Edward Zigler's legacy in the study of persons with intellectual disability: the developmental approach and the advent of a more rigorous and compassionate science

Edward Zigler transformed the science and humanity of the work with persons with intellectual disability. The developmental approach is Ed's great contribution to the field of intellectual disability as it both led to more conceptually compelling and methodologically rigorous science and provided an alternative to the Zeitgeist of segregation, defect, and pathology that had prevailed for decades. In an entirely unique way, the developmental approach allowed a seamless integration of increasingly precise science with concern for the “whole child” and their family. Thus, Ed's legacy led to a discipline in which scholarship and compassion prevail hand in hand as the integrity of science and of the person are mutually informative and interdependent.     

Morphine tolerance attenuates the resolution of postoperative pain and enhances spinal microglial p38 and extracellular receptor kinase phosphorylation

Persistent postoperative pain is a very common phenomenon which severely affects the lives of patients who develop it following common surgical procedures. Opioid analgesics are of limited efficacy in the treatment of persistent pain states because of side effects including antinociceptive tolerance. We have previously shown that surgical incision injury and morphine tolerance share similar mechanisms, including a CNS role of spinal cord glia. We therefore hypothesized that prior chronic morphine exposure would inhibit the resolution of postoperative allodynia through increased glial ionized calcium-binding adaptor protein 1 (Iba1) and glial fibrillary acidic protein (GFAP) protein expression and mitogen activated protein kinase (MAPK) activation. To test this hypothesis, rats were implanted with s.c. osmotic minipumps on day zero, releasing saline or morphine for 7 days preceding or 7 days preceding and following paw incision surgery, which was completed on day seven. Thermal hyperalgesia and mechanical allodynia were assessed postoperatively every 3 days. Chronic morphine attenuated the resolution of postoperative thermal hyperalgesia and mechanical allodynia through day 20. However, no changes in Iba1 or GFAP expression were observed in the spinal cord dorsal horn between groups. Assessment of MAPK protein phosphorylation revealed that chronic morphine administration enhanced both p38 and extracellular receptor kinase (pERK) phosphorylation compared to saline on day 20. p-p38 and pERK immunofluorescence were only observed to colocalize with a marker of microglial cells and not with markers of astrocytes or neurons. Together, these data demonstrate that chronic morphine administration attenuates the resolution of postoperative allodynia in association with microglial p38 and extracellular receptor kinase (ERK) phosphorylation, independent of changes in Iba1 and GFAP expression.     

Carotid surgery following previous carotid endarterectomy is safe and effective

With the perceived high risk of repeat carotid surgery, carotid angioplasty and stenting have been advocated recently as the preferred treatment of recurrent carotid disease following carotid endarterectomy. An experience with the operative treatment of recurrent carotid disease to document the risks and benefits of this procedure is presented. A review of a prospectively acquired vascular registry over a 10-year period (Jan. 1990-Jan. 2000) was undertaken to identify patients undergoing repeat carotid surgery following previous carotid endarterectomy. All patients were treated with repeat carotid endarterectomy, carotid interposition graft, or subclavian-carotid bypass. The perioperative stroke and death rate, operative complications, life-table freedom from stroke, and rates of recurrent stenosis were documented. During the study period 56 patients underwent repeat carotid surgery, comprising 6% of all carotid operations during this period. The indication for operation was symptomatic disease recurrence in 41 cases (73%) and asymptomatic recurrent stenosis >/=80% in 15 cases (27%). The average interval from the prior carotid endarterectomy to the repeat operation was 78 months (range 3 weeks-297 months). The operations performed included repeat carotid endarterectomy with patch angioplasty in 31 cases (55%), interposition grafts in 19 cases (34%), and subclavian-carotid bypass in 6 cases (11%). There were three perioperative strokes with one resulting in death for a perioperative stroke and death rate of 5.4%. One minor transient cranial nerve (CN IX) injury occurred. Mean follow-up was 29 months (range, 1-116 months). Life-table freedom from stroke was 95% at 1 year and 90% at 5 years. Recurrent stenosis (>/=80%) developed in three patients (5.4%) during follow-up, including one internal carotid artery occlusion. Two patients (3.6%) underwent repeat surgery. Repeat surgery for recurrent cerebrovascular disease following carotid endarterectomy is safe and provides durable freedom from stroke. Most patients are candidates for repeat endarterectomy with patching, but interposition grafting is often required. These results strongly support the continued role of repeat carotid surgery in the treatment of recurrent carotid disease.     

Immediate breast reconstruction for stage III breast cancer using transverse rectus abdominis musculocutaneous (TRAM) flap

