-Form 36 version 1 (SF-36v1) at the appropriate time points: prenatal, two weeks, and six months post-surgery.

Results

Parents in both groups did not differ by demographic characteristics. Patients who received prenatal counseling had significantly longer ventilatory time and length of stay (LOS) in the ICU and in the hospital compared to those who did not receive prenatal counseling (all P < .01). Mothers and fathers had similar SF-36v1 mental and physical component summary (MCS, PCS) post-surgery scores when compared by counseling status. Prenatal MCS scores for mothers and fathers (47 vs. 41; P = .24) were similar to those at six months post-surgery (47 vs. 47; P = .90).

Conclusions

When hospital LOS was controlled between groups stratified by AFCC counseling status, MCS scores were comparable prenatally and were sustained at six months post-surgery for both parents. These findings may reflect the support services parents received beginning in the prenatal period.     

Reinterpretation of cross-sectional images in patients with head and neck cancer in the setting of a multidisciplinary cancer center

BACKGROUND AND PURPOSE: Patients referred to tertiary care centers frequently arrive with images obtained at outside institutions; these images require reinterpretation. We assessed the clinical value of reinterpreting cross-sectional imaging studies of patients with head and neck cancer, in the setting of a multidisciplinary cancer center. METHODS: Outside CT and MR images of 136 patients with known or presumed head and neck cancer were reinterpreted by a neuroradiologist. Clinical history and findings on physical examination were available. Reinterpretation was performed before review of outside reports, which were subsequently compared with those generated at the cancer center. Changes in interpretation were noted, and their effects on TNM staging, patient care, and prognosis were assessed. Reliability and statistical significance of rates of change in diagnosis were analyzed with 95% confidence intervals (CIs) and the sign test, respectively. Verification of change in diagnosis was confirmed by pathologic analysis (75%), characteristic radiologic findings (18%), or clinical and imaging follow-up (7%). RESULTS: Change in interpretation occurred in 56 patients (41%) (95% CI: 33-49%, P <.001). Forty-six patients (34%) had a change in T, N, and/or M staging (26-42%, P <.001). Change in T stage occurred in 27 cases (20%) (13-27%, P <.001) (upstaged in 22, downstaged in five), and a change in N stage in 26 cases (19%) (12-26%, P <.001) (upstaged in 20, downstaged in six). Two patients (1.5%) had missed systemic metastases. Three patients with an initial diagnosis of cancer were found to be cancer-free, and six patients had a diagnosis of new second primary cancers that were missed at original interpretation. One patient had a missed middle cerebral artery aneurysm. Changes in image interpretation altered treatment in 55 (98%) of 56 patients and affected prognosis in 53 patients (95%) (P <.001). CONCLUSION: Reinterpretation of cross-sectional images in the setting of a multidisciplinary cancer center has a significant effect on staging, management, and prognosis in patients with head and neck cancer.     

A recombinant human glucagon-like peptide (GLP)-1-albumin protein (albugon) mimics peptidergic activation of GLP-1 receptor-dependent pathways coupled with satiety, gastrointestinal motility, and glucose homeostasis

Peptide hormones exert unique actions via specific G protein-coupled receptors; however, the therapeutic potential of regulatory peptides is frequently compromised by rapid enzymatic inactivation and clearance from the circulation. In contrast, recombinant or covalent coupling of smaller peptides to serum albumin represents an emerging strategy for extending the circulating t(1/2) of the target peptide. However, whether larger peptide-albumin derivatives will exhibit the full spectrum of biological activities encompassed by the native peptide remains to be demonstrated. We report that Albugon, a human glucagon-like peptide (GLP)-1-albumin recombinant protein, activates GLP-1 receptor (GLP-1R)-dependent cAMP formation in BHK-GLP-1R cells, albeit with a reduced half-maximal concentration (EC(50)) (0.2 vs. 20 nmol/l) relative to the GLP-1R agonist exendin-4. Albugon decreased glycemic excursion and stimulated insulin secretion in wild-type but not GLP-1R(-/-) mice and reduced food intake after both intracerebroventricular and intraperitoneal administration. Moreover, intraperitoneal injection of Albugon inhibited gastric emptying and activated c-FOS expression in the area postrema, the nucleus of the solitary tract, the central nucleus of the amygdala, the parabrachial, and the paraventricular nuclei. These findings illustrate that peripheral administration of a larger peptide-albumin recombinant protein mimics GLP-1R-dependent activation of central and peripheral pathways regulating energy intake and glucose homeostasis in vivo.     

