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PubMed2000

The pineal gland and cancer. I. Pinealectomy corrects congenital hormonal dysfunctions and prolongs life of cancer-prone C3H/He mice.

Hormonal derangements almost invariably anticipate and signal the onset of tumors. Chronic, nocturnal melatonin administration delays aging in normal strains of mice. On the contrary it promotes and accelerates the onset of tumors in the cancer-prone strain of C3H/He mice. Grafting of a young pineal gland into aging mice prolongs their longevity and maintains juvenile circadian hormonal functions while pinealectomy (Px) does the opposite. We investigated if Px in C3H/He mice would modify their congenitally deranged pituitary function and affect their longevity. It was found that contrarily to Px in normal mice, Px in C3H/He mice remarkably maintains juvenile night levels of thyroid hormones and lipids, preserves a cell-mediated immune response and significantly prolongs their life. The pineal gland and its pathology may be the key for understanding, not only the causes of metabolic aging, but also the origin of those congenital or progressive aging-related hormonal alterations preceding onset of all tumors and thus allow preventive corrective interventions with pineal-derived agents.

Aging↗
PubMedDate not supplied

Xenotransplantation of retinal pigment epithelial cells into RCS rats.

PURPOSE: Successful engraftment of retinal pigment epithelial cells (RPE) to treat RPE-related retinopathy will depend, at least in part, on controlling the immune response. In order to understand this process we evaluated the fate of RPE xenografts in the subretinal space, anterior chamber, and subcutis of nonimmunosuppressed Royal College of Surgeons rats. METHODS: Freshly isolated adult porcine RPE cells were used as xenografts and implanted when recipients were 17 to 21 days old. The extent of photoreceptor rescue by subretinal transplants was determined by counting the maximum layers of surviving photoreceptor nuclei in histologic sections. Cellular immune response was evaluated by immunohistochemistry. RESULTS: Compared to non- or sham-injected eyes, subretinal xenografts in RPE-transplanted eyes were able to induce a dramatic rescue effect (P <.01). However, the effect was not absolute and photoreceptor cell degeneration was only delayed. Xenografts both in the anterior chamber and in the subcutaneous tissue led to an inflammatory cellular infiltration. CONCLUSION: RPE xenografts in subcutaneous space and in the anterior chamber are rejected by a delayed but vigorous inflammatory cell infiltration. Subretinal RPE xenografts are protected from a strong cellular rejection, but seem to undergo a slow functional deterioration, reflected by a decline in their capability to rescue adjacent photoreceptors.

Animals↗
PubMed1981

Early surgical excision and grafting of burns including tangential excision.

Early excision and grafting of burns with the advent of infection control, has become a most important part of any successful therapy in burn management. By this technique, an open wound is primarily closed, and thus circumvents the possibility of infection. There is less discomfort, more rapid restoration of function, quicker discharge from hospital and earlier rehabilitation. Metabolic needs are lessened and with less scar, the cosmetic result is improved. Excision is made between the third and fifth day postburn if possible, but more delay may be necessary to determine which burns are superficial and able to spontaneously heal. No area greater than 10% of body surface area is excised and grafted at one operative session and for large burns staged excisions are necessary. A limitation of 1 1/2 hours on the operation is made so as to control shock and hypothermia and to assure a quick recovery with early re-establishment of nutrition. Ketamine is the common anaesthetic employed and viable fat is preferred as the surface on which to graft. Tangential excision is a complementary form of early excision grafting to a specific depth, and may be used alone or in conjunction with other techniques. It is of value in selected burns of the deep partial skin loss variety, especially scalds, which predominate in children. Several slices of necrotic skin are taken until a punctate bleeding surface is reached in the deep dermis and a thin to moderate thickness allograft is immediately applied. The conservation of the deep dermis limits the area to be grafted, with the likelihood of less scar formation and a resultant graft of improved texture.

Breast↗
PubMed1983

Problems in toe-to-hand transfers.

The problems encountered by the author in 70 cases of toe-to-hand transfers are considered under three main headings: (1) operative problems (2) post-operative problems and (3) functional problems. The operative problem of preserving the integrity of the donor vessels is related to the varying patterns of vasculature of the foot. Bony fixation of the donor toe to the recipient site and the selection of veins of the right size and length are the other main operative problems. The post-operative problems are concerned with the problem of survival of the transplanted toe and these include venous congestion, diminished arterial blood flow due to thrombosis or spasm, bleeding and delayed healing, especially at the donor site. In thumb reconstructions, both motor and sensory functional recovery were good when reconstruction was done at the M-P joint level, but less satisfactory if done at a more proximal level. Similarly, the functional problem in finger reconstructions resembled those of thumb reconstruction. At the donor site, the main foot functions were maintained, though delayed healing and scarring may prove troublesome in a few cases.

