Bone Disease in the Common Marmoset: Radiographic and Histological Findings.

The common marmoset (Callithrix jacchus) is a New World primate that is used in biomedical research due to its small size and relative ease of handling compared with larger primates. Although bone disease in common marmosets is well recognized, there are very few detailed descriptions in the literature that cover the range of lesions seen in these animals. For all animals used to model human disease, it is important to be aware of background lesions that may affect the interpretation of study findings. This retrospective study details bone diseases encountered in marmoset breeding colonies at 2 different institutions. Affected marmosets at Johns Hopkins University had lesions compatible with diagnoses of rickets, fibrous osteodystrophy and osteopenia. Affected marmosets at the Wisconsin National Primate Research Center exhibited severe lesions of osteoclastic bone resorption and remodeling that had an unusual distribution and were not easily categorized into a known disease entity. The purpose of this report is to document these naturally occurring skeletal lesions of common marmosets and suggest an approach to evaluating skeletal disease in prospective studies of these animals that will allow the most accurate diagnoses.

Neurocognitive dysfunction and pharmacological intervention using guanfacine in a rhesus macaque model of self-injurious behavior.

Self-injurious behavior (SIB) is a common comorbidity of psychiatric disorders but there is a dearth of information about neurological mechanisms underlying the behavior, and few animal models exist. SIB in humans is characterized by any intentional self-directed behavior that leads to wounds, whereas in macaques it is not always accompanied by wounds. We describe a cohort of rhesus macaques displaying SIB as adults, in which changes within the central nervous system were associated with the SIB. In these macaques, increases in central nervous system striatal dopamine (DA) receptor binding (BPND) measured by positron emission tomography (PET) [11C]raclopride imaging correlated with severity of wounding (rs=0.662, P=0.014). Furthermore, utilizing standardized cognitive function tests, we showed that impulsivity (stop signal reaction time, SSRT) and deficits in attentional set shifting (intra-/extradimensional shift) were correlated with increased severity of SIB (rs=0.563, P=0.045 and rs=0.692, P=0.009, respectively). We also tested the efficacy of guanfacine, an α2A adrenergic agonist that acts to improve postsynaptic transmission of neuronal impulses, in reducing SIB. A subset of these animals were enrolled in a randomized experimenter-blinded study that demonstrated guanfacine decreased the severity of wounding in treated animals compared with vehicle-only-treated controls (P=0.043), with residual beneficial effects seen for several weeks after cessation of therapy. Animals with the highest severity of SIB that received guanfacine also showed the most significant improvement (rs=-0.761, P=0.009). The elevated PET BPND was likely due to low intrasynaptic DA, which in turn may have been improved by guanfacine. With underlying physiology potentially representative of the human condition and the ability to affect outcome measures of disease using pharmacotherapy, this model represents a unique opportunity to further our understanding of the biology and treatment of SIB in both animals and humans.

Proton resonance frequency chemical shift thermometry: experimental design and validation toward high-resolution noninvasive temperature monitoring and in vivo experience in a nonhuman primate model of acute ischemic stroke.

BACKGROUND AND PURPOSE: Applications for noninvasive biologic temperature monitoring are widespread in biomedicine and of particular interest in the context of brain temperature regulation, where traditionally costly and invasive monitoring schemes limit their applicability in many settings. Brain thermal regulation, therefore, remains controversial, motivating the development of noninvasive approaches such as temperature-sensitive nuclear MR phenomena. The purpose of this work was to compare the utility of competing approaches to MR thermometry by using proton resonance frequency chemical shift. We tested 3 methodologies, hypothesizing the feasibility of a fast and accurate approach to chemical shift thermometry, in a phantom study at 3T. MATERIALS AND METHODS: A conventional, paired approach (difference [DIFF]-1), an accelerated single-scan approach (DIFF-2), and a new, further accelerated strategy (DIFF-3) were tested. Phantom temperatures were modulated during real-time fiber optic temperature monitoring, with MR thermometry derived simultaneously from temperature-sensitive changes in the water proton chemical shift (∼0.01 ppm/°C). MR thermometry was subsequently performed in a series of in vivo nonhuman primate experiments under physiologic and ischemic conditions, testing its reproducibility and overall performance. RESULTS: Chemical shift thermometry demonstrated excellent agreement with phantom temperatures for all 3 approaches (DIFF-1: linear regression R(2) = 0.994; P < .001; acquisition time = 4 minutes 40 seconds; DIFF-2: R(2) = 0.996; P < .001; acquisition time = 4 minutes; DIFF-3: R(2) = 0.998; P < .001; acquisition time = 40 seconds). CONCLUSIONS: These findings confirm the comparability in performance of 3 competing approaches to MR thermometry and present in vivo applications under physiologic and ischemic conditions in a primate stroke model.

