Angle-stable interlocking nailing in a canine critical-sized femoral defect model for bone regeneration studies: In pursuit of the principle of the 3R's.

Introduction: Critical-sized long bone defects represent a major therapeutic challenge and current treatment strategies are not without complication. Tissue engineering holds much promise for these debilitating injuries; however, these strategies often fail to successfully translate from rodent studies to the clinical setting. The dog represents a strong model for translational orthopedic studies, however such studies should be optimized in pursuit of the Principle of the 3R's of animal research (replace, reduce, refine). The objective of this study was to refine a canine critical-sized femoral defect model using an angle-stable interlocking nail (AS-ILN) and reduce total animal numbers by performing imaging, biomechanics, and histology on the same cohort of dogs. Methods: Six skeletally mature hounds underwent a 4 cm mid-diaphyseal femoral ostectomy followed by stabilization with an AS-ILN. Dogs were assigned to autograft (n = 3) or negative control (n = 3) treatment groups. At 6, 12, and 18 weeks, healing was quantified by ordinal radiographic scoring and quantified CT. After euthanasia, femurs from the autograft group were mechanically evaluated using an established torsional loading protocol. Femurs were subsequently assessed histologically. Results: Surgery was performed without complication and the AS-ILN provided appropriate fixation for the duration of the study. Dogs assigned to the autograft group achieved radiographic union by 12 weeks, whereas the negative control group experienced non-union. At 18 weeks, median bone and soft tissue callus volume were 9,001 mm3 (range: 4,939-10,061) for the autograft group and 3,469 mm3 (range: 3,085-3,854) for the negative control group. Median torsional stiffness for the operated, autograft treatment group was 0.19 Nm/° (range: 0.19-1.67) and torque at failure was 12.0 Nm (range: 1.7-14.0). Histologically, callus formation and associated endochondral ossification were identified in the autograft treatment group, whereas fibrovascular tissue occupied the critical-sized defect in negative controls. Conclusion: In a canine critical-sized defect model, the AS-ILN and described outcome measures allowed refinement and reduction consistent with the Principle of the 3R's of ethical animal research. This model is well-suited for future canine translational bone tissue engineering studies.

Minimally invasive application of a radial plate following placement of an ulnar rod in treating antebrachial fractures. Technique and case series.

OBJECTIVE: To describe a surgical technique for placement of a minimally invasive radial plate following application of an ulnar rod (MIPR) for treatment of antebrachial fractures. METHODS: Medical records (November 2005-June 2009) were searched to identify dogs with diaphyseal radius and ulna fractures stabilised by MIPR. Data retrieved included signalment, weight, limb affected, cause of injury, open versus closed fracture, number of fragments, implant size, number of screws used and cortices engaged, number of open screw holes, operative time, rod removal, complications and time to radiographic healing. To be included, dogs had to have evidence of radiographic healing during follow-up. RESULTS: Eight dogs with diaphyseal radius and ulna fractures treated with MIPR were included in the case series. All fractures were due to trauma and two fractures were open (grade 1). Rod loosening and osteomyelitis of the ulna occurred in one case which subsequently resolved with rod removal. Healing occurred in all cases with no implant failures. Median time to radiographic union was 10.5 weeks (mean ± SD = 17 ± 15 weeks; range 4-52 weeks). CLINICAL RELEVANCE: Use of MIPR constructs on diaphyseal fractures of the radius and ulna is an effective technique for managing these fractures using principles of biological osteosynthesis. An intramedullary rod in the ulna assists with fracture reduction and stabilisation and rod removal is recommended once fracture healing has occurred.

Nautilus growth and longevity: evidence from marked and recaptured animals.

Study of Nautilus belauensis i its natural habitat in Palau, West Caroline Islands, shows that growth is slow (0.1 millimeter of shell per day on the average) and decreases as maturity is approached and that individuals may live at least 4 years beyond maturity. Age estimates for seven animals marked and recaptured between 45 and 355 days after release range from 14.5 to 17.2 years. These data indicate that the life-span of Nautilus may exceed 20 years and that its life strategy is very different from that of other living cephalopods.

Nautilus movement and distribution in palau, Western caroline islands.

Long-term movement of up to 150 kilometers in 332 days by tagged, living Nautilus, and postmortem shell drift of 1000 kilometers in 138 days, corroborate and explain the cosmopolitan distribution of many fossil shelled cephalopods.