Amputation, Traumatic↗
PubMedDate not supplied

[Renal transplantectomy: surgical technics and results. Apropos of 60 patients].

Nephrectomy of a non-functioning renal transplant after renal transplantation is a delicate operation which the authors evaluate on the basis of a retrospective analysis of 62 patients. A review of the literature helps to more clearly define the indications, optimal time of the operation and the operative technique. A subcapsular approach, by simplifying the operation, constitutes an important factor in reducing the operative morbidity in the late forms. "Early" transplantectomies are often more serious because of the recently operated patient's fragile status and immunosuppression, responsible for frequent infectious complications. Transplantectomy should therefore not be delayed once the permanent loss of transplant function has been confirmed.

Adolescent↗
PubMed1984

Current state of flexor tendon surgery.

Successful restoration of function after flexor tendon injuries continues to present a challenge to the treating surgeon. Primary repair of tendon and associated injuries is the treatment of choice in clean wounds in all zones of the hand. In cases of untidy wounds or when associated injuries preclude primary repair, delayed primary or secondary repair may be performed. Tendon grafting in one or two stages is reserved for late secondary cases in which scarring of the bed, loss of pulleys, permanent retraction of the tendon ends, or joint contractures prevent direct repair. Meticulous attention to detail such as adequate exposure, careful opening and closing of the sheath, gentle handling of the tendons, a secure, smooth tendon juncture and proper postoperative splinting is essential for a successful outcome of direct repair. Tendon grafts done as a secondary procedure require the same attention to minutiae for an adequate functional outcome.

Biomechanical Phenomena↗
PubMed2005

Management of open fractures.

Open fractures are high-energy injuries that require a principle-based approach, starting with detailed evaluation of patient status and injury severity. Early, systemic, wide-spectrum antibiotic therapy should cover gram-positive and gram-negative organisms, and a common regimen is a 3-day administration of a first-generation cephalosporin and an aminoglycoside, supplemented with ampicillin or penicillin to cover anaerobes in farm or vascular injuries. Local antibiotic delivery with the bead pouch technique increases the local concentration of antibiotics, minimizes systemic toxicity, and prevents secondary wound contamination. Thorough irrigation and surgical debridement is critical for prevention of infection. Primary wound closure remains controversial because of concerns for gas gangrene. Partial wound closure is an alternative, with delayed wound closure within 3 to 7 days. In the presence of extensive soft tissue damage, local or free muscle flaps should be transferred to achieve coverage. Stable fracture fixation should be achieved with a method suitable for the bone and soft tissue characteristics. Early bone grafting is indicated for bone defects, unstable fractures treated with external fixation, and delayed union. A management plan guided by the above principles will achieve the goals of prevention of infection, fracture healing, and restoration of function in most of these challenging injuries.

Adult↗
PubMed2003

In vitro senescence occurring in normal human endothelial cells can be rescued by ectopic telomerase activity.

Telomerase activation is a means to delay in vitro replicative senescence in human cells via telomere maintainence; however, this enzymatic activity is virtually absent in almost all normal somatic cells. As a result, cell senesce, leading to an eventual loss of graft function. Aging allografts, either due to cell injury related to transplantation and/or the use of organs from older donors, pose a threat to the long-term survival of a graft as constitutive cells of an aging organ have a much reduced ability to thrive after transplantation. In our study, human endothelial cells were found to undergo replicative senescence in culture with an increase in the percentage of senescent cells (beta-gal staining at pH 6) and a decrease in both the fraction of S-phase cycling cells and the proliferative index measured using CFDA-SE dye. Aging endothelial cells also demonstrated slow rates of proliferation and migration compared to younger cells. Unlike control cells that were transfected with an irrelevant gene vector, telomerase-transfected endothelial cells recovered rapidly after media replacement in cultures that had been serum starved for 2 weeks. Telomerase-transfected cells also retained a high proliferative index comparable to young cells as opposed to untransfected control cells. This young phenotype provided by telomerase expression through restoration of the telomeres may help to increase the longevity of organ transplants.

