Modulation of antigen-specific T cell response by a non-mitogenic anti-CD3 antibody

Suppression of T cell response is the key to enhance graft survival and control autoimmune diseases. A mitogenic anti-CD3 monoclonal antibody (mAb), OKT3, has been used for decades to control acute rejection in organ transplantation. Although effective, the clinical use was limited by its side effects, such as cytokine release mediated by T cell activation. A low mitogenic humanized OKT3 with reduced FcR-binding (hgammaOKT3 Ala-Ala) was generated and tested in several clinical studies. Although hgammaOKT3 Ala-Ala demonstrated maintained efficacy and better safety it still activated T cells. To investigate if a non-mitogenic anti-CD3 mAb can be equally effective in immune suppression, a chimeric non-FcR-binding anti-mouse CD3 mAb (anti-CD3 IgG2a Ala-Ala) was generated. Unlike the hgammaOKT3 Ala-Ala, the mouse IgG2a Ala-Ala anti-CD3 mAb did not induce T cell activation as measured by proliferation, cytokine production and apoptosis. Nevertheless, the IgG2a Ala-Ala anti-CD3 mAb was equally effective in the inhibition of antigen-specific CD4+ T cell activation in vitro to that of the mitogenic anti-CD3 mAb (Anti-CD3 IgG2a). In vivo, the IgG2a Ala-Ala anti-CD3 mAb only induced transient reduction of peripheral and spleen T cells and did not trigger detectable cytokine release. Nonetheless, this non-mitogenic anti-CD3 mAb significantly prolonged islet graft survival as effectively as the mitogenic anti-CD3 mAb in an allogenic islet transplantation model. These results demonstrated that a non-mitogenic anti-CD3 mAb could be used as an effective immune modulator. It may also indicate that a true non-mitogenic version of OKT3 could further improve its safety profile for clinical use.     

Oral rehydration for viral gastroenteritis in adults: a randomized, controlled trial of 3 solutions

BACKGROUND: Pedialyte and Gatorade are advocated for the treatment of dehydration in viral gastroenteritis, but there is limited evidence to support their use. We examine the efficacy, safety, and palatability of Pedialyte, Gatorade, and a New Oral Rehydration Solution (N-ORS). This was a randomized double-blind trial conducted in an inpatient, community hospital. Seventy-five consecutive adult patients (male, 42; female, 33) admitted with viral gastroenteritis were randomized to receive Gatorade, Pedialyte, or N-ORS for 48 hours. A yogurt/rice diet was allowed ad libitum. Stool and urine output, electrolytes, fluid intake, body weight, hematocrit, and palatability of solutions were measured. RESULTS: Sixty completed the study. Stool frequency, consistency, and body weight improved (p < .001) in all 3 groups, but there was no difference between groups. Likewise, urine output, hematocrit, and correlations between fluid ingested, stool weight, or urine output were similar. At admission and 24 and 48 hours later, hypokalemia was observed in 7, 10, and 8 patients with Gatorade; 3, 2, and 1 with N-ORS; and 2, 2, and 1 with Pedialyte, respectively. Similarly, hyponatremia was observed in 6, 9, and 3 patients with Gatorade; 5, 3, and 4 with N-ORS; and 4, 5, and 4 with Pedialyte. Tastewise, Gatorade and N-ORS were rated higher (p < .05) than Pedialyte. Limitations were a smaller sample size and higher dropout (20%). CONCLUSIONS: Gatorade and N-ORS seem to be as effective as Pedialyte in correcting dehydration and in improving bowel symptoms. All 3 solutions were safe. Unlike other groups, hypokalemia persisted in the Gatorade group. Gatorade and N-ORS may be effective in the treatment of dehydration associated with mild viral gastroenteritis.     

The new training paradigms and the unfilled match positions of 2004: Will history repeat itself?

OBJECTIVE: The new millennium has seen an increase in vascular residency vacancies. The American Board of Vascular Surgery recently proposed new training paradigms, but their impact on recruitment remains unknown. We surveyed vascular fellows regarding factors and timing of career decisions to determine an optimal strategy for recruitment. METHODS: Surveys were sent electronically to vascular residents for completion. Data were analyzed using SPSS software. Additional data were obtained from the National Resident Matching Program. RESULTS: Of the 90 fellows that responded, 84% committed to vascular surgery during residency. Of these, 18% decided during postgraduate year 1, 54% by year 2, 84% by year three, and 95% by year 4. Sixteen percent of all trainees decided in medical school. Seventy-three percent of residents performed a minimum of 20 to 50 cases before reaching a decision. Among the group deciding between years 2 to 4 of residency, there was a significant difference in the number of vascular rotations before career commitment (P = .0001). In the 2004 Match, 21% of vascular residency positions were unfilled, up from 12% in 2003, 9% in 2002, and 4% in 2001. CONCLUSIONS: Leaders in the field of vascular surgery have proposed focused training through the new paradigms. The incline in unmatched vascular residency positions over the past 4 years highlights the importance of a strategic plan to optimize recruitment. Few current trainees decided early in training about career choice, and volume appears critical to the decision process. Utilizing the current matching system (an 18-month process) and without any proactive change in recruitment, an integrated program after medical school would be reasonable for only 16% of applicants, or the 3+3 option for 54% of residents. For the new paradigms to be successful and to prevent more unfilled positions, increased medical student integration into vascular rotations and early active exposure to endovascular and open procedures during general surgical training will be necessary across the country.     

