Subject Index to Volume 3

By monodimensional thin-layer electrophoresis on 5 X 10-cm cellulose layers o-aminolevulinic acid (oAL) is rapidly separated from interfering substances. Detection with a cupric nitrate-Ninhydrin sequence adds specificity and permits detection of as little as 10 ng/lLl of urine. Confirmation can be obtained on two-dimensional chromatograms (5 X 5 em) with the use of either Ninhydrin or a modified MauzeraUasGranick reagent for detection. The quantity of (’)Al can be estimated by visual or densitometric comparison with standards. The method is rapid and inexpensive and is suggested for use in conjunction with the more expensive column chromatographic technique.     

Swedish Norms for the Harvard Group Scale of Hypnotic Susceptibility,Form A

This article examines the norms for a Swedish adaptation of the Harvard Group Scale of Hypnotic Susceptibility, Form A (HGSHS:A) (Shor & Orne, 1962). In total, 291 subjects (199 females and 92 males) participated in the study. Comparisons are made between the Swedish sample and reference samples,which include English versions of the HGSHS:A from the United States and Australia, as well as 5 translated versions from Italy, Finland, Denmark, Spain, and Germany. In the Swedish sample, females scored significantly higher than males. Generally, however, the normative data from the Swedish sample are congruent with the reference samples and therefore can be used as a tool for initial screening of hypnotic susceptibility in Sweden.     

Changes in sense of coherence in old age – a 5‐year follow‐up of the Umeå 85+ study

Scand J Caring Sci; 2013; 27; 13–19 Changes in sense of coherence in old age – a 5‐year follow‐up of the Umeå 85+ study Objective: This study aims to describe the changes in sense of coherence (SOC) over time and relate these changes to negative life events among very old people. Design: Prospective and longitudinal study. Subjects: 190 old women and men participated, of whom 56 could be included in the 5‐year follow‐up. Methods: The mean SOC score from the first and second data collection were compared using a paired sample t‐test. The relationship between the index of negative life events and the changes on SOC score between the two data collections was investigate using linear regression. Main outcome measures: Antonovsky’s SOC scale and an index of negative life events including severe physical and mental diseases, various losses as losses of spouses, cognitive and functional ability. Result: For the whole group of subjects (n = 56), the SOC scores was higher (70.1 vs. 73.7, p = 0.029) at the second point measure. The most common negative life events at follow‐up were loss of independence in activities in daily living and decrease in cognitive function. A significant correlation between the index of negative life events and changes in SOC over 5 years was found (p = 0.025). The more negative life events, the more decrease in SOC. Conclusion: We concluded that there is a risk of decreased SOC and thereby quality of life when negative life events accumulate among very old people. Nursing interventions might play an important role for maintaining and perhaps strengthening SOC among old people exposed to negative life events.     

Cerebrospinal Fluid Density Influences Extent of Plain Bupivacaine Spinal Anesthesia

Background: The attempts to explain the unpredictability of extent of spinal block provided by plain local anesthetic solutions have resulted in many clinical reports; however, causes of this uncertainty are as yet unknown. Recently, normal values of the human cerebrospinal fluid densities have been studied showing important interindividual variations, especially between females and males. The current study was designed to evaluate as primary endpoint the influence of cerebrospinal fluid density values on the extent of spinal block with plain bupivacaine. The ancillary endpoints were search of factors explaining the interindividual differences in cerebrospinal fluid density values reported and determination of the relation between upper extent and regression of spinal anesthesia.

Methods: Sixty-four consecutive patients undergoing peripheral orthopedic surgery with spinal block were enrolled. Spinal anesthesia was performed in the lateral decubitus position with the operated side upward. Two milliliters of cerebrospinal fluid was sampled before injection of 3 ml plain bupivacaine 0.5%. The patient was immediately turned supine and remained in the horizontal position until the end of the study. Maximal sensory block level and time to sensory regression to L4 were determined for each patient enrolled. Cerebrospinal fluid and bupivacaine densities as well as cerebrospinal proteins, glucose, sodium, and chloride concentrations were measured.