Cell Cycle↗
PubMed1996

Long-term outcome of unilaterally transplanted parkinsonian patients. I. Clinical approach.

Five patients with Parkinson's disease, unilaterally transplanted with foetal mesencephalic cells into putamen (n=1) or putamen and caudate (n=4), were followed throughout a period of 15-36 months after surgery, according to the recommendations of the core assessment programme for intracerebral transplantations (CAPIT). All these patients exhibited an increase in the fluorodopa uptake in the grafted putamen, which was most significant in the first and last patient of the series. Long-term bilateral improvement of skilled hand movements was observed, starting between the third and sixth month after grafting, and confirmed by the statistical analysis of CAPIT timed tests. A mild to moderate effect on the amount of 'off' time and 'on-off' fluctuations was observed, whereas, apart from one case, no other clear effect on gait, walking and speech was found. One patient included in the study, already suffering slight cognitive impairment, clearly exhibited progression of a dementia process after surgery. Daily living activities were clearly improved in only one of the other four patients. At the end of the study period, all patients needed L-dopa therapy at a similar or higher dose than before grafting, but, in most of them, other dopaminergic drugs were reduced or stopped. All patients exhibited bilateral dyskinesias before grafting that were greatly decreased in intensity a few months after surgery. Delayed asymmetrical dyskinesias, occurring on the side displaying the better motor improvement, i.e. contralateral to the graft, were observed in three patients. These results suggest that neural transplants may influence two central mechanisms involved in motor function and the onset of dyskinesias. These effects are likely to occur through complex interactions with the post-synaptic dopaminergic receptors. The occurrence of dyskinesias might simply reflect increased presynaptic storage and release of dopamine. Alternatively, it might, in part, represent some other long-term deleterious effect of the graft. Since PET-scan data indicate that the reinnervation obtained is sub-optimal, it will be of interest to obtain a larger and denser reinnervation of the host striatum and to try, thereafter, to reduce the dose of L-dopa.

Aged↗
PubMed2002

Soft tissue allografts for knee reconstruction in sports medicine.

Soft tissue allografts are an important substitute tissue for the reconstruction of deficient ligaments, torn menisci, and osteochondral defects during knee surgery. Interest in allografts for soft tissue reconstruction has arisen from the demand to obtain a stable knee with restoration of function and protection against additional injury. Use of allografts for soft tissue reconstruction is associated with less donor tissue site morbidity and reduced surgical time. Nevertheless, use of allografts has a potential for disease transmission, delayed graft incorporation, and host versus donor immunologic response to the graft. Experimental studies and animal models have provided information about the biologic aspects of graft incorporation and remodeling and have contributed to the development of methods of graft preparation and transplantation. Clinical studies of allograft transplantation in humans have helped to define surgical indications and techniques and have allowed for the assessment of clinical outcome. The current authors review the current literature concerning the basic and clinical principles of soft tissue allografts for knee reconstruction, and underscore the scientific basis for the clinical application of allograft tissue during knee surgery.

Adult↗
PubMed2005

Clinical application of population pharmacokinetic methods developed for immunosuppressive drugs.

After a brief overview of the relevant exposure indices for cyclosporine (CsA) and mycophenolate mofetil (MMF), as well as of the different steps necessary to develop maximum a posteriori Bayesian estimators (MAP-BE), this paper presents applications of MAP-BE for CsA or MMF to clinical cases and clinical trials. Ina renal transplant patient under CsA, grade I chronic allograft nephropathy was found at the sixth month posttransplantation, with CsA CO slightly above the target range and C2 markedly below; the AUCO0-12 h Bayesian estimate was quite high, at 5.6 mg h/L, as compared with a mean value of 4.3+0.9 mg.h/L in stable renal transplants at this period; the inconsistent C2 level found could be explained by delayed absorption of CsA in this patient, in which case C2 no longer represents the major part of the AUC. The patient was switched to sirolimus, which resulted in a slow and significant improvement of graft function with no acute rejection. In a 50-year-old female renal transplant recipient administered MMF and CsA and with a very favorable outcome otherwise, progressive anemia appeared 8 months posttransplantation. Clinical investigations were negative,but Bayesian estimation showed a rather high MPA AUCO0-12 h (69.8 mg h/L). After MMF dose reduction, hemoglobin level progressively returned to normal, without erythropoietin injection or blood transfusion. Finally, the feasibility of accurate dose adjustment using these MAP-BE is shown through preliminary results from 2 ongoing multicenter clinical trials, 1 evaluating an AUC-controlled cyclosporine-sparing strategy in stable renal transplants, the second evaluating the benefit of MMF therapeutic drug monitoring based on MPA AUCO0-12 h in de novo renal transplant recipients.