Tracheal occlusion conditioning causes stress, anxiety and neural state changes in conscious rats.

Evidence from human and animal studies indicates that mechanical loads to breathing are stressful stimuli and evoke compensatory behaviours. Conditioning of stressful stimuli is known to cause changes in basal stress levels and behaviour. Individuals with respiratory obstructive diseases repeatedly experience bouts of airway obstruction, which may act as a form of conditioning, and often have affective disorders, such as anxiety and depression. It is unknown whether the development of affective disorders in these individuals results from the unexpected recurring respiratory perturbations. To investigate this possibility, we developed a model to elicit tracheal occlusion (TO) in conscious rats and exposed them to 10 days of TO conditioning. We hypothesized that healthy, conscious animals exposed to TO conditioning would develop stress and anxiety and would have modulated neural activity in respiratory, stress, discriminative and affective neural regions. Following TO conditioning, rats had increased basal corticosterone levels, greater adrenal weights and elevated anxiety levels compared with animals not receiving TO. Significant increases in cytochrome oxidase staining were found in brainstem respiratory nuclei, periaqueductal grey, dorsal raphe, thalamus and insular cortex. These results suggest that healthy animals develop stress and anxiety responses to respiratory load conditioning via inescapable tracheal occlusions, which may be mediated through state changes in specific brain nuclei.

A comparison of 5-day and 8-day drainage following mastectomy and axillary clearance.

AIMS: Mastectomy and axillary clearance are standard operations for the treatment of breast carcinoma. Drainage of the mastectomy site and axilla is often required to allow accumulating blood and inflammatory fluids to escape. However, there is a lack of data relating to how long suction drains should stay in situ after major breast surgery. In our study we have tried to address this deficit by comparing the efficacy of 5-day post-operative drainage with 8-day post-operative drainage. METHODS: Patients requiring mastectomy and axillary clearance were randomized to having drains removed on day 5 or day 8 post-operatively. The number of lymphoceles, aspirations and total aspiration volumes in chest and axillary drains were compared. RESULTS: From a total of 121 patients enrolled into the study, 64 patients were randomized to the 5-day group and 57 to the 8-day group. There were significant differences regarding the number of aspirations and total aspiration volumes in chest and axillary drains between the two groups, favouring 8-day drainage. However the number of lymphoceles drained in the 5-day group was significantly higher than the 8-day group. CONCLUSIONS: Five-day post-operative drainage is as safe as 8-day post-operative drainage in the management of patients undergoing major breast surgery, but results in an increase in lymphocele aspiration and aspiration volume.

Monitoring the health status and impact of treatment on Americans: the Medicare Beneficiary Health Status Registry.

OBJECTIVE: A major new survey program, the Medicare Beneficiary Health Status Registry (MBHSR), has been proposed to improve the monitoring of the health status of Medicare beneficiaries. The MBHSR would collect data by mail with telephone follow up of nonrespondents to permit economical assessment of a total Registry of approximately 200,000 Medicare beneficiaries, approximately 54,000 of whom would be surveyed in any given year. (Surveys would be conducted of samples of new enrollees who would be reinterviewed every five years.) METHOD: To assess the feasibility of that approach, a field test was conducted with a probability sample (n = 1,922) that comprised approximately equal numbers of new Medicare enrollees (aged, 65) and current beneficiaries (age range, 76-80). The field test was designed to assess the quality of the data that this design would produce. FINDINGS: Results indicate that the proposed design of the MBHSR could achieve response rates of approximately 80% among both age cohorts using a survey instrument that took 30 minutes to complete. Internal reliability of Activities of Daily Living, Instrumental Activities of Daily Living, Mobility, Mental Health Index, General Health, and Prostate Symptomatology scales ranged from 0.77 to 0.93. When measurements were repeated approximately 30 days after the initial survey, moderate to high levels of cross temporal correlation (range, 0.64-0.96) were found for most indexes, with the exception of prostate symptomatology. In addition, an earlier comparison of survey responses in the MBHSR field test to Medicare payment records indicated that the MBHSR field test obtained highly accurate reports of most of the major surgeries that were recorded in Medicare claims files. CONCLUSION: The design proposed for the MBHSR is feasible. If implemented, it should produce acceptably high rates of response and data quality.

The quality of health data obtained in a new survey of elderly Americans: a validation study of the proposed Medicare Beneficiary Health Status Registry (MBHSR).