Results: A highly significant correlation between cerebrospinal fluid density and maximal sensory block level was found (P = 0.0004). However, this correlation was poorly predictive (R2 = 0.37). Cerebrospinal fluid density, proteins, and glucose concentrations were significantly higher in men than in women: 1.000567 +/- 0.000091 versus 1.000501 +/- 0.000109 g/ml (P = 0.014), 0.46 +/- 0.18 versus 0.32 +/- 0.13 g/l (P = 0.001), and 3.27 +/- 0.7 versus 2.93 +/- 0.5 mm (P = 0.023), respectively. A highly significant (P = 0.0004) and predictive (R2 = 0.73) inverse correlation was found between maximal upper sensory extent and sensory regression to L4.     

Solitary fibrous tumors of the pleura: clinical characteristics, surgical treatment and outcome

Objective: The aim of this paper is to study clinical characteristics, surgical treatment and outcome of patients with solitary fibrous tumor of the pleura operated in our institutions in a 20-year period. Methods: Clinical records of all patients operated for solitary fibrous tumors of the pleura between 1981 and 2000 were reviewed retrospectively. Tumors were classified as malignant in the presence of at least one of the following criteria: (1) high mitotic activity; (2) high cellularity with crowding and overlapping of nuclei; (3) presence of necrosis; (4) pleomorphism; otherwise they were considered as benign. Results: Sixty patients (mean age 55 years) were operated in this period. None had asbestos exposure. Symptoms were present in 31 cases. Surgical approaches included thoracotomy (n=53), video-assisted thoracoscopy (n=6), and median sternotomy (n=1). Tumors originated from visceral pleura in 48 cases, from parietal, mediastinal or diaphragmatic pleura in seven, two and three cases, respectively; their mean diameter was 8.5 cm. Tumors could be resected with their implantation basis in 49 patients. In the remaining 11, extended resections were performed, including lung parenchyma (lobectomy, n=4, pneumonectomy, n=2), osteomuscular chest wall structures (n=2), diaphragm (n=2), and pericardium (n=1). Two postoperative deaths (due to myocardial infarction and pulmonary embolism, respectively) occurred. Tumors were pathologically benign in 38 cases and malignant in 22 cases. Mean follow-up was 88 months. Resection was complete in all the patients with benign tumors and no recurrence occurred. Resection was considered as complete in 21/22 malignant tumors. Local recurrence was observed in two cases. Both could be successfully managed by iterative exeresis (no extended resection had been initially performed). Metastatic disease (responsible for patient's death) was observed following the only incomplete resection. Actuarial 5- and 10-year survival rates were 97% for benign tumors and 89% for malignant ones. Conclusions: Surgical resection provided cure in all the patients with benign tumors. As insufficiency of exeresis is associated with all recurrences in malignant tumors, completeness of resection is in our experience the best prognostic factor in these forms.     

Graft Loss After Pediatric Liver Transplantation

OBJECTIVE: To describe the epidemiology and causes of graft loss after pediatric liver transplantation and to identify risk factors. SUMMARY BACKGROUND DATA: Graft failure after transplantation remains an important problem. It results in patient death or retransplantation, resulting in lower survival rates. METHODS: A series of 157 transplantations in 120 children was analyzed. Graft loss was categorized as early (within 1 month) and late (after 1 month). Risk factors were identified by analyzing recipient, donor, and transplantation variables. RESULTS: Kaplan-Meier 1-month and 1-, 3-, and 5-year patient survival rates were 85%, 82%, 77%, and 71%, respectively. Graft survival rates were 71%, 64%, 59%, and 53%, respectively. Seventy-one of 157 grafts (45%) were lost: 18 (25%) by death of patients with functioning grafts and 53 (75%) by graft-related complications. Forty-five grafts (63%) were lost early after transplantation. Main causes of early loss were vascular complications, primary nonfunction, and patient death. Main cause of late graft loss was fibrosis/cirrhosis, mainly as a result of biliary complications or unknown causes. Child-Pugh score, anhepatic phase, and urgent transplantation were risk factors for early loss. Donor age, donor/recipient weight ratio, blood loss, and technical-variant liver grafts were risk factors for late loss. CONCLUSIONS: To prevent graft loss after pediatric liver transplantation, potential recipients should be referred early so they can be transplanted in an earlier phase of their disease. Technical-variant liver grafts are risk factors for graft survival. The logistics of the operation need to be optimized to minimize the length of the anhepatic phase.     

