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Background: Universal Leukocyte Reduction (ULR) of blood components can minimize the incidence of many untoward reactions to blood transfusion. However, the cost of this process will be substantial. It has been suggested that the cost might be Offset by a reduction in the incidence of postoperative infection, thereby shortening the length of hospital stay (LOS), thus reducing the total cost of hospital care for transfused patients (pts). Reports of reduced LOS have relied on purely retrospective analyses, without proper control for other confounding factors. Since we instituted a policy of ULR at our 870 bed hospital for a period of 2 years (1992-3), we have the unique opportunity to examine LOS prior to, during and after discontinuing ULR. This capability provides a control for confounding factors that might affect LOS over time. Methods: Transfused patients undergoing coronary artery bypass graft surgery (CABG) were divided into 3 groups: Group 1=1991 (prior to ULR); Group 2=1992-3 (during ULR); and Group 3=1994 (following ULR). Three groups of controls were non-transfused CABG pts during these same time periods (Groups 4, 5 and 6). We examined hospital records to determine LOS, cost of hospital care, and incidence of postoperative infection. Analysis of variance was performed to compare the means among the three groups of pts and controls. Results: A total of 1217 pts received transfusion (Group 1=416, Group 2=404, Group 3=317). Controls were 508 pts (Group 4=152, Group 5=182, Group 6=174). Mean LOS for the transfused groups was 19, 17 and 14 days, respectively (p=0.001). For controls it was 12, 11 and 9 days, respectively (p=0.001). Mean cost of hospital care for transfused pts was: Group 1=$103,000, Group 2=$123,000, Group 3=$121,000 (p=0.001). For controls: Group 4=$66,000, Group 5=$72,000, Group 6=$78,000 (p=0.004). Mean incidence of any postoperative infection was: Group 1=11%, Group 2=13%, Group 3=7% (p=0.04). For controls: Group 4=7%, Group 5=7%, Group 6=2% (p=0.06). Discussion: Although there was a statistically significant reduction in LOS for transfused pts over the study periods, there was no evidence that the 1992-3 time period showed anything other than being an intermediate in the general time trend for decreasing LOS and increasing cost of hospital care. Furthermore, these trends paralleled those of non-transfused control pts. Finally, rates of postoperative infection showed no decline during the ULR years. Conclusion: ULR has been shown to reduce many of the complications of blood transfusion, but our data suggest that the cost may not be offset by reduced LOS and cost of hospital care. [ABSTRACT FROM AUTHOR]

Presents a case report on transfusion-associated graft-versus-host disease (TA-GVHD) in an immunocompetent recipient of unirradiated directed donor blood. Occurrence of TA-GVHD; Cause of TA-GVHD; Medical condition of the patient; Requirement for a definitive demonstration of TA-GVHD.

Background: The goal of autologous (auto) blood collection prior to elective surgery is primarily to reduce patient (pt) exposure to allogeneic (allo) blood. Commensurate with the increased safety of allo blood, the value of auto programs has been questioned. Furthermore, for certain groups of pts the very premise that auto predeposit prevents or reduces exposure to allo blood has been challenged. A tool designed to limit excessive exposure to allo blood while minimizing the wastage of untransfused auto units is the schedule of optimal preoperative collection of autologous blood (SOPCAB). We studied the transfusion requirements of pts undergoing radical retropubic prostatectomy (RP) in order to determine their optimal auto predeposit collection strategy. Methods: Records of all pts undergoing RP from 7/1/95 to 6/20/96 were evaluated. Transfusion requirements (auto and allo), discharge hct, and length of hospital stay were determined for two groups of pts: those who predeposited auto blood and those who did not. There were no recognizable clinical differences between those pts who chose to participate as auto donors and those who did not. For the purpose of this study, the SOPCAB is defined as the number of preoperatively collected units needed to protect approximately 90% of pts from exposure to allo blood. Results: The SOPCAB for the 86 auto participants was 2 units (that is, 88% of pts received either 0, 1, or 2 units of blood perioperatively). For the 26 pts not predepositing, the SOPCAB was 0 (88% received no transfusion). The mean length of stay (4.5 days for each group) and discharge hct (33% for auto donors and 31% for non-donors) were not significantly different. Moreover, of pts predepositing auto blood, 72 (84%) received perioperative transfusion, whereas of pts who did not predeposit, only 3 (12%) were transfused. Conclusion: Recent studies of pts undergoing routine gynecologic procedures have suggested that auto predeposit may be unnecessary. However, such procedures are typically not associated with substantial blood loss. We chose to examine transfusion requirements in RP, a procedure historically known to have high transfusion rates. In fact, in 1986 the SOPCAB for RP at our institution was 3 units. Clearly, improvements in surgical technique and transfusion practice require that institutions undertake periodic review of auto collection strategies. However, of particular importance, our current finding that RP pts who do not donate auto blood are rarely transfused supports the contention that auto donation may predispose these pts to receive blood transfusion. [ABSTRACT FROM AUTHOR]