Treatment of posttraumatic stress disorder with amitriptyline and placebo.

Amitriptyline hydrochloride was compared with placebo in 46 veterans with chronic posttraumatic stress disorder. Treatment continued up to 8 weeks, and efficacy was measured by five observer and two self-rated scales. Percent recovery rates were higher for amitriptyline than placebo on two measures. In patients who completed 4 weeks (n = 40), better outcome with amitriptyline was noted on the Hamilton depression scale only. In the group completing 8 weeks of treatment (n = 33), the drug was superior to placebo on Hamilton depression, Hamilton anxiety, Clinical Global Impression severity, and Impact of Event scales. There was no evidence for drug effects on the structured interview for posttraumatic stress disorder. Drug-placebo differences were greater in the presence of comorbidity in general, although recovery rates were uniformly low in the presence of major depression, panic disorder, and alcoholism. At the end of treatment, 64% of the amitriptyline and 72% of the placebo samples still met diagnostic criteria for posttraumatic stress disorder.

Serum concentrations of canine interleukin-1 receptor antagonist protein in healthy dogs after incubation using an autologous serum processing system.

The objectives of this study were to optimize and validate a canine IL-1RA ELISA using commercially available reagents and to determine the effect of an autologous serum processing system (IRAP II) on IL-1RA concentrations in canine serum. The clinical detection limit of the optimized ELISA was 188.8 to 39,965.6 pg/mL. The observed-to-expected ratio (O:E) for three serial dilutions for four serum samples ranged from 109.6 to 132.2%. The O:E for four serum samples spiked with four concentrations of canine IL-1 RA ranged from 98.7 to 114.3%. Coefficients of variances for intra- and interassay variability ranged from 1.4 to 3.0 and 6.3 to 9.8, respectively. The ELISA was sensitive, linear, accurate, precise, and reproducible. Mean±SD serum concentration of IL-1RA in 12 healthy dogs was 396.6±208.0 pg/mL. There was a significant increase in IL-1RA when blood was incubated in the IRAP II system (15,955.0±6421.0 pg/mL, P<0.0001).

Leukoencephalopathy in elderly depressed patients referred for ECT.

Using brain magnetic resonance imaging (MRI) and high-resolution computed tomography (CT), we identified changes in the subcortical white matter in 44 of 67 elderly depressed inpatients (66%) referred for electroconvulsive therapy (ECT). This "leukoencephalopathy" was frequently associated with other structural brain changes, including cortical atrophy, lateral ventricular enlargement, and lacunar infarctions of the basal ganglia and thalamus. Many (58%) of the patients had developed late-onset depressive disorders, and the majority (86%) had been refractory to and/or intolerant of antidepressant drug therapy. Nevertheless, all but 1 of the 44 patients subsequently responded to a course of ECT, which in general was well tolerated. Although the precise etiology of the leukoencephalopathy remains unclear, clinical data suggest that it may result from arteriosclerotic disease of the medullary arteries that supply the subcortical brain regions. Several lines of evidence suggest that leukoencephalopathy may have implications for the pathophysiology of depressive illness, at least in some elderly patients.

Caffeine augmentation of ECT.

In a randomized, double-blind, placebo-controlled pilot study of 40 depressed inpatients, the authors compared two techniques for maintaining seizure duration during pulse unilateral ECT: pretreatment with intravenous caffeine versus electrical stimulus intensity dosing. Both techniques effectively maintained seizure duration, but with caffeine this was accomplished without any increase in mean stimulus intensity over the course of ECT. There were no differences between the two techniques in therapeutic outcome or cognitive side effects from ECT, and caffeine pretreatment was well tolerated. The authors discuss the clinical and research implications of these findings with respect to strategies for maintaining seizure duration during ECT.

Social consequences of psychiatric disorders, I: Educational attainment.

