Gene therapy for spinal applications

Gene therapy is a promising drug delivery mechanism for the treatment of spinal disorders. Currently, the technique has been most useful in enhancing growth factor therapy for spinal fusion, intervertebral disc regeneration, and spinal cord injury healing. Gene therapy allows for the high-level local production of growth factors, obviating the need for slow release carriers or continuous infusion pumps that are otherwise necessary because of the short half-lives of most peptide growth factors. Although continuous expression is desirable, growth factor therapy is usually intended to be transient. The typical expression profile of Ad vectors--at a high level over 2 weeks or so--has been ideal, leading to its widespread use in these applications. Despite the ability of Ad to deliver genes directly in vivo, however, the cell-based ex vivo approach has been used widely in spinal applications. In spinal cord injury, cells such as peripheral nerve or Schwann cells may provide a permissive substrate for axonal growth [51]. For spinal fusion and IVD regeneration, ex vivo manipulation of cells facilitates gene transfer, because bone and IVD tissue are too dense to be penetrated by injection of Ad or other vectors. The use of cells may be advantageous in these applications in which new tissue formation is the goal. Finally, the use of genetically modified cells may decrease the inflammatory reaction induced by Ad vectors. Although gene therapy for spinal disorders has been centered around Ad-mediated transfer of single growth factor genes, the options for candidate genes and vectors are growing rapidly. Ad vectors are being improved by decreasing their immunogenicity and altering their tropism [2]. Vectors based on other viruses (such as herpes, adeno-associated virus, and lentivirus) are being developed, also with lower immunogenicity and with longer durations of expression [26,67]. Regulated expression, such as with the tetracycline regulated promoter, is being developed so that genes can be turned on or off as needed. Such regulation may be sensitive even to physiologic cues in the future [68,69]. Finally, the high throughput technologies, such as the gene chip, are elucidating thousands of genes that may be good candidates for the enhancement of bone healing and IVD and spinal cord regeneration. Genes whose products not only support bone, fibrocartilage, or axon growth but also neutralize natural inhibitors or promote tissue remodeling and maturation may be good future candidates. In the future, a series of vectors with multiple genes that are regulated by physiologic cues might be used to enhance spinal fusion, restore IVD tissue, or support spinal cord healing.     

Fetal therapy for giant hepatic cysts

Cystic mesenchymal hamartoma is an extremely rare, benign tumor. Rapid growth to a giant size can pose a threat not only in early childhood but also during fetal life. The experience with 2 antenatally diagnosed giant hepatic cysts with widely disparate approaches to management, treatment, and outcome is presented. A giant hepatic cyst was diagnosed on routine screening ultrasound scan. Because of its extremely massive size, the cyst was treated in utero with repeated aspirations, primarily for obstetric considerations. The infant did well, and the lesion was excised laparoscopically during the neonatal period. A second fetus with a giant hepatic cyst was not treated in utero, and the pregnancy continued to term. Nonimmune hydrops fetalis developed, and the fetus was delivered prematurely at 34 weeks. At birth, the infant was noted to have diffuse neurologic injury and no urine output despite normal-appearing kidneys. The lesion was excised during the neonatal period by open laparotomy. Observations at the time of surgery and pathologic studies of the placenta showed aneurysmal dilatation of the placental veins suggesting in utero compression of the fetal intraabdominal umbilical vein. The infant died shortly after birth. The experience with these 2 cases suggests the possibility that giant mesenchymal hamartoma diagnosed in utero may cause umbilical venous obstruction leading to ischemia during fetal life. Decompression of giant hepatic cysts may reverse this phenomenon and allow normal fetal development. J Pediatr Surg 37:E31.     

Fulminant hepatic failure from primary hepatic lymphoma: successful treatment with orthotopic liver transplantation and chemotherapy

Systemic lymphomas may involve the liver but rarely cause fulminant hepatic failure (FHF). Acute liver failure from primary hepatic lymphoma (PHL) is even less common with most patients succumbing to the sequelae of FHF before the correct diagnosis is made. We report a patient who underwent successful orthotopic liver transplant (OLT) and chemotherapy for FHF secondary to PHL. This previously-well male developed profound coagulopathy and encephalopathy 6 weeks after the onset of jaundice and fatigue. Workup failed to reveal the underlying cause of his liver failure and the patient soon required urgent OLT. Pathologic evaluation of his explanted liver revealed a malignant T-cell rich, large B-cell non-Hodgkin's lymphoma with widespread hepatocellular necrosis. The patient made an excellent clinical recovery and is undergoing CHOP-Rituxan chemotherapy. This scenario demonstrates that lymphoma should be considered in the differential diagnosis of FHF without clear etiology because of the potential for intervention with transplant and chemotherapy.     