Mushroom (amatoxin) poisoning from ingestion is a rare but life-threatening medical emergency characterized by gastrointestinal symptoms before progression to multisystem organ failure in severe cases. Many therapies of amatoxin intoxication have been described, including supportive care, medical therapies, detoxification strategies, and liver transplant. The evidence supporting these therapies remains limited due to the rarity of amatoxin poisoning and challenge of a timely diagnosis. We report a case of amatoxin poisoning in Los Angeles causing severe liver injury without acute liver failure treated successfully using medical therapies, gallbladder drainage, and plasma exchange., (© 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.)

Background: There is a small but growing number of thrombotic thrombocytopenic purpura (TTP) cases attributed to immune checkpoint inhibitor therapy, with nivolumab and ipilimumab therapy being the most frequently described in the literature., Study Design and Methods: This report evaluates the course of a patient with a history of metastatic adenocarcinoma of the lung who developed TTP following treatment with the PD-1 inhibitor Pembrolizumab. The patient was treated with six sessions of therapeutic plasma exchange and appeared to be in remission. Exacerbation occurred 4 days later, and seven more sessions of plasma exchange were performed along with four total doses of Rituximab, and a steroid taper with monitoring of platelet counts and ADAMTS13 activity., Results: His platelet count recovered to a peak of 318,000 UL with an ADAMTS13 activity of 77% at the time of discharge. The patient has been following up regularly for outpatient testing with no TTP relapse as of the completion of this report., Discussion: This is one of a few cases of Pembrolizumab-associated TTP reported in the literature with successful complete remission following treatment. Plasma exchange in this setting may be an especially beneficial therapeutic intervention because of the removal of both the anti-ADAMTS13 antibody as well as the immune system upregulating anti-PDL1 monoclonal antibody with replacement of ADAMTS13 from donor plasma. Longer duration of plasma exchange and monitoring for normalization of ADAMTS13 levels in addition to platelet count before cessation of treatment may improve durable remission rates in this entity., (© 2023 AABB.)

Anti-D in individuals with a weak D phenotype is an unexpected finding that may require additional investigation to determine whether the anti-D is an autoantibody or alloantibody. Further investigation may also include assessment of the patient's RHD genotype and exclusion of anti-G. We present a case of an 84-year-old man with the weak D type 2 genotype who developed an unexpected anti-D along with anti-C. Individuals with the weak D type 2 genotype are thought not to be at risk for developing alloanti-D, although the distinction between alloanti-D and autoanti-D may be difficult to ascertain. Furthermore, investigations may affect transfusion recommendations. This patient was restricted to crossmatch-compatible, D-C- red blood cells even though the clinical significance of the anti-D was uncertain. This report is one of a few reported cases of an individual with the weak D type 2 genotype with demonstrable anti-D but without evidence for alloanti-D., (© 2022 S. Phou et al., published by Sciendo.)

Background: COVID-19 convalescent plasma (CCP) is plasma collected from individuals who have recovered from SARS-CoV-2 infection. The FDA Emergency Use Authorization restricts use of CCP to high-titer units only. The purpose of this study was to determine if donor ABO blood group was associated with SARS-CoV-2 antibody response, and subsequent qualification as high-titer CCP., Methods: All CCP donations collected from April 21, 2020 to September 1, 2020 were included. The Abbott ARCHITECT semi-quantitative chemiluminescent microparticle immunoassay was used to assess IgG antibodies to the nucleocapsid protein of SARS-CoV-2. Units with a S/C value ≥4.5 were considered high titer., Results: A total of 232 CCP donations were evaluated. There were no significant differences in the distribution of sex, age, and interval from symptom resolution to donation by ABO blood group. The mean SARS-CoV-2 IgG antibody S/C value was significantly lower in blood group O donations (3.6), compared to blood group A (5.0) donations (p < .001). There was no difference in antibody response between the other blood group pairings. Blood group O donations resulted in a lower percentage of high-titer units (35%), compared to blood group A (60%), B (58%), and AB (65%) donations., Conclusion: Blood group O donations were found to have significantly lower levels of SARS-CoV-2 IgG nucleocapsid antibodies compared to blood group A donations and were less likely to produce CCP units that qualified as high titer. These findings may aid donor recruitment to promote availability of high-titer CCP to meet patient needs., (© 2021 AABB.)