OBJECTIVE: This is the first in a series of investigations of the social consequences of psychiatric disorders based on the National Comorbidity Survey. Data on the relationship between preexisting psychiatric disorders and subsequent educational attainment are presented. METHOD: The National Comorbidity Survey is a nationally representative survey of 8,098 respondents in the age range 15-54 years. A subsample of 5,877 respondents completed a structured psychiatric interview and a detailed risk factor battery. Diagnoses of DSM-III-R anxiety disorders, mood disorders, substance use disorders, and conduct disorder were generated, and survival analyses were used to project data on school terminations to the total U.S. population. RESULTS: Early-onset psychiatric disorders are present in more than 3.5 million people in the age range of the National Comorbidity Survey who did not complete high school and close to 4.3 million who did not complete college. The most important disorders are conduct disorder among men and anxiety disorders among women. The proportion of school dropouts with psychiatric disorders has increased dramatically in recent cohorts, and persons with psychiatric disorders currently account for 14.2% of high school dropouts and 4.7% of college dropouts. CONCLUSIONS: Early-onset psychiatric disorders probably have a variety of adverse consequences. The results presented here show that truncated educational attainment is one of them. Debate concerning whether society can afford universal insurance coverage for the treatment of mental disorders needs to take these consequences into consideration.

Social consequences of psychiatric disorders, II: Teenage parenthood.

OBJECTIVE: The subject of this study was the relation between retrospectively reported early-onset psychiatric disorders and subsequent teenage parenthood in the general population. METHOD: The data were from 5,877 respondents aged 15-54 years in the National Comorbidity Survey, a nationally representative household survey. Information on respondents' DSM-III-R anxiety disorders, mood disorders, substance abuse disorders, and conduct disorder, age at the birth of the first child, and teenage sexual activity was collected in face-to-face interviews. RESULTS: Early-onset psychiatric disorders were associated with subsequent teenage parenthood among both females and males, with significant odds ratios of 2.0-12.0 and population attributable risk proportions of 6.2%-33.7%. Disaggregation analyses showed that disorders were associated with increased probability of sexual activity but not with decreased probability of using contraception. CONCLUSIONS: These results add to a growing body of evidence that psychiatric disorders are associated with a variety of adverse life consequences. The current policy debate concerning universal insurance coverage needs to take this into consideration. Planners of interventions aimed at preventing teenage pregnancy should consider including a mental health treatment component in their intervention packages. Mental health professionals treating adolescents need to be sensitized to their higher risk of pregnancy, while family doctors and specialists treating teenage mothers or their children need to be sensitized to the mothers' higher risk of psychiatric disorder.

PIP: Data from the US National Comorbidity Survey on 5877 respondents 15-54 years of age were used to assess the relationship between retrospectively identified early-onset psychiatric disorders and subsequent adolescent parenthood. Between 21-24% of the sample's male and female age cohorts reported having their first child at ages 15-19 years. The cumulative and conditional probability curves for adolescent parenthood were consistently higher among men and women with prior psychiatric diagnoses of anxiety, affective, addictive, and conduct disorders than among those without psychiatric diagnoses. The diagnosis most predictive of adolescent parenthood was addictive disorders. The population attributable risk proportions of births of first children to teenagers associated with the psychiatric disorders were 11.1% in the teenage female subsample with premarital childbearing, 6.2% in the teenage female subsample with marital childbearing, and 33.7% in the teenage male subsample with premarital parenthood. Physicians and mental health professionals who work with adolescents with psychiatric conditions should be aware of the increased risk of adolescent pregnancy and a mental health component should be added to adolescent pregnancy prevention programs.

Predicting response to amitriptyline in posttraumatic stress disorder.

OBJECTIVE: This study evaluated the relation between baseline clinical phenomena and response to amitriptyline in patients with posttraumatic stress disorder (PTSD). METHOD: Data were obtained from an 8-week placebo-controlled, double-blind study of combat veterans. Bivariate and multivariate statistics were used to evaluate the relations between the following variables and outcome: age, depression, anxiety, severity of PTSD symptoms, personality, psychiatric comorbidity, level of exposure to trauma, and individual symptoms of depression, anxiety, and traumatic stress. Outcome measures were scores on the Clinical Global Impression scale, Hamilton Rating Scale for Depression, Hamilton Rating Scale for Anxiety, and Impact of Event Scale. RESULTS: Drug response was related to lower baseline levels of depression, neuroticism, combat intensity, anxious mood, impaired concentration, somatic symptoms, feelings of guilt, and one intrusion and four avoidance symptoms of PTSD. CONCLUSIONS: The results demonstrate that response to amitriptyline is related to measures of depression, anxiety, PTSD, personality, and intensity of combat trauma. Similar relationships were not observed in the placebo group, suggesting a specific relationship to the drug.

Internal consistency of DSM-III diagnoses using the symptom scales of the Child Assessment Schedule.