Exercise Alleviates Lipid-Induced Insulin Resistance in Human Skeletal Muscle–Signaling Interaction at the Level of TBC1 Domain Family Member 4

Excess lipid availability causes insulin resistance. We examined the effect of acute exercise on lipid-induced insulin resistance and TBC1 domain family member 1/4 (TBCD1/4)-related signaling in skeletal muscle. In eight healthy young male subjects, 1 h of one-legged knee-extensor exercise was followed by 7 h of saline or intralipid infusion. During the last 2 h, a hyperinsulinemic-euglycemic clamp was performed. Femoral catheterization and analysis of biopsy specimens enabled measurements of leg substrate balance and muscle signaling. Each subject underwent two experimental trials, differing only by saline or intralipid infusion. Glucose infusion rate and leg glucose uptake was decreased by intralipid. Insulin-stimulated glucose uptake was higher in the prior exercised leg in the saline and the lipid trials. In the lipid trial, prior exercise normalized insulin-stimulated glucose uptake to the level observed in the resting control leg in the saline trial. Insulin increased phosphorylation of TBC1D1/4. Whereas prior exercise enhanced TBC1D4 phosphorylation on all investigated sites compared with the rested leg, intralipid impaired TBC1D4 S341 phosphorylation compared with the control trial. Intralipid enhanced pyruvate dehydrogenase (PDH) phosphorylation and lactate release. Prior exercise led to higher PDH phosphorylation and activation of glycogen synthase compared with resting control. In conclusion, lipid-induced insulin resistance in skeletal muscle was associated with impaired TBC1D4 S341 and elevated PDH phosphorylation. The prophylactic effect of exercise on lipid-induced insulin resistance may involve augmented TBC1D4 signaling and glycogen synthase activation.Studies in human and rodent models have revealed deleterious effects of excess lipid availability on peripheral insulin sensitivity (1,2). Intracellular increases in fatty acid metabolites, such as diacylglycerol (DAG) and ceramide, may play critical roles in mediating lipid-induced insulin resistance by inducing serine phosphorylation of insulin-receptor substrate 1 (IRS-1) (3–6) and consequently inhibiting downstream signaling to GLUT4 translocation. However, recent reports challenge such causality. These studies revealed unaltered signal transduction at the level of IRS-1, IRS-1–associated phosphatidylinositol-3-kinase (PI3K) activity, Akt, and TBC1 domain family member 4 (TBC1D4) phosphorylation (phospho-Akt-substrate [PAS] an unspecific antibody recognizing phosphorylated Akt substrate motifs), after 2–7 h of lipid infusion (7–11). When DAG and/or ceramide levels were reported, no changes in skeletal muscle DAG or ceramide levels were found after lipid infusion (7,11).We recently showed that lactate release in human skeletal muscle is augmented along with reduced respiratory exchange ratio (RER) values during lipid infusion (11). This could indicate suppressed activity of the pyruvate dehydrogenase (PDH) complex, which in turn could lead to a reduction in glucose uptake according to the Randle cycle (12). Here, we wished to investigate whether this increase in leg lactate release and reduced RER values were accompanied by altered regulation of PDH, measured by site-specific phosphorylation.Exercise increases peripheral insulin sensitivity (13–15). After an acute bout of exercise, the ability for insulin to stimulate glucose uptake in skeletal muscle is increased several hours into recovery (14,16). This effect can be ascribed to adaptations in the exercised muscle rather than changes in systemic factors (13,17,18) and is observed in both healthy and insulin-resistant states (e.g., obesity) (19) and type 2 diabetes (20). A recent study has shown that a single bout of exercise can prevent subsequent lipid-induced impairments in whole-body glucose tolerance assessed by an intravenous glucose tolerance test (IVGTT) (2). It was hypothesized that repartitioning fatty acids toward intramuscular triacylglycerol (IMTG) synthesis and storage rather than DAG or ceramide might be a primary mediator of the beneficial effects of exercise on lipid-induced impairments in glucose tolerance (2). Enhanced insulin sensitivity after a bout of exercise is associated with increased GLUT4 recruitment to the plasma membrane (21) and not with altered protein synthesis (e.g., GLUT4 protein) (22), but has not been associated with altered signal transduction through the insulin receptor, IRS-1, PI3K, or Akt (13,22,23). Recently, the hypothesis was put forward (24) that the guanosine triphosphatase (GTPase) activating proteins TBC1 domain family member 1 (TBC1D1) and 4 (TBC1D4) might serve as points of convergence for insulin dependent and independent signaling pathways to GLUT4 translocation. In agreement with this hypothesis, PAS phosphorylation of TBC1D4 is elevated along with insulin-stimulated glucose uptake for up to 27 h after exercise in skeletal muscle of rats (25), and we recently showed that phosphorylation of TBC1D4 on specific residues was elevated 4 h after a single bout of exercise in human skeletal muscle (26).TBC1D4/D1 are multikinase substrates proposed to be involved in contraction- and insulin-stimulated glucose uptake in mice (27,28), and exercise and insulin both substantially increase TBC1D4/D1 phosphorylation in human skeletal muscle (29,30). TBC1D4/D1 contain several phosphorylation sites distinctly phosphorylated by various kinases, including Akt and 5′AMP-activated protein kinase (AMPK) (28,31–33). Phosphorylation of TBC1D4/D1 and subsequent 14-3-3 binding is proposed to lead to inactivation of the GTPase-activating proteins, decreasing their inhibitory function on the GLUT4 translocation process and thus, potentially, increasing the GLUT4 capacity of the surface membrane.In the current study we tested the hypothesis that prior exercise prevents subsequent lipid-induced insulin resistance in human skeletal muscle through regulation of the signaling molecules TBC1D4/TBC1D1.