Survival of severe congenital diaphragmatic hernia has morbid consequences

Background/Purpose

Fetal tracheal occlusion (TO) was developed in an attempt to enhance prenatal lung growth and improve survival in fetuses with severe congenital diaphragmatic hernia (CDH). We conducted a randomized, controlled clinical trial in 24 fetuses with severe left CDH (liver herniated into the thorax and low lung-to-head ratio) to compare survival after endoscopic fetal TO vs standard perinatal care (control) and prospectively followed up the 16 survivors (9 control, 7 TO) to compare neurodevelopmental, respiratory, surgical, growth, and nutritional outcomes.

Methods

At 1 and 2 years old, subjects underwent evaluation consisting of medical and neurological history and physical, developmental testing, nutritional assessment, oxygen saturation and pulmonary function testing, chest radiograph, and echocardiogram. Growth and developmental measures were corrected for prematurity. Data were analyzed by Mann-Whitney rank sum test, Fisher's Exact test, and logistic and linear regression.

Results

Infants with TO were significantly more premature at birth (control vs TO, 37.4 ± 1.0 vs 31.1 ± 1.7 weeks; P < .01). Growth failure (z score for weight <2 SDs below mean) was severe in both groups at 1 year of age (control vs TO, 56% vs 86%; P = .31). There was considerable catch-up growth by age 2 years (growth failure: control vs TO, 22% vs 33%; P = .19). There were no differences in other growth parameters. There were also no differences in neurodevelopmental outcome at 1 and 2 years. Supplemental oxygen at hospital discharge was a significant predictor of worse neurodevelopmental outcome at 1 and 2 years old (P = .05 and P = .02, respectively). Hearing loss requiring amplification has been diagnosed in 44% of the group (control vs TO, 44% vs 43%; P = 1.0).

Conclusions

In this group of infants with severe CDH, there were no differences in outcome at 2 years old despite significant prematurity in the TO group. Oxygen supplementation at hospital discharge identified the most vulnerable group with respect to neurodevelopmental outcome, but all infants had significant growth failure, and hearing impairment is a substantial problem in this population. Severe CDH carries significant risk of chronic morbidity.     

Cutaneous graft-versus-host reaction lacks evidence of cutaneous cytomegalovirus by the immunoperoxidase technique

Sixty skin biopsy specimens from 21 bone-marrow transplant patients were evaluated for the presence of cytomegalovirus (CMV) using two monoclonal antibodies to early and late antigens. Each patient had at least one biopsy showing an acute graft-versus-host reaction (GVHR), grade 2, and one positive culture for CMV from blood, bone marrow or urine. In no case could CMV antigens be identified in biopsies showing an acute or chronic cutaneous GVHR or in any other of the skin biopsies obtained from these patients. While CMV may play a role in immunologic events culminating in graft-versus-host disease (GVHD), this immunoperoxidase study did not reveal evidence of viral antigens in tissue displaying features of cutaneous GVHR.     

Effective management for older people with heart failure: from acute to palliative care paradigms

None     

Studies on isolated gut mucosal lymphocytes in inflammatory bowel disease

Digestive Diseases and Sciences - To determine whether a defective proliferation of gut mucosal lymphocytes is a contributory factor to the pathogenesis of inflammatory bowel disease, we assessed...     

Systematic Plan of Evaluation Part II: Assessment of Program Outcomes

As an accrediting agency recognized by the U.S. Department of Education (USDE) and the Council for Higher Education Accreditation (CHEA), the Accreditation Commission for Education in Nursing (ACEN) has established Accreditation Standards and Criteria for the evaluation of nursing programs, including the evaluation of outcomes. This article focuses on the essential components and processes for systematic evaluation of program outcomes, including licensure examination pass rate, program completion rate, and job placement rate.