Internal consistency of the major diagnostic categories for children was assessed, using the symptom scale scores of the Child Assessment Schedule. Alpha coefficients were calculated for three samples: 116 nonpsychotic psychiatrically disturbed children, 63 children with cystic fibrosis, and 177 children from a community based sample. For the psychiatric sample, a high level of internal consistency was demonstrated for all the symptom scales (i.e., attention deficit, conduct, anxiety, and depression). For the nonpsychiatric samples, the attention deficit and depression scales were reliable, with lower levels of endorsement and more variability observed for the other scales. These results are supportive of the clustering of diagnostic criteria present in DSM-III.

Role of serotonin in hypothalamo pituitary adrenal axis escape from dexamethasone suppression.

1. The authors investigated the role of serotonin in the hypothalamo pituitary adrenal escape from depression. 2. Maximal dose of fenfluramine was administered to normal individuals pretreated with dexamethasone. 3. Fenfluramine had only a minimal and inconsistent effect on the hypothalamo pituitary adrenal axis in the presence of dexamethasone.

RU486 in depression.

RU486 is a synthetic glucocorticoid antagonist. The authors used RU486 to examine the hypothesis that the elevated plasma cortisol and ACTH in patients is due to suprahypophyseal stimulation of the anterior pituitary. Seven patients and matched controls were studied before and after the administration of RU486. RU486 produced an increase in HPA activity in depressed patients. Thus providing support for the hypothesis that there is increased suprahypophyseal stimulation of the anterior pituitary.

Management of general medical patients with symptoms of depression.

This article describes the management of depressive symptoms in a group of ambulatory patients in general medical care during a 1-year period. It also examines patient outcomes by types of management and aggressiveness of treatment. Subjects are 112 male patients longitudinally enrolled in a V.A. General Medical Clinic who screened positively on both the Zung Self-rating Depression Scale and the DSM-III criteria. Medical records were abstracted to obtain information on mental health management. During the follow-up year, 48% of the moderately depressed patients received some form of mental health management compared to 92% of the severely depressed patients. Of the treatment modes, only patients who had a mental health clinic visit and/or psychiatric consultation were significantly more improved than those not so treated--but only at 6 months (p = 0.09) and 9 months (p = 0.02). Actual treatment experience was then classified into three levels based on intensity, duration, and combinations of treatments. Of the three levels, only those patients in the moderately aggressively treated condition were significantly more improved at 3 months (p = 0.02) and at 6 months (p = 0.04) than those in the no-treatment condition.

Prevention of laboratory animal allergy.

Laboratory animal allergy (LAA) is a significant occupational hazard for workers in a number of research settings, including the pharmaceutical industry. Prevention of allergy and asthma is important because the illness can affect health and career. In a major pharmaceutical company, in an effort to prevent LAA, a comprehensive program to reduce exposure to environmental allergens was developed. The program included education, engineering controls, administrative controls, use of personal protective equipment, and medical surveillance. A prospective survey of five years of data was completed to determine the effect of the program on the prevalence and incidence of LAA. After instituting this program, we found that the prevalence of LAA ranged from 12%-22% and that the incidence was reduced to zero during the last two years of observation. We concluded that LAA is preventable through the implementation of a comprehensive effort to reduce exposure to allergens.

Differences between individuals with self-reported irritable bowel syndrome (IBS) and IBS-like symptoms.

Although there are several symptom classification systems for irritable bowel syndrome (IBS), for example, the Manning or Rome criteria, there has been no previous research on how well these classifications correspond to each other or to persons diagnosed with IBS. We examined data from the Digestive Disorders Supplement of the 1989 National Health Interview Survey (NHIS) to assess demographic, socioeconomic, and health status characteristics of two groups of IBS sufferers--those who met the Manning or Rome criteria and those who reported having IBS but did not meet either criteria. The results showed that the overlap between estimates of IBS and persons with IBS-like symptoms depended on the definition of IBS. There were socioeconomic differences between the two IBS groups and higher rates of functional or work-related activity limitation and health care utilization for all IBS groups relative to US national averages. In summary, these findings indicate that IBS affects a large portion of the US population, regardless of the definition used to describe the condition. Our results suggest that there is a large undiagnosed population with numerous symptoms consistent with IBS, but further research is required to determine the differences between people who do and do not seek care, their impact on the health care system, and future therapies to reduce symptomatology and suffering.