The Medicare Beneficiary Health Status Registry (MBHSR) is a proposed new survey program that would collect health status indicators annually from large probability samples of Medicine beneficiaries. For reasons of economy, the MBHSR would use mail survey procedures with telephone follow-up of nonrespondents. Because of concerns about response rates and the validity and reliability of the data obtained by such methods, a large-scale (N = 1,922) field test was conducted. The field test assessed the validity of MBHSR survey reports of past medical treatment and conditions by comparing those reports with Medicare claims data. It assessed the (internal) reliability of MBHSR survey responses by comparing responses with logically related survey questions from the MBHSR. Analyses indicate that the MBHSR survey procedures using a combination of mail data collection with telephone follow-up of nonrespondents produced relatively high levels of sensitivity and specificity in identifying medical treatments and procedures previously recorded in Medicare claims data. In addition, the MBHSR Field Test obtained, in general, relatively high levels of internal consistency in survey reports.

Necrotizing enterocolitis can be caused by polycythemic hyperviscosity in the newborn dog.

Although necrotizing enterocolitis has been associated with polycythemia in human infants, a causal relationship has not been established. Forty-six unanesthetized puppies were studied (age 6 to 14 days). Normovolemic polycythemia (Hct 0.70) was induced in 19 pups by exchange transfusion with 75 ml/kg packed red blood cells. Hypervolemic polycythemia (Hct 0.70) was induced in 14 pups by transfusion with 50 ml/kg RBC. Thirteen pups received exchange transfusion with whole blood and served as controls (Hct 0.40). Gross autopsy was performed on all pups 24 hours after transfusion or at death. Necrotizing enterocolitis was defined as areas of violaceous discoloration of the bowel associated with blood in the intestinal lumen. Although lesions appeared throughout the bowel in some pups, involvement of the distal small bowel was most common. Diagnosis was confirmed by microscopic examination. Both gross and microscopic lesions appeared similar to those in necrotizing enterocolitis in human infants. The disorder was seen in 11 of 19 pups with normovolemic polycythemia, eight of 14 pups with hypervolemic polycythemia, and only one of 13 control animals (P less than 0.01). Polycythemia can cause necrotizing enterocolitis in the newborn dog.

Effect of polycythemia on vascular volume in the newborn dog.

The effect of polycythemia [hematocrit (Hct) 64-80] on blood volume (BV) was studied in 27 unanesthetized, splenectomized newborn dogs (age 6-14 days, postsplenectomy 5-13 days). Normovolemic polycythemia (N) was induced in nine pups by exchange transfusion with 75 ml/kg of adult, packed (to Hct 95) red blood cells (RBC). Hypervolemic polycythemia (H) was induced in 11 pups by transfusion of RBC (50 ml/kg). Seven pups received exchange transfusion with 75 ml/kg of whole blood and served as controls (C). Red cell volume (RCV, 51CrRBC) and plasma volume (PV, 125I-fibrinogen and Evans blue) were measured prior to and at 1, 2, and 4 h after transfusion, before the pups received fluid orally. The pups were fed 8 ml X kg-1 X h-1 after 4 h, and measurements were repeated at 8 and 24 h. BV fell in C prior to 4 h by 10 +/- 4% (SD) (P less than 0.01) and then rose to initial levels. BV rose in the N pups by 17 +/- 9 (P less than 0.01), 14 +/- 5 (P less than 0.01), 9 +/- 10 (P less than 0.1), 17 +/- 9 (P less than 0.01), and 31 +/- 17% (P less than 0.01) at 1, 2, 4, 8, and 24 h post transfusion. BV rose in the H pups by 41 +/- 8, 35 +/- 10, 23 +/- 11, 27 +/- 6, and 43 +/- 9% (all P less than 0.01). Thus newborn dogs with induced N or H equilibrate rapidly to a BV significantly higher than C levels.(ABSTRACT TRUNCATED AT 250 WORDS)

A double-blind clinical trial of mianserin versus amitriptyline: differentiation by adverse symptomatology.

A 6-week double-blind comparison of mianserin, a new antidepressant, and amitriptyline allowed us to explore the problem of demonstrating main effect differences in drug/drug trials when the focus is primarily only upon efficacy or upon common adverse symptomatology. Statistical analyses of standard psychiatric rating scales revealed no significant treatment differences, while both treatment groups exhibited significant parallel improvement across time. Examination of treatment emergent symptoms indicated that, while it evoked fewer anticholinergic symptoms than amitriptyline, mianserin exhibited a different profile of adverse symptomatology. The usefulness of a measure of the benefit/risk ratio was described as a means of clarifying drug/drug comparisons.