Background: The management of stage III breast cancer is challenging; it often includes multimodal treatment with systemic therapy and/or radiation therapy and surgery. Immediate breast reconstruction has not traditionally been performed in these patients. We review the results of immediate transverse rectus abdominis musculocutaneous (TRAM) flap in 21 patients treated for stage III breast cancer. Methods: Data have been collected retrospectively on 21 patients diagnosed with stage III breast cancer between 1987 and 1994. All patients had mastectomy and immediate TRAM reconstruction. Thirteen patients received primary systemic therapy, 10 patients received postoperative consolidation radiotherapy to the operative site, and 3 patients received preoperative radiation. Results: Mean follow-up for the group was 26 months. Two patients died with disseminated disease: neither of them developed local disease recurrence in the operative site; 82% of the patients followed for at least two years are free of disease. Sixty-two percent of the patients received preoperative chemotherapy, the remaining patients received postoperative multiagent chemotherapy and/or radiation therapy. Two of the patients received autologous bone marrow transplants after their adjuvant therapy. Ten patients had postoperative radiotherapy for consolidation; three patients received preoperative radiation. Conclusions: Immediate TRAM reconstruction for stage III breast cancer is not associated with a delay in adjuvant therapy or an increased risk of local relapse. It facilitates wide resection of involved skin without skin grafting. Radiation therapy can be delivered to the reconstructed breast when indicated without difficulty. Breast reconstruction facilitates surgical resection of stage III breast cancer with primary closure and should be considered if the patient desires immediate breast reconstruction.Results of this study were presented at the 48th Annual Cancer Symposium of The Society of Surgical Oncology, Boston, Massachusetts, March 23–26, 1995.     

Vasopressin in the treatment of milrinone-induced hypotension in severe heart failure

The use of phosphodiesterase inhibitors such as milrinone in the treatment of severe heart failure is frequently restricted because they cause vasodilation and hypotension. In patients with decompensated heart failure with hypotension after treatment with milrinone, low doses of vasopressin restored blood pressure without inhibiting the inotropic effect of milrinone.     

Speech acts and the pragmatic deficits of autism

In a videotaped free-play session with a parent, autistic children were compared with mental-age matched Developmental Language Delay (DLD) children and with normally developing (ND) 2-year-olds in the use of communicative acts by parent and child. Groups were matched for language level. Autistic children had more incidents of no responses, produced less affirming, turn-taking vocalization, and gesture, and were less likely to initiate communication than other children. Parent groups differed only in a greater amount of initiating and use of imperatives by parents of autistic children. Few relations between parent behaviors and child behaviors were found. Nonresponses by all children were concentrated subsequent to parent imperatives and questions, but no group differences were found in the distribution of nonresponses to various parent communicative acts. Results are interpreted to support the hypothesis that autistic children's language can serve a number of useful functions but that their pattern of language functions differs from that of nonautistic language-impaired children and much younger normal children of similar language level.     

Estrogenic properties of raloxifene,but not tamoxifen,on D2 and D3 dopamine receptors in the rat forebrain

The present study investigated the estrogenic specificity of the modulation of dopamine D(2) and D(3) receptors by comparing the effects of estradiol with tamoxifen or raloxifene. These compounds have estrogenic and/or antiestrogenic activity depending on the target tissue. Two weeks after ovariectomy of female rats, we observed a 60% decrease in the uterine weight, which was prevented by a replacement therapy of 2 weeks with 17beta-estradiol. A tamoxifen or raloxifene treatment of 2 weeks increased uterine weights by 35 and 15%, respectively, but significantly less than estradiol treatment. Ovariectomy decreased dopamine D(2) receptor specific binding (20%) in the dorsolateral part of the anterior striatum and these receptors were left unchanged in the other parts of the striatum as well as in the olfactory tubercle and the nucleus accumbens. 17beta-Estradiol and raloxifene, but not tamoxifen treatment prevented this decrease. Ovariectomy left dopamine D(3) receptor specific binding unchanged. However, estradiol and raloxifene treatment decreased dopamine D(3) receptor binding in the islands of Calleja, the core and shell of the nucleus accumbens and the dorsal part of the anterior striatum, compared with ovariectomized rats. Our results show that raloxifene, but not tamoxifen, has an agonist estrogenic activity on dopamine receptors. Furthermore, estradiol and raloxifene have opposite effects on specific binding to dopamine D(2) and D(3) receptors.     

Perinatal expression of heat-shock protein 27 in brain regions and nonneural tissues of the piglet

Important stressful events occur at birth or within the few hours that follow this event. To unravel a possible involvement of stress proteins, it is important to determine their levels of expression. Expression of HSP27 protein was determined by Western blotting in several nonneural tissues and in brain regions of the developing pig (fetal to adult). Maximum levels of expression were observed in heart, liver, and lung. In kidney, the expression was reduced during the first hours of life. Brain parts included whole brain, cerebellum, cortex, hippocampus, hypothalamus, and striatum. HSP27 immunogenicity was observed in all the brain regions studied. In whole brain, cerebellum, cortex, hippocampus, and hypothalamus extracts, the levels of HSP27 were decreased during the first hours of age (4 h to 2 d). In striatum, levels of expression were very low—if detectable—during the early postnatal days of life. Changes in environmental parameters, like temperature and/or hypoxia can be possibly related to differential expressions of HSPs, which can result in severe adverse developmental outcomes. The results are discussed in terms of using the newborn piglet as a model to study different forms of stress on the heat-shock protein postnatal expression.     

Renal blood flow regulation, autoregulation, and vasomotor nephropathy

Renal blood flow and renal perfusion pressure are regulated by two control mechanisms. The first, extrinsic, actually involves a complex interaction of vasomotor effects between opposing neurohormonal systems. The second, intrinsic mechanism, renal autoregulation, depends on changes in afferent arteriolar tone in response to the renal perfusion pressure itself. This article reviews these two mechanisms, how they normally respond to stress, and the clinical implications of certain situations in which these control mechanisms are disrupted.