Background: Severity of illness in COVID-19 is consistently lower in women. A focus on sex as a biological factor may suggest a potential therapeutic intervention for this disease. We assessed whether adding progesterone to standard of care (SOC) would improve clinical outcomes of hospitalized men with moderate to severe COVID-19., Research Question: Does short-term subcutaneous administration of progesterone safely improve clinical outcome in hypoxemic men hospitalized with COVID-19?, Study Design and Methods: We conducted a pilot, randomized, open-label, controlled trial of subcutaneous progesterone in men hospitalized with confirmed moderate to severe COVID-19. Patients were randomly assigned to receive SOC plus progesterone (100 mg subcutaneously twice daily for up to 5 days) or SOC alone. In addition to assessment of safety, the primary outcome was change in clinical status on day 7. Length of hospital stay and number of days on supplemental oxygen were key secondary outcomes., Results: Forty-two patients were enrolled from April 2020 to August 2020; 22 were randomized to the control group and 20 to the progesterone group. Two patients from the progesterone group withdrew from the study before receiving progesterone. There was a 1.5-point overall improvement in median clinical status score on a seven-point ordinal scale from baseline to day 7 in patients in the progesterone group as compared with control subjects (95% CI, 0.0-2.0; P = .024). There were no serious adverse events attributable to progesterone. Patients treated with progesterone required three fewer days of supplemental oxygen (median, 4.5 vs 7.5 days) and were hospitalized for 2.5 fewer days (median, 7.0 vs 9.5 days) as compared with control subjects., Interpretation: Progesterone at a dose of 100 mg, twice daily by subcutaneous injection in addition to SOC, may represent a safe and effective approach for treatment in hypoxemic men with moderate to severe COVID-19., Trial Registry: ClinicalTrials.gov; No.: NCT04365127; URL: www.clinicaltrials.gov., (Copyright © 2021 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Context: Controversy persists over: 1) how best to restore low serum 25-hydroxyvitamin D (25D) levels (vitamin D2 [D2] vs vitamin D3 [D3]); 2) how best to define vitamin D status (total [protein-bound + free] vs free 25D); and 3) how best to assess the bioactivity of free 25D., Objective: To assess: 1) the effects of D2 vs D3 on serum total and free 25D; and 2) whether change in intact PTH (iPTH) is more strongly associated with change in total vs free 25D., Design: Participants previously enrolled in a D2 vs D3 trial were matched for age, body mass index, and race/ethnicity. Participants received 50 000 IU of D2 or D3 twice weekly for 5 weeks, followed by a 5-week equilibration period. Biochemical assessment was performed at baseline and at 10 weeks., Setting and Participants: Thirty-eight adults (19 D2 and 19 D3) ≥18 years of age with baseline 25D levels <30 ng/mL were recruited from an academic ambulatory osteoporosis clinic., Outcome Measures: Serum measures were total 25D, free 25D (directly measured), 1,25-dihydroxyvitamin D, calcium, and iPTH. Urine measure was fasting calcium:creatinine ratio., Results: Baseline total (22.2 ± 3.3 vs 23.3 ± 7.2 ng/mL; P = .5) and free (5.4 ± 0.8 vs 5.3 ± 1.7 pg/mL; P = .8) 25D levels were similar between D2 and D3 groups. Increases in total (+27.6 vs +12.2 ng/mL; P = .001) and free (+3.6 vs +6.2 pg/mL; P = .02) 25D levels were greater with D3 vs D2. Percentage change in iPTH was significantly associated with change in free (but not total) 25D, without and with adjustment for supplementation regimen, change in 1,25-dihydroxyvitamin D, and change in calcium., Conclusions: D3 increased total and free 25D levels to a greater extent than D2. Free 25D may be superior to total 25D as a marker of vitamin D bioactivity.