Combined Risk Allele Score of Eight Type 2 Diabetes Genes Is Associated With Reduced First-Phase Glucose-Stimulated Insulin Secretion During Hyperglycemic Clamps

OBJECTIVE

At least 20 type 2 diabetes loci have now been identified, and several of these are associated with altered β-cell function. In this study, we have investigated the combined effects of eight known β-cell loci on insulin secretion stimulated by three different secretagogues during hyperglycemic clamps.

RESEARCH DESIGN AND METHODS

A total of 447 subjects originating from four independent studies in the Netherlands and Germany (256 with normal glucose tolerance [NGT]/191 with impaired glucose tolerance [IGT]) underwent a hyperglycemic clamp. A subset had an extended clamp with additional glucagon-like peptide (GLP)-1 and arginine (n = 224). We next genotyped single nucleotide polymorphisms in TCF7L2, KCNJ11, CDKAL1, IGF2BP2, HHEX/IDE, CDKN2A/B, SLC30A8, and MTNR1B and calculated a risk allele score by risk allele counting.

RESULTS

The risk allele score was associated with lower first-phase glucose-stimulated insulin secretion (GSIS) (P = 7.1 × 10⁻⁶). The effect size was equal in subjects with NGT and IGT. We also noted an inverse correlation with the disposition index (P = 1.6 × 10⁻³). When we stratified the study population according to the number of risk alleles into three groups, those with a medium- or high-risk allele score had 9 and 23% lower first-phase GSIS. Second-phase GSIS, insulin sensitivity index and GLP-1, or arginine-stimulated insulin release were not significantly different.

CONCLUSIONS

A combined risk allele score for eight known β-cell genes is associated with the rapid first-phase GSIS and the disposition index. The slower second-phase GSIS, GLP-1, and arginine-stimulated insulin secretion are not associated, suggesting that especially processes involved in rapid granule recruitment and exocytosis are affected in the majority of risk loci.Type 2 diabetes is a polygenic disease in which the contribution of a number of detrimental gene variants in combination with environmental factors is thought to be necessary for the development of disease. In the past 2 years, results of several genome-wide association studies (GWASs) have been published (1–5), leading to a rapidly increasing number of detrimental type 2 diabetes susceptibility loci. More recently, it has indeed been shown that combining information from these diabetes loci into a risk allele score for all loci enhances diabetes risk (6–9). However, the predictive power of this combined risk allele score is yet insufficient to substitute or largely improve predictive power of known clinical risk factors (8,9). At present, little is known about how these gene variants in combination affect insulin secretion or insulin resistance. Based on recent data, mainly obtained from oral glucose tolerance tests (OGTTs), it was shown that a combined risk allele score from gene variants associated with type 2 diabetes is associated with insulin secretion and not with insulin sensitivity (10–13). However, the OGTT is unable to distinguish between first- and second-phase insulin secretion. Furthermore, other secretagogues, like glucagon-like peptide (GLP)-1 and arginine, were not included in these studies.It is thought that the rapid recruitment and release of insulin granules from the readily releasable pool (RRP) is responsible for the first phase of insulin secretion, whereas the slower prolonged second phase involves recruitment to the membrane of more distant granules and de novo insulin synthesis. Although the exact pathways regulating both phases of glucose-stimulated insulin secretion (GSIS) are not completely resolved, it seems logical that they are at least in part different. This is further corroborated by our recent observation that the heritability for both phases of GSIS in twins is derived from partly nonoverlapping sets of genes (13a).Also, other nonglucose, stimuli-like incretins and amino acids can evoke an insulin response. Detailed phenotypic investigations of the response to these different stimuli may help to elucidate which processes are primarily affected by these loci. Previously, we have already shown that type 2 diabetes genes/loci can have different effects on first- and second-phase GSIS, as measured using hyperglycemic clamps. Also, based on the method of stimulation (i.e., oral versus intravenous), the outcome may differ substantially (14–17), which provides further clues about the mechanism by which they affect insulin secretion.In this study, we genotyped gene variants in TCF7L2, KCNJ11, HHEX/IDE, CDKAL1, IGF2BP2, SLC30A8, CDKN2A/CDKN2B, and MTNR1B in 447 hyperglycemic clamped subjects (256 with normal glucose tolerance [NGT] and 191 with impaired glucose tolerance [IGT]) from four independent studies in the Netherlands and Germany. These eight loci were chosen based on the fact that they were reproducibly associated with β-cell function in various studies (rev. in 18,19). A combined risk allele score of all eight gene variants was calculated for each individual and tested against the various detailed measurements of β-cell function using the hyperglycemic clamp, generally considered to be the gold standard for quantification of first- and second-phase GSIS (20). Furthermore, we also assessed the combined effect of these eight genes on two other stimuli, GLP-1 and arginine-stimulated insulin secretion during hyperglycemia, in a subset of the study sample (n = 224). The latter test provides an estimation of the maximal insulin secretion capacity of a subject and may, according to animal studies, serve as a proxy for β-cell mass (21).     

