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Biomedical subjects

Phillip Ruiz

Publications and source records attributed to Phillip Ruiz.

At least 19 recordsLinked to original sources

IRF-4 and c-Rel expression in antiviral-resistant adult T-cell leukemia/lymphoma.

Adult T-cell leukemia/lymphoma (ATLL) is a generally fatal malignancy. Most ATLL patients fare poorly with conventional chemotherapy; however, antiviral therapy with zidovudine (AZT) and interferon alpha (IFN-alpha) has produced long-term clinical remissions. We studied primary ATLL tumors and identified molecular features linked to sensitivity and resistance to antiviral therapy. Enhanced expression of the proto-oncogene c-Rel was noted in 9 of 27 tumors. Resistant tumors exhibited c-Rel (6 of 10; 60%) more often than did sensitive variants (1 of 9; 11%). This finding was independent of the disease form. Elevated expression of the putative c-Rel target, interferon regulatory factor-4 (IRF-4), was observed in 10 (91%) of 11 nonresponders and in all tested patients with c-Rel+ tumors and occurred in the absence of the HTLV-1 oncoprotein Tax. In contrast, tumors in complete responders did not express c-Rel or IRF-4. Gene rearrangement studies demonstrated the persistence of circulating T-cell clones in long-term survivors maintained on antiviral therapy. The expression of nuclear c-Rel and IRF-4 occurs in the absence of Tax in primary ATLL and is associated with antiviral resistance. These molecular features may help guide treatment. AZT and IFN-alpha is a suppressive rather than a curative regimen, and patients in clinical remission should remain on maintenance therapy indefinitely.

Adult↗

Current status of transplantation of the small intestine.

The evolution of small bowel transplantation has been significant over the past 20 years to the point at which it can now be considered a viable and often successful option in the treatment of many forms of short bowel syndrome. A refinement of surgical techniques, improved immunosuppression, enhanced understanding of gut immunology, and better treatment and prevention of complications have contributed to a marked improvement in graft and patient survival. Whereas this transplant population is still beset with many potential complications after isolated bowel or multivisceral transplantation and long-term graft survival (like with other solid organ transplants) remains a challenge, the future holds promise for a continuation of the current positive trend of improvement in several areas.

Adult↗

Prolongation of skin graft survival by exogenous ubiquitin.

Recently, it was shown that exogenous ubiquitin has anti-inflammatory actions in vivo and that the ubiquitin-decapeptide 50-59 has immunosuppressive effects similar to cyclosporine. Immunosuppressive effects of the native ubiquitin molecule and its therapeutic potential in transplantation are unknown. We tested the hypothesis that ubiquitin inhibits alloreactivity and increases allograft survival in a murine model of skin transplantation in fully mismatched strain combinations (C3H/HEJ-DBA2). Ubiquitin dose-dependently inhibited mixed leukocyte reaction in C3H/HEJ splenocytes in vitro. Intraperitoneal ubiquitin administration (25 microg/h for 14 days) was well-tolerated, dose-dependently increased ubiquitin serum concentrations and median allograft survival from 10 days (with albumin; control) to 17 days in DBA2 mice (survival ratio: 1.7, 95% confidence interval: 1.266-2.134; P=0.0005). The in vivo effects in this study combined with our previous work strongly indicate that ubiquitin is a potent immune modulator with broad therapeutic potential. Ubiquitin treatment could be a novel strategy to improve immunosuppressive regimens in transplantation.

Animals↗

Angiotensin II causes hypertension and cardiac hypertrophy through its receptors in the kidney.

Essential hypertension is a common disease, yet its pathogenesis is not well understood. Altered control of sodium excretion in the kidney may be a key causative feature, but this has been difficult to test experimentally, and recent studies have challenged this hypothesis. Based on the critical role of the renin-angiotensin system (RAS) and the type I (AT1) angiotensin receptor in essential hypertension, we developed an experimental model to separate AT1 receptor pools in the kidney from those in all other tissues. Although actions of the RAS in a variety of target organs have the potential to promote high blood pressure and end-organ damage, we show here that angiotensin II causes hypertension primarily through effects on AT1 receptors in the kidney. We find that renal AT1 receptors are absolutely required for the development of angiotensin II-dependent hypertension and cardiac hypertrophy. When AT1 receptors are eliminated from the kidney, the residual repertoire of systemic, extrarenal AT1 receptors is not sufficient to induce hypertension or cardiac hypertrophy. Our findings demonstrate the critical role of the kidney in the pathogenesis of hypertension and its cardiovascular complications. Further, they suggest that the major mechanism of action of RAS inhibitors in hypertension is attenuation of angiotensin II effects in the kidney.