Background: Human cytomegalovirus (HCMV) is the major viral etiology of congenital infection and birth defects. Fetal transmission is high (30%-40%) in primary maternal infection, and symptomatic babies have permanent neurological, hearing, and vision defects. Recurrent infection is infrequently transmitted (2%) and largely asymptomatic. Congenital infection is also associated with intrauterine growth restriction (IUGR)., Methods: To investigate possible underlying HCMV infection in cases of idiopathic IUGR, we studied maternal and cord sera and placentas from 19 pregnancies. Anti-HCMV antibodies, hypoxia-related factors, and cmvIL-10 were measured in sera. Placental biopsy specimens were examined for viral DNA, expression of infected cell proteins, and pathology., Results: Among 7 IUGR cases, we identified 2 primary and 3 recurrent HCMV infections. Virus replicated in glandular epithelium and lymphatic endothelium in the decidua, cytotrophoblasts, and smooth muscle cells in blood vessels of floating villi and the chorion. Large fibrinoids with avascular villi, edema, and inflammation were significantly increased. Detection of viral proteins in the amniotic epithelium indicated transmission in 2 cases of IUGR with primary infection and 3 asymptomatic recurrent infections., Conclusions: Congenital HCMV infection impairs placental development and functions and should be considered as an underlying cause of IUGR, regardless of virus transmission to the fetus.

Metatropic dysplasia is a clinical heterogeneous skeletal dysplasia characterized by short extremities, a short trunk with progressive kyphoscoliosis, and craniofacial abnormalities that include a prominent forehead, midface hypoplasia, and a squared-off jaw. Dominant mutations in the gene encoding TRPV4, a calcium permeable ion channel, were identified all 10 of a series of metatropic dysplasia cases, ranging in severity from mild to perinatal lethal. These data demonstrate that the lethal form of the disorder is dominantly inherited and suggest locus homogeneity in the disease. Electrophysiological studies demonstrated that the mutations activate the channel, indicating that the mechanism of disease may result from increased calcium in chondrocytes. Histological studies in two cases of lethal metatropic dysplasia revealed markedly disrupted endochondral ossification, with reduced numbers of hypertrophic chondrocytes and presence of islands of cartilage within the zone of primary mineralization. These data suggest that altered chondrocyte differentiation in the growth plate leads to the clinical findings in metatropic dysplasia., (Copyright 2010 Wiley-Liss, Inc.)

Background and Objectives: Intravenous Ig (IVIG) is used in renal transplantation for desensitization and treatment of antibody-mediated rejection (AMR). The infusion of high-dose IVIG is generally well tolerated, but there are reports of hemolytic anemia induced by anti-blood group antibodies present in IVIG. Here, we report our experience with IVIG-induced hemolytic anemia (IH) in ESRD patients receiving IVIG for desensitization or treatment of AMR., Design, Setting, Participants, & Measurements: All patients receiving IVIG for desensitization or for treatment of AMR were monitored for evidence of acute anemia and hemolysis. Markers of hemolysis, including direct antiglobulin tests, were recorded. Five different IVIG products were tested for isohemagglutinin titers., Results: There were 18 cases of IH in 16 patients. All identified cases received the IVIG product Gamunex, Gammagard liquid, or Privigen. All patients developing hemolysis were non-O blood types. Isohemagglutinin titers ranged from 1:2 to 1:64 in the various IVIG products, with higher titers noted in the liquid, nonlyophilized products., Conclusions: Acute IH is a significant complication of high-dose IVIG infusion. Identified risk factors include non-O blood type of the recipient and administration of liquid IVIG preparations with high titer anti-A/B IgG antibodies. We recommend monitoring hemoglobin 48 to 72 h after IVIG infusion. If the hemoglobin decreases, a hemolytic work-up is recommended. Hemolysis could be avoided in at risk patients by choosing a low titer product. However, other complications such as acute renal failure or thrombosis may be seen because the low titer products are usually hyperosmotic.