Sympathetic Neural Adaptation to Hypocaloric Diet With or Without Exercise Training in Obese Metabolic Syndrome Subjects

OBJECTIVE

Sympathetic nervous system (SNS) overactivity contributes to the pathogenesis and target organ complications of obesity. This study was conducted to examine the effects of lifestyle interventions (weight loss alone or together with exercise) on SNS function.

RESEARCH DESIGN AND METHODS

Untreated men and women (mean age 55 ± 1 year; BMI 32.3 ± 0.5 kg/m²) who fulfilled Adult Treatment Panel III metabolic syndrome criteria were randomly allocated to either dietary weight loss (WL, n = 20), dietary weight loss and moderate-intensity aerobic exercise (WL+EX, n = 20), or no treatment (control, n = 19). Whole-body norepinephrine kinetics, muscle sympathetic nerve activity by microneurography, baroreflex sensitivity, fitness (maximal oxygen consumption), metabolic, and anthropometric measurements were made at baseline and 12 weeks.

RESULTS

Body weight decreased by −7.1 ± 0.6 and −8.4 ± 1.0 kg in the WL and WL+EX groups, respectively (both P < 0.001). Fitness increased by 19 ± 4% (P < 0.001) in the WL+EX group only. Resting SNS activity decreased similarly in the WL and WL+EX groups: norepinephrine spillover by −96 ± 30 and −101 ± 34 ng/min (both P < 0.01) and muscle sympathetic nerve activity by −12 ± 6 and −19 ± 4 bursts/100 heart beats, respectively (both P < 0.01), but remained unchanged in control subjects. Blood pressure, baroreflex sensitivity, and metabolic parameters improved significantly and similarly in the two lifestyle intervention groups.