Angiotensin II↗

Liver glycogen bodies: ground-glass hepatocytes in transplanted patients.

Ground-glass hepatocytes have been described in Lafora's disease, fibrinogen deposition, hepatitis B, type IV glycogenosis, and alcohol aversion (cyanamide) therapy. We encountered ground-glass hepatocytes with intracytoplasmic inclusions in four liver biopsies from three transplanted patients who had none of the above-mentioned underlying diseases. One patient was a 4-year-old boy who had a kidney transplant for severe ureterovesical reflux. Patient 2 was a 52-year-old man who had two liver transplants because of hepatitis C. The third patient was a 7-month-old girl who underwent a multivisceral transplant because of necrotizing enterocolitis and liver failure induced by total parenteral nutrition. The patients developed liver abnormalities from 45 days to 4 years after their transplants. The livers showed conspicuous ground-glass hepatocytes in 90% of the children's samples and 30% of the adult liver cells. The cytoplasmic bodies stained strongly for Gomori methenamine-silver; they were positive for periodic acid-Schiff without diastase, but negative after diastase digestion. They were negative for colloidal iron and hepatitis B core and surface antigens. Electron microscopy revealed non-membrane bound aggregates of glycogen. Idiopathic ground-glass hepatocytes occur in transplanted patients and represent accumulation of altered glycogen. However, their clinical significance and cause are not entirely elucidated.

Child, Preschool↗

The importance of analyzing graft and patient survival by cause of failure: an example using pediatric small intestine transplant data.

BACKGROUND: Although graft and patient survival are vital in reporting overall results of clinical transplant studies, these outcomes do not account for distinct types of graft failure and death, which clearly exist in pediatric small intestine transplantation (Itx). The use of a cause-specific hazard (CSH) approach may provide more precise identification and thus greater insight as to why certain factors are prognostically important. METHODS: Among 119 pediatric patients who received primary Itx at our center since 1994, Cox model stepwise regression analyses were performed to identify prognostic factors for the following CSH rates: intestinal graft failure (IGF)/death due to rejection, death due to infection not triggered by IGF, and intestinal graft loss/death due to other causes. RESULTS: Two factors were associated with a significantly higher rate of developing IGF due to rejection (23 such failures): receiving an isolated intestine or liver-intestine transplant (P=0.00001) and receiving no induction agent (P=0.006). Conversely, age at transplant <1 year was the single factor associated with a significantly higher death rate due to infection (P=0.0005) (21 such deaths). Two characteristics were associated with a significantly higher death rate due to other causes: being in the hospital pretransplant (P=0.007) and not receiving daclizumab induction therapy (P=0.02) (24 such deaths). Although these four factors (transplant type/age/hospital status/induction therapy) were, for the most part, associated with graft/patient survival, the CSH analysis more precisely identified their prognostic value and achieved greater statistical power. CONCLUSIONS: A CSH approach should be used in conjunction with overall outcome analyses.

Cohort Studies↗

A randomized long-term trial of tacrolimus/sirolimus versus tacrolimums/mycophenolate versus cyclosporine/sirolimus in renal transplantation: three-year analysis.