Cancer vaccine trials have failed to yield robust immune-correlated clinical improvements as observed in animal models, fueling controversy over the utility of human cancer vaccines. Therapeutic vaccination represents an intriguing additional therapy for glioblastoma multiforme (GBM; grade 4 glioma), which has a dismal prognosis and treatment response, but only early phase I vaccine trial results have been reported. Immune and clinical responses from a phase II GBM vaccine trial are reported here. IFN-gamma responsiveness was quantified in peripheral blood of 32 GBM patients given therapeutic dendritic cell vaccines. Posttreatment times to tumor progression (TTP) and survival (TTS) were compared in vaccine responders and nonresponders and were correlated with immune response magnitudes. GBM patients (53%) exhibited >or=1.5-fold vaccine-enhanced cytokine responses. Endogenous antitumor responses of similar magnitude occurred in 22% of GBM patients before vaccination. Vaccine responders exhibited significantly longer TTS and TTP relative to nonresponders. Immune enhancement in vaccine responders correlated logarithmically with TTS and TTP spanning postvaccine chemotherapy, but not with initial TTP spanning vaccination alone. This is the first report of a progressive correlation between cancer clinical outcome and T-cell responsiveness after therapeutic vaccination in humans and the first tracing of such correlation to therapeutically exploitable tumor alteration. As such, our findings offer unique opportunities to identify cellular and molecular components of clinically meaningful antitumor immunity in humans.

Useful and meaningful counseling following the discovery of a fetal loss or fetal anomalies requires an accurate diagnosis. In order to achieve this, our center utilized a multidisciplinary approach which included an ultrasonographer, perinatologist, genetic counselor, dysmorphologist, clinical geneticist, and pathologist. In this article, we report our experience with the analysis and evaluation of 534 cases seen between 1989 and 2000. In total, we were able to identify the cause of fetal loss in 369 cases (69%). In 98/369 cases (18.4%) the condition was attributed to a Mendelian process and in 78 (14.6%), to chromosomal abnormalities. The overall average maternal age was 31.6 years, the maternal age in cases of chromosomal abnormality was slightly higher (33.3 years). Our findings described below reiterate the clinical usefulness of a team specifically trained in the approach to fetal loss and/or fetal anomalies., ((c) 2007 Wiley-Liss, Inc.)

We report on six cases from four families with the newly described skeletal disorder diaphanospondylodysostosis (DSD). The characteristic radiographic findings included abnormal ossification of vertebral bodies, posterior rib gaps, missing ribs, and a downward tilt of the pubic rami, but normal long bones. The typical facial features of DSD cases were ocular hypertelorism, a short nose, depressed nasal bridge, and low set ears. Other distinctive findings included a short neck with bell-shaped thorax, and nephroblastomatosis. A history of consanguinity and affected siblings with unaffected parents supports autosomal recessive inheritance. Skeletal histology showed incomplete ossification of the ribs, vertebral bodies, and sacrum as well as incomplete formation of intervertebral discs. The posterior ribs were comprised of bone with intervening cartilage interrupted by dense fibrous tissue and skeletal muscle fascicles. These findings suggest abnormal development and differentiation of the paraxial mesoderm. Because of phenotypic similarities of DSD to Pax1 and Meox1 deficient mice, we sequenced genomic DNA from three unrelated DSD cases. No mutations were identified in the PAX1 and MEOX1 exons or flanking intronic sequences, excluding them as likely causative genes., (2007 Wiley-Liss, Inc)

Congenital polyvalvular disease is a spectrum of macroscopic and microscopic anomalies of the 4 valves of the heart. It is most commonly associated with chromosomal abnormalities, such as trisomy 13 and trisomy 18. Kowal-Vern et al. and Bartram et al. describe a total of 4 cases of congenital polyvalvular disease in patients with normal chromosomes by standard banding pattern analysis. Each of their patients, however, had associated extracardiac anomalies. Of the 8 previously reported cases of congenital polyvalvular disease with no extracardiac anomalies, chromosome analysis was not performed. We report a prenatally diagnosed case of polyvalvular disease with normal chromosomes and no extracardiac anomalies.

Lissencephaly is a brain malformation characterized by absence of gyral formation, resulting in a smooth brain surface. Histologic study shows severe anomalies of cerebral cortical development. Several lissencephaly syndromes have been described. Here we report a familial syndrome of lissencephaly, cleft palate, diffuse agyria, and severe cerebellar hypoplasia. Microscopic examination of the abnormally thick cerebral cortex showed absence of cortical layering, with preservation of the pia-glial barrier. This is the first report of recurrent lissencephaly with cleft palate and severe cerebellar hypoplasia in which these unique neuropathology findings are described. Autosomal recessive inheritance is suggested by recurrence in sibs within the same family, but germ cell mosaicism for a dominant mutation is not excluded., (Copyright 1999 Wiley-Liss, Inc.)