CONCLUSIONS

The addition of moderate-intensity aerobic exercise training to a weight loss program does not confer additional benefits on resting SNS activity. This suggests that weight loss is the prime mover in sympathetic neural adaptation to a hypocaloric diet.The metabolic syndrome (MetS) is an increasingly prevalent multidimensional risk factor for cardiovascular disease and type 2 diabetes (1). Its etiology is complex and incompletely understood, but thought to involve the interplay between metabolic susceptibility, lifestyle factors, and the acquisition of excess visceral adiposity (2). Scientific studies performed over the last 2 decades strongly support the relevance of the sympathetic nervous system (SNS) in both the pathogenesis and target organ complications of MetS obesity (3).Several indexes of SNS activity, such as urinary norepinephrine excretion, norepinephrine spillover from sympathetic nerves, and postganglionic muscle sympathetic nerve activity (MSNA) are increased in subjects with MetS, even in the absence of hypertension (4–7). Among the adiposity indexes, abdominal visceral fat is most strongly associated with elevated MSNA (8). Because of the bidirectional relationship between sympathetic activation and insulin resistance, much debate has focused on their chronology. Prospective studies with 10–20 years follow-up indicate that elevated plasma norepinephrine concentration (9) and sympathetic reactivity (10) precede and predict future rise in BMI and development of insulin resistance. Although seemingly counterintuitive, sympathetic activation may be causally linked to obesity via β-adrenoceptor desensitization (11) and insulin resistance (12,13). In established obesity, metabolic, cardiovascular (baroreflex impairment), and medical conditions (obstructive sleep apnea) contribute significantly to sympathetic neural drive and further aggravate insulin resistance, hence establishing a vicious cycle (3,7). Chronic sympathetic activation is associated with an increased prevalence of preclinical cardiovascular and renal changes that are recognized predictors of adverse clinical prognosis (3,14,15).Weight loss and exercise are recommended as first-line treatments for MetS. The Diabetes Prevention Program and the Oslo Diet and Exercise Study have shown the marked clinical benefits of intensive lifestyle intervention on the resolution of the MetS (16,17). Individually, both weight loss (5) and exercise training (18,19) cause sympathoinhibition and improvement in MetS components. We have previously reported that moderate weight loss (7% of body weight) by diet alone is accompanied by reductions in whole-body norepinephrine spillover and MSNA and improvement in spontaneous cardiac baroreflex function in middle-aged MetS subjects (5). Because exercise is often added to energy restriction in the treatment of obesity, it is pertinent to clarify its additive benefits. Augmented improvements in metabolic, anthropometric, and cardiovascular parameters have been observed after combined exercise training and dietary weight loss in some (17,20,21), but not other studies (22), and there are limited data regarding their combined effect on sympathetic activity (23). Exercise training may potentially augment weight loss induced sympathoinhibition by promoting a greater loss of fat relative to lean mass (20,21), by further improvement in insulin sensitivity (24) and reduction in plasma leptin concentration (21), and by potentiation of baroreceptor sensitivity (18).The present study was conducted to 1) test the hypothesis that weight loss by combined hypocaloric diet and aerobic exercise training would be associated with greater sympathoinhibition and improvement in MetS components than hypocaloric diet alone and 2) to examine the interrelationships between reduction in sympathetic tone and concurrent changes in anthropometric, metabolic (insulin sensitivity, plasma leptin concentration), and cardiovascular parameters. A moderate-intensity bicycle riding protocol was chosen as the exercise intervention, based on an earlier study that demonstrated attenuation in whole-body and renal norepinephrine spillover rates with this regimen in healthy men (19).     

The outcome of children with intractable seizures: a 3- to 6-year follow-up of 67 children who remained on the ketogenic diet less than one year

PURPOSE: To determine the long-term outcome of children with difficult-to-control seizures who remained on the ketogenic diet for <1 year. METHODS: Between 1994 and 1996, 150 children with epilepsy, refractory to at least two medications, initiated the ketogenic diet according to the Hopkins protocol. Three to six years after diet initiation, all the families were contacted by telephone or questionnaire to assess their child's current seizure status, medications, and therapies. RESULTS: Sixty-seven children discontinued the diet within 1 year of initiation. Follow-up data were available for 54 of these children. Ten subsequently had surgery, and three underwent VNS implantation. These operated-on children were significantly more likely to be >50% controlled at follow-up than were those managed with medications alone (p < 0.05). A statistically significant difference in long-term outcome was noted between those who responded while on the diet, even if they discontinued it before 1 year, and those who did not (p < 0.05), but no statistical correlation was found between length of time that they had remained on the diet and long-term prognosis. CONCLUSIONS: Almost half of the children who discontinued the diet during the first year had a decrease in seizures when assessed 3-6 years later. Twenty-two percent of these had become seizure free without surgery. We were unable to ascertain whether this may have been due to new medications. Those who saw some improvement while on the diet were more likely to have a favorable long-term outcome. Resective surgery, in children who were candidates, or vagal nerve stimulation (VNS) implantation, was more likely to result in significant seizure improvement than was management with medications alone. Whether or not the diet was effective, most families did not regret trying it and would recommend it to others.