Optimal utilization of donor grafts with extended criteria: a single-center experience in over 1000 liver transplants

OBJECTIVE: Severely limited organ resources mandate maximum utilization of donor allografts for orthotopic liver transplantation (OLT). This work aimed to identify factors that impact survival outcomes for extended criteria donors (ECD) and developed an ECD scoring system to facilitate graft-recipient matching and optimize utilization of ECDs. METHODS: Retrospective analysis of over 1000 primary adult OLTs at UCLA. Extended criteria (EC) considered included donor age (>55 years), donor hospital stay (>5 days), cold ischemia time (>10 hours), and warm ischemia time (>40 minutes). One point was assigned for each extended criterion. Cox proportional hazard regression model was used for multivariate analysis. RESULTS: Of 1153 allografts considered in the study, 568 organs exhibited no extended criteria (0 score), while 429, 135 and 21 donor allografts exhibited an EC score of 1, 2 and 3, respectively. Overall 1-year patient survival rates were 88%, 82%, 77% and 48% for recipients with EC scores of 0, 1, 2 and 3 respectively (P < 0.001). Adjusting for recipient age and urgency at the time of transplantation, multivariate analysis identified an ascending mortality risk ratio of 1.4 and 1.8 compared to a score of 0 for an EC score of 1, and 2 (P < 0.01) respectively. In contrast, an EC score of 3 was associated with a mortality risk ratio of 4.5 (P < 0.001). Further, advanced recipient age linearly increased the death hazard ratio, while an urgent recipient status increased the risk ratio of death by 50%. CONCLUSIONS: Extended criteria donors can be scored using readily available parameters. Optimizing perioperative variables and matching ECD allografts to appropriately selected recipients are crucial to maintain acceptable outcomes and represent a preferable alternative to both high waiting list mortality and to a potentially futile transplant that utilizes an ECD for a critically ill recipient.     

Metamizol (dipyrone,optalgin) in pregnancy,is it safe? A prospective comparative study

AIM: To assess the teratogenic effect of metamizol when used during the first trimester of pregnancy. METHODS: One hundred and eight women who used metamizol during the first trimester of pregnancy were recruited from 4 teratogen information centers in Israel (3) and in Italy (1). The study group was paired for age, smoking habits and alcohol consumption with a comparative group exposed to acetaminophen. RESULTS: Maternal demographics and history, birth weight, gestational age at delivery, rate of live births, spontaneous abortions and fetal distress were comparable in both groups. The rate of major malformations in the metamizol group (3%) did not differ significantly from the rate in the comparative group (2%) (P = 0.57, relative risk = 1.55, 95% confidence interval 0.26-9.05). CONCLUSIONS: Our data may suggest that exposure to metamizol during the first trimester of pregnancy is probably not associated with a significantly increased risk for malformations or spontaneous abortions.     

A sign of subarachnoid bleeding on cranial computed tomograms of pediatric head trauma patients

Of 109 children examined by cranial computed tomography soon after an acute head injury, a density in the region of the falx was identified in 24 patients, but disappeared on subsequent studies. The density measures in the range of blood and is thought to represent subarachnoid blood. It can be confused with falx calcification in adolescents and adults, but falx calcification is normally not seen in the pediatric population.     

Ochronosislike pigmentation from hydroquinone bleaching creams in American blacks

Two patients had pitch-black pigmentation and colloid milium formation following the use of 2% hydroquinone-containing bleaching creams. These are among the first known cases in American blacks, although this phenomenon has been recognized previously in African blacks. Ultrastructural studies indicated that the pigment was due to the formation of elastotic fibers. These fibers attained an enormous size and disintegrated, leaving irregular fibers and fragments dispersed in the dermis. It is important that this clinical picture be recognized, since the use of these bleaching creams is widespread.     

Computed tomography in meningitis

Summary Computed tomography in 34 cases of meningitis has revealed a spectrum of findings. In acute cases these include enlargement of the subarachnoid spaces, generalized contrast enhancement of the meninges and ependyma, sterile and pyogenic subdural collections, cortical infarction, and cerebral necrosis.