Area Under Curve↗
PubMedDate not supplied

Does cerebral angiography of cadaveric kidney donors interfere with graft function?

Cerebral angiography is used to diagnose brain death of cadaver kidney donors. Clinical and animal data suggest that angiographic contrast media may potentiate the noxious effect of renal ischemia. In order to find out if cerebral angiography of cadaveric kidney donors prior to nephrectomy interferes with function or survival of the renal grafts, two groups of cadaveric donors were compared. One group had been exposed to contrast medium from cerebral angiography in median 18 hours before nephrectomy and the other had not. There was no difference in graft survival and function between the two groups. In a previous investigation angiography was performed two hours before explantation and in that investigation there was a shorter graft survival in the angiography group than in a control group. A delay of 12 hours is suggested between cerebral angiography and explanation, to decrease the combined harmful effects of contrast media and ischemia on renal grafts.

Adolescent↗
PubMed1985

The effect of delayed function on long term survival of renal allografts.

The experience at a single center with 297 consecutive cadaver renal transplants over the past 12 years is reviewed with special attention to acute post-transplant ischemic renal injury (ATN). Sixty-seven patients received kidneys which failed to function immediately (22.5 per cent). Twenty-five (8.4 per cent) never showed any function (NF), and 42 (14.1 per cent) developed delayed function (ATN). The over-all incidence of this complication has exhibited a downward trend in the past 12 years and the possible reasons for this are discussed. The overall rate of patient survival and functional grafts observed for to 12 years by actuarial methods were found to be no different by statistical analysis (ATN versus IF). When patients were subgrouped according to quality of renal function attained by four months post-transplantation, ATN patients with good renal function (serum creatinine levels of less than 2 milligrams per deciliters) demonstrated similar patient and functional graft survival rates when compared with IF patients with similarly good renal function. Thirty-eight per cent of patients with ATN never achieved good renal function (serum creatinine levels of more than 2.0 milligrams per deciliters) and were compared with 8 per cent of IF patients who likewise never achieved good renal function. These two groups were also found to be statistically similar with regard to the rates of patient survival and functional grafts. Thus, it is likely that, although the presence of ATN may predispose a patient to a higher risk of never achieving good renal function, the eventual long term outlook is similar for patients with ATN and those with IF. The most important determining factor in terms of ultimate functional graft survival appears to be relative to the quality of renal function in the early post-transplantation period.

Actuarial Analysis↗
PubMed1997

No trend toward a spontaneous improvement of hyperparathyroidism and high bone turnover in normocalcemic long-term renal transplant recipients.

Although hyperparathyroidism is a common feature in renal transplant recipients, the long-term course of parathyroid hormone (PTH) secretion in these patients is not well established, and the actual contribution of PTH to posttransplant bone disease remains incompletely understood. Therefore, we studied calcium-regulating hormones and serum osteocalcin, as a marker of bone remodeling, in 82 normocalcemic renal transplant recipients with good renal function who had received a graft 6 to 73 months previously and in 82 healthy subjects matched for age and sex. In all subjects, fasting serum and 24-hour urinary samples were collected. The transplant recipients had excessive PTH secretion (serum PTH, 6.9 +/- 0.5 pmol/L in recipients v 3.0 +/- 0.1 pmol/L in healthy subjects; P < 0.001) and high bone turnover (osteocalcin, 16.6 +/- 0.8 microg/L v 8.0 +/- 0.3 microg/L; P < 0.001). (Values are mean +/- SEM.) In addition, transplant recipients had a slightly higher ionized calcium than the healthy subjects, providing definite evidence of an inappropriate PTH secretion in renal transplant recipients. Furthermore, in subgroups of 25 recipients and 25 healthy controls matched for creatinine clearance, the results superimposed those obtained in the whole groups, suggesting that excessive PTH secretion and high bone turnover in renal transplant recipients did not merely reflect the moderately reduced renal function of some recipients. In the whole group of transplant recipients, PTH correlated positively with osteocalcin (r = 0.40; P < 0.001), suggesting that PTH contributes at least partly to posttransplant bone disease. Conversely, there was no correlation between serum PTH or osteocalcin and the delay from grafting. Therefore, our results provide no evidence for a spontaneous improvement of either persistent hyperparathyroidism or high bone turnover in normocalcemic long-term renal transplant recipients.