BACKGROUND: We report three-year (interim) effects of combining sirolimus (Siro) vs. mycophenolate mofetil (MMF) as adjunctive therapy with calcineurin inhibitors (CI) in renal transplantation in the three different CI-based regimens. METHODS: Between May 2000 and December 2001, 150 recipients of deceased donor (DD) and living donor (LD) kidney transplants were randomized into three groups (n=50/group): Group A (Tacro/Siro), Group B (Tacro/MMF) and Group C (CsA/Siro). This report details drug dosing and monitoring, protocol discontinuance, biopsy-proven rejection, graft failure, other adverse events, and death at 36 months postoperatively. RESULTS: Actual patient and graft survival respectively in Group A was 90% and 82%, in Group B was 92% and 88%, and in Group C was 96% and 88% (not significant). Biopsy-confirmed acute rejection incidents showed a trend in favor of Group B (10%) vs. Group A (26%) and Group C (20%) combined (P=0.07). The geometric mean */SE serum creatinine concentration and arithmetic mean +/- SE Cockroft-Gault creatinine clearance calculations, respectively, were 1.39*/1.1 and 72.8+/-4.3 for Group A, 1.36*/1.1 and 72.1+/-4.1 for Group B, and 1.60*/1.1 and 61.8+/-3.8 for Group C, a statistically favorable difference for Group B over Group C (P=0.04). There was also less de novo development of posttransplant diabetes mellitus and lipid disorders in Group B vs. A and C (P<0.04). CONCLUSIONS: This three-year (interim) analysis has indicated a trend towards better graft function, fewer endocrine disorders, and fewer acute rejection episodes comparing adjunctive MMF and Tacro vs. Siro and Tacro or Siro and CsA, in the dosages used.

Adolescent↗

Composite tissue allotransplantation: classification of clinical acute skin rejection.

BACKGROUND: Composite tissue allotransplantation (CTA) is a recently introduced option for limb replacement and reconstruction of other nonreconstructible tissue defects. As with recipients of other allotransplants, CTA recipients can experience rejection episodes that are presumed to be mediated by immune mechanisms similar to those affecting solid organ grafts. However, a systematic examination of this process has not been performed, and there are no standardized criteria for the description of severity or type of rejection. METHODS: We collected biopsies from human limb allografts and abdominal walls in various stages of rejection for histological and immunohistochemical analysis to formulate a CTA rejection scheme. Biopsies were ranked by severity and reproducibility of the system was tested using a second set of biopsies. Tissue slides were examined blindly by three pathologists and the nonparametric Kendall coefficient of concordance (W) was used to assess the amount of agreement among the pathologists in their classification grades. RESULTS: Rejection initially appeared as a perivascular infiltrate progressing to involve the dermis. Arteritis was observed only in the medium to large size arteries of the subcutis. Myositis was seen occasionally. Perineural involvement without frank neuritis was present in advanced rejection. The infiltrate was predominantly CD4+ in milder cases and CD8+ in advanced cases. HLA-DR was minimally expressed in keratinocytes even in severe rejection. Kendall's W was 0.9375 (p< or =0.0001). CONCLUSIONS: Based on this survey, we proposed an initial classification system for acute rejection in the skin of a CTA and demonstrated that this system is easily reproduced by independent pathologists.

Antigens, Surface↗

Intestinal and multivisceral transplantation in children.

OBJECTIVE: To describe a single-center experience of pediatric intestinal transplantation (Itx) and to provide an overview of the children who underwent this procedure along with their outcomes. SUMMARY BACKGROUND DATA: Pediatric Itx presents multiple challenges because of the very young ages at which patients require transplantation and their higher susceptibility to infectious complications. METHODS: We have performed 141 Itx in 123 children with a median age of 1.37 years. Primary grafts included isolated intestine (n = 28), liver and intestine (n = 27), multivisceral (n = 61), and multivisceral without the liver (n = 7). Two protocol modifications were introduced in 1998: daclizumab induction and frequent rejection surveillance. In 2001, indications for multivisceral transplantation were expanded, and induction with Campath-1H was introduced. RESULTS: Actuarial patient survival at 1 and 3 years for group 1 (January 1994 to December 1997, n = 25), group 2 (January 1998 to March 2001, n = 29), group 3a (April 2001 to present, daclizumab, n = 51), and group 3b (April 2001 to present, Campath-1H, n = 18) was 44%/32%, 52%/38%, 83%/60%, and 44%/44%, respectively (P = 0.0003 in favor of group 3a). Severe rejection implied a dismal prognosis (65% mortality at 6 months). Observed incidence of severe rejection in groups 1, 2, 3a, and 3b was 32%, 24%, 14%, and 11%, respectively. In multivariable analysis, use of a multivisceral (with or without liver) transplant (P = 0.002), induction with daclizumab (P = 0.005), patient at home prior to transplant (P = 0.007), and age at transplant > or =1 year (P = 0.02) favorably influenced patient survival. Multivisceral transplant was protective with respect to the mortality rate due to rejection, while an older age at transplant was associated with both a lower incidence rate of developing respiratory infection and lower risk of mortality following the respiratory infection. Survivors are off parenteral nutrition and have demonstrated significant growth catch-up. CONCLUSIONS: Itx in children still is a high-risk procedure but has now become a viable option for children who otherwise have no hope for survival. Control of respiratory infection is of particular importance in the younger children.

Adolescent↗

Gastrointestinal tract ulcers in pediatric intestinal transplantation patients: etiology and management.

One of the observed complications in patients after intestinal transplantation is the occurrence of ulcers in the native or transplanted gastrointestinal tract. Previous reports have described the appearance of ulcers but have not described any systemic approach to accurately diagnose the etiology of the ulcer. We evaluated 112 intestinal transplantation patients at our institution, in which endoscopic examination identified ulcer formation in 11 patients. No common or defining demographic or clinical variables were found in the patients with ulcers. Biopsies were obtained from the ulcer edge as well as the intervening mucosa. The most common changes in the ulcers were compatible with post-transplant lymphoproliferative disorder (PTLD), acute rejection, and viral infections. These changes could occur simultaneously and retrospective analysis showed that ulcers could have concomitant etiologies. Endoscopically directed biopsies of ulcer edges often displayed morphologic changes compatible with acute rejection of the graft. Some patients were treated for rejection based on the changes within the mucosa outside the ulcer bed, and they responded with resolution of the ulcers. Our findings demonstrate that PTLD and acute rejection are the most common causes of chronic ulcer formation and reinforce the concept that biopsy samples should be collected simultaneously from both the ulcer edge and intervening mucosa.

Child↗

Utilization of dried blood spot citrulline level as a noninvasive method for monitoring graft function following intestinal transplantation.

BACKGROUND: Citrulline concentrations have been proposed as a marker for intestinal allograft rejection. We instituted dried blood spot (DBS) specimen monitoring of citrulline to simplify sample collection posttransplant. This study demonstrates the correlation between plasma and dried blood spot specimen citrulline concentrations after intestinal transplantation. METHODS: Plasma and DBS samples were analyzed by hydrophilic interaction chromatography tandem mass spectrometry. Comparison of the strength of linear correlation was made according to the type of surgery, sonication time, DBS citrulline levels, and the time interval between the blood sample collection and the assay date. RESULTS: A very strong linear correlation exists between the plasma and DBS citrulline concentrations (r=0.87; P<0.001). The correlation between plasma and DBS citrulline concentrations was maintained when evaluating only the intestinal transplant recipients. There was no significant difference in the strength of linear correlation according to sonication time, cirtrulline concentrations, or length of time to assay date. CONCLUSIONS: DBS citrulline monitoring will ease sample collection following intestinal transplantation and improve the ability to detect intestinal dysfunction and rejection by a noninvasive means.

Adult↗

Composite tissue allotransplantation: classification of clinical acute skin rejection.

BACKGROUND: Composite tissue allotransplantation (CTA) is a recently introduced option for limb replacement and reconstruction of other nonreconstructible tissue defects. As with recipients of other allotransplants, CTA recipients can experience rejection episodes that are presumed to be mediated by immune mechanisms similar to those affecting solid organ grafts. However, a systematic examination of this process has not been performed, and there are no standardized criteria for the description of severity or type of rejection METHODS: We collected biopsies from human limb allografts and abdominal walls in various stages of rejection for histological and immunohistochemical analysis to formulate a CTA rejection scheme. Biopsies were ranked by severity and reproducibility of the system was tested using a second set of biopsies. Tissue slides were examined blindly by three pathologists and the nonparametric Kendall coefficient of concordance (W) was used to assess the amount of agreement among the pathologists in their classification grades. RESULTS: Rejection initially appeared as a perivascular infiltrate progressing to involve the dermis. Arteritis was observed only in the medium to large size arteries of the subcutis. Myositis was seen occasionally. Perineural involvement without frank neuritis was present in advanced rejection. The infiltrate was predominantly CD4+ in milder cases and CD8+ in advanced cases. HLA-DR was minimally expressed in keratinocytes even in severe rejection. Kendall's W was 0.9375 (p<or=0.0001). CONCLUSIONS: Based on this survey, we proposed an initial classification system for acute rejection in the skin of a CTA and demonstrated that this system is easily reproduced by independent pathologists.