Adolescent↗
PubMed1998

[Immunopathologic studies on the effects of immunosuppressant FK 506 on penetrating keratoplasty rejection model in rat].

OBJECTIVES: To study the immunopathologic process of rejection, the effect of certain immune cells and molecules on rejection and elucidate the immunosuppressive mechanism of FK 506. METHODS: By using immunohistochemical techniques, the expression of CD(4)(+) cells, CD(8)(+) cells, macrophages, IL-2 receptor, MHC-II antigen, intercellular adhesion molecule-1 (ICAM-1) and lymphocyte function-associated antigen-1 (LFA-1) in rejected corneal grafts were studied. RESULTS: Immunohistochemical studies showed diffuse infiltration of CD(4)(+) cells, CD(8)(+) cells and macrophages, and strong expression of IL-2 receptor, MHC-II antigen, ICAM-1 and LFA-1 in rejected corneal grafts, especially in the acute rejection stage. FK 506 can inhibit the expression of these cells and molecules in the grafts. CONCLUSION: Keratoplasty rejection is significantly related to delayed type of hypersensitivity and cytotoxic T cells, and immune adhesion molecules and MHC-II antigen also affect the rejection process.

Animals↗
PubMed1993

Oncotic pressure, albumin and ileus: the effect of albumin replacement on postoperative ileus.

The effect of decreased colloid oncotic pressure, as seen in hypoalbuminemia and hypoproteinemia, upon intestinal function has been well delineated in the surgical literature. Patients undergoing abdominal aortic aneurysm resection or aortoiliac or aortofemoral bypass grafts are almost uniformly hypoalbuminemic postoperatively; with these two facts in mind, a prospective, randomized clinical study was undertaken to identify the role of serum albumin concentration on the length of postoperative ileus in this population. The main hypothesis was that patients whose albumin levels dropped below 3.5 gm/dL would have a more prolonged postoperative hospital course as a result of delay in return of bowel function when compared with those patients in whom the low albumin levels were exogenously acutely replenished to > 3.5 gm/dL. Albumin was replaced to a level greater-than or equal to 3.5 g/dL in one group of 37 patients (AR), with a control group of 32 patients (NR) not receiving any albumin. Return of bowel function was measured by the postoperative day that flatus was documented, as well as the postoperative day oral intake was resumed. Mean values were determined for each group, and t tests did not reveal a significant difference in postoperative day of flatus (AR mean = 4.06 days, NR mean = 4.16 days) or postoperative day of oral intake (AR mean = 4.0, NR mean = 3.75). Additional comparisons between the groups involving the number of postoperative days until a regular diet was begun (AR mean = 6.06, NR mean = 5.48) and length of postoperative hospital stay (AR mean = 9.16, NR mean = 8.43) failed to reveal significant differences.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗
PubMed1985

Regulation of transplantation immunity in vivo by monoclonal antibodies recognizing host class II restriction elements. II. Effects of anti-Ia immunotherapy on host T cell responses to graft alloantigens.

Results of the preceding report demonstrated that in vivo treatment with monoclonal anti-I-A antibodies provided an effective means of prolonging the survival of murine tail skin allografts. The mechanism of antibody action was shown to include the activation of alloantigen-specific suppressor T cells (Ts), although the relationship between Ts expression and graft survival was not determined. This issue was addressed in the current studies through a kinetic analysis of suppressor and effector T cell responses in control and treated allograft recipients. Donor-specific delayed-type hypersensitivity (DTH) and cytotoxic T lymphocyte (CTL) responses were detectable in untreated A/J recipients of B10.A allografts 8 days after transplantation, rising to near maximum levels by day 12. Rejection in these animals occurred by day 11. In contrast, the predominant cellular response of anti-I-A treated animals for 12 days after transplantation was that of transferable suppression, DTH and CTL reactivity not being evident until day 15, coincident with the decay of Ts activity. Rejection in these animals was observed approximately 19 days post-transplant. CTL responsiveness in the latter group could not be reconstituted by the addition of antigen-presenting cells to the secondary in vitro culture system, nor was the CTL deficit due to antibody carry-over. It is considered that the altered expression of effector cell responses to graft alloantigens is due at least in part to the in vivo inhibition of helper T cell activity by anti-I-A-induced Ts, and that rejection in the treated host results from an eventual decline in the functional expression of this regulatory T cell subset.

Animals↗