Acute Disease↗

Ocular adnexal lymphoma: a clinicopathologic study of a large cohort of patients with no evidence for an association with Chlamydia psittaci.

Non-Hodgkin lymphomas are among the most common primary tumors occurring in the ocular adnexa. Herein, we present a 14-year single-institution experience in 62 patients with primary ocular adnexal lymphomas (OALs). Association with Chlamydia psittaci infection is examined in 57 tumor specimens. Extranodal marginal zone lymphoma (EMZL) was the most frequent histologic subtype (89%). The majority of patients with EMZL (84%) presented with stage E-extranodal (IE), however only 16% had an advanced stage. All stage IE patients were treated with local radiotherapy, whereas patients with disseminated disease received systemic therapy with or without local irradiation. All but 1 patient with EMZL achieved complete remission (CR). During a median follow-up of 52 months (range, 3-153 months), the estimated 5-year overall survival (OS) and freedom from progression (FFP) were 96% and 79%, respectively. During the follow-up, 22% of patients relapsed, mainly in extranodal sites, and 4% transformed to diffuse large B-cell lymphoma. None of the patients exhibited local orbital failure in the radiation field. None of the OAL specimens harbored C psittaci DNA. Our study demonstrates that EMZLs, accounting for the majority of primary OALs, are characterized by an indolent natural history with frequent, continuous extranodal relapses. In South Florida, OALs are not associated with C psittaci infections.

Adult↗

Intrahepatic biliary strictures without hepatic artery thrombosis after liver transplantation: an analysis of 1,113 liver transplantations at a single center.

BACKGROUND: Intrahepatic biliary strictures (IHBS) without hepatic artery thrombosis (HAT) is a serious complication and known to increase the risk of graft failure after liver transplantation. This manuscript describes the incidence, risk factors, clinical pictures, management, and outcomes. METHODS: Between 1994 and 2002, 1,113 liver transplantations were performed in 974 adult patients. Data was retrospectively analyzed in terms of incidence, risk factors, clinical pictures (type of strictures), management (radiologic, surgical management), and outcomes. RESULTS: Sixteen (1.4%) grafts had IHBS without HAT. Specific risk factors were not identified from donors or recipients. However, ischemic factors from the donors were suspected from non-heart-beating donors (n=1) and cardiac-arrest donors (n=2). Three types of IHBS were identified: (1) diffuse type (n=7), (2) bilateral proximal type (n=7), and (3) unilateral type (n=2). Overall success rate of radiologic interventions was 31.3% (5/16). Of the 11 patients who did not improve, 6 died: diffuse type (3/7, 42.9%), bilateral type (3/7, 42.9%), and unilateral (0/2, 0%). Three patients had retransplantation, and two patients are waiting retransplantation. The majority of the IHBS were diffuse or bilateral (14/16, 87.5%), and rate of the graft failure was high (10/14, 71.4 %). Overall graft survival of IHBS was lower than that without IHBS (P=0.025). CONCLUSIONS: The majority of the IHBS without HAT were of a diffuse or bilateral proximal type. Patients with diffuse or bilateral proximal type have a low success rate from radiologic intervention and may benefit from early retransplantation.

Adult↗

Diagnostic testing of vitrectomy specimens.

PURPOSE: To assess the usefulness of diagnostic tests that are performed on vitrectomy specimens from patients with suspected lymphoma or infection. DESIGN: Noncomparative, retrospective, interventional case series. METHODS: Seventy-eight consecutive patients (84 eyes) underwent pars plana vitrectomy for diagnostic purposes. Vitrectomy with cytologic, cytofluorographic, or microbiologic analysis of vitreous samples was performed. The main outcome measures were the efficiency of diagnostic procedure and positive and negative predictive values (PPV and NPV). RESULTS: There were 28 patients (33 eyes) with suspected intraocular lymphoma and 50 patients (51 eyes) with suspected infection, which was subdivided into chronic endogenous endophthalmitis, atypical chorioretinitis, or chronic postoperative inflammation. Vitreous testing led to a diagnosis in 48 of 78 patients (61.5%); 14 patients with a final diagnosis of lymphoma/leukemia, and 34 patients with a final diagnosis of infection. When preoperative indication was compared with final clinical diagnosis, the efficiency of the diagnostic procedure of cytologic evaluation, flow cytometry, and bacterial/fungal culture was 67%, 79%, and 96%, respectively. For lymphoma, the PPV of cytologic evaluation was 100% and the NPV 60.9%. For infection, the PPV of bacterial/fungal culture was 100% and the NPV 94.9%. CD22+ B lymphocytes >or=20% of total cells on cytofluorographic analysis had a PPV of 88% for lymphoma. A cytofluorographic CD4:CD8 T-lymphocyte ratio >or=4 had a PPV of 70% for immunologically mediated uveitis. Surgical complications were rare and manageable. CONCLUSION: Diagnostic vitrectomy in selected patients with carefully planned testing is an effective means of supporting diagnoses in intraocular lymphoma, chronic intraocular infections, and atypical chorioretinitis. Flow cytometry quantitates the percentages and ratios of various cell types and is helpful in contrasting intraocular lymphoma with immunologically mediated uveitis.

Adult↗

Intestinal transplantation in children: a summary of clinical outcomes and prognostic factors in 108 patients from a single center.

We performed 124 intestinal transplants on 108 children (median age, 1.5 years) since 1994. Initial graft types included isolated intestine (I) (n=26), liver and intestine (LI) (n=26), multivisceral (MV) (n=50), and multivisceral without liver (MMV) (n=6). Four groups were defined by type of induction therapy: none, OKT3, or cyclophosphamide (August 1994-December 1997, n=25), early experience with daclizumab (January 1998-December 2000, n=26), recent experience with daclizumab (January 2001-April 2004, n=40), and Campath-1H (January 2001-April 2004, n=17). Actuarial patient survival at 1 year for groups 1-4 was 44%+/-10%, 54%+/-10%, 83%+/-6%, and 41%+/-12%, respectively, with group 3 having the most favorable survival (P=0.0004). Using Cox stepwise regression, the hazard rate of developing severe rejection was significantly higher in patients with transplant type I or LI (P=0.0002), with no difference between these groups (P=0.24) but a significantly higher rate for LI versus MV (P=0.005). Three factors associated with improved patient survival were recipient of MV or MMV (P=0.008), age at transplantation greater than 1 year (P=0.01), and use of daclizumab (P=0.0006). Cause-specific hazard analysis revealed a decreased rate of rejection-related mortality for recipients of MV or MMV (P=0.0007), whereas age greater than 1 year indicated a lower rate of infection-related mortality (P=0.0009). Pediatric intestinal transplantation provides an increasingly realistic chance of survival, particularly with the more recent use of daclizumab and multivisceral transplantation. A protective effect of multivisceral transplantation appears to exist with respect to the development of severe rejection.

Antibodies, Monoclonal↗

100 multivisceral transplants at a single center.

OBJECTIVE: The objective of this study was to summarize the evolution of multivisceral transplantation over a decade of experience and evaluate its current status. SUMMARY BACKGROUND DATA: Multivisceral transplantation can be valuable for the treatment of patients with massive abdominal catastrophes. Its major limitations have been technical and rejection of the intestinal graft. METHODS: This study consisted of an outcome analysis of 98 consecutive patients who received multivisceral transplantation at our institution. This represents the largest single center experience to date. RESULTS: The most common diseases in our population before transplant were intestinal gastroschisis and intestinal dysmotility syndromes in children, and mesenteric thrombosis and trauma in adults. Kaplan Meier estimated patient and graft survivals for all cases were 65% and 63% at 1 year, 49% and 47% at 3 years, and 49% and 47% at 5 years. Factors that adversely influenced patient survival included transplant before 1998 (P = 0.01), being hospitalized at the time of transplant (P = 0.05), and being a child who received Campath-1H induction (P = 0.03). Among 37 patients who had none of these 3 factors (15 adults and 22 children), estimated 1- and 3-year survivals were 89% and 71%, respectively. Patients transplanted since 2001 had significantly less moderate and severe rejections (31.6% vs 67.6%, P = 0.0005) with almost half of these patients never developing rejection. CONCLUSIONS: Multivisceral transplantation is now an effective treatment of patients with complex abdominal pathology. The incidences of serious acute rejection and patient survival have improved in the most recent experience. Our results show that the multivisceral graft seems to facilitate engraftment of transplanted organs and raises the possibility that there is a degree of immunologic protection afforded by this procedure.

Adolescent↗