Objective: To assess the efficacy of pulse/synchronization cyclophosphamide/apheresis in patients with proliferative lupus nephritis., Methods: Eighteen patients with Class III or IV renal biopsies and chronicity indices <6 were prospectively randomized to receive 6 courses of parenteral cyclophosphamide over 8 months along with prednisone. Nine of these patients also received 3 daily plasmaphereses prior to each of the 6 courses of cyclophosphamide. Assessments compiled at 6 and 24 months included serum creatinine, albumin, anti DNA, 24-hour urine protein, and C3 complement along with SLAM scores., Results: Two out of nine patients in each group evolved end stage renal disease and 3/9 patients in each group went into a renal remission at 24 months. Serum albumin, C3 complement, and SLAM scores improved in both groups, and anti-DNA improved in the pulse/synchronization patients (P < 0.025). No intergroup comparisons were significant., Conclusion: The addition of pulse/synchronization apheresis to cyclophosphamide therapy does not improve the course of patients with proliferative lupus nephritis.

Plasma exchange (PE) is considered first-line treatment for thrombotic thrombocytopenic purpura (TTP) to the point that many clinicians regard it as definitive therapy. Studies have reported response rates to PE ranging from 39% to 78%. In our experience, a minority of patients have been cured solely by PE. While adjuvant therapies (e.g., vincristine, splenectomy) have proved effective in anecdotal reports, protocols using these therapies in the treatment of TTP have not been established. Management of TTP over a 15-year period was reviewed to evaluate (1) the rate of cure accomplished by PE alone, and (2) the potential benefit of additional therapies. The records of 29 consecutive patients with TTP treated by PE were reviewed and classified according to response to PE alone and the need for adjuvant therapy. Eight patients (28%) achieved remission and long-term survival with PE alone. With the addition of adjuvant therapy another 13 patients survived, bringing the total survival to 72%. Fifteen patients were treated with vincristine in addition to PE. Only three of seven patients receiving vincristine after failing to respond completely to PE survived, but survival increased to 88% (7 of 8) when vincristine was administered within 3 days of beginning PE. These data suggest that PE alone may not be sufficient therapy for most patients with TTP. Additional therapy is often needed to achieve long-term survival. While controlled trials will be necessary to prove the efficacy of vincristine, we believe that, given the minimal risk of vincristine toxicity and the grave consequences of ineffective therapy, routine administration of vincristine early in the course of PE should be considered.

Cervical teratomas are rare tumours which are the result of abnormal prenatal development. They are usually detected at birth, but can occasionally remain silent until adulthood. Obstruction of the airway is the major challenge in the neonatal period. Prenatal diagnosis allows for early consultation with paediatric surgical specialists, so that the time and place of delivery can be addressed, and planning for resuscitative efforts can be organized in advance. If the airway is quickly stabilized and resection of the tumour is not delayed, the prognosis is good. Cervical teratomas in neonates are usually benign; however, malignant transformation and metastasis can occur as a rare event, influencing long-term survival and prognosis. We present two cases of neonatal cervical teratoma detected prenatally by ultrasound. In one case, termination of the pregnancy was elected. In the other case, the child was delivered at 36 weeks' gestation, an airway was secured, and subtotal resection of the tumour was performed. No developmental or neurological deficit has been detected on long-term follow-up at 5 years of age. We present a review of the literature, with attention to outcome and potential for malignancy in neonatal cervical teratomas, in order to provide help in decision-making, once prenatal diagnosis is made.

We report an autopsy case of tuberous sclerosis complex (TSC) in a 20-week gestational age female fetus. The brain showed lesions suggestive of early cortical tubers and subependymal hamartomatous nodules. The large cells within these nodular clusters were variably immunoreactive for glial fibrillary acidic protein (GFAP) and vimentin and negative for synaptophysin and neurofilament. Subependymal radial glia expressed both vimentin and GFAP, but subpial radial glia either did not express these markers (in contrast to an age-matched control) or were absent. Tuberin expression was noted in heterotopic neurons in the white matter and brain cells consistent with Cajal Retzius cells in the neocortical molecular layer, very weakly in superficial cortical neurons, neurons in the basal ganglia, Purkinje cells and external granular cells of cerebellum, cranial nerve nuclei neurons, occasional germinal matrix cells, ependymal cells, choroid plexus epithelium, and pituitary gland neuroendocrine cells; it was not seen within the cells of subependymal nodules. The pattern of tuberin immunoreactivity was similar to that which we have observed in older TSC patients. Proliferating cell labeling indexes were comparable in the germinal matrix of the TSC patient and an age-matched control. Abnormal subpial radial glia may be responsible for some of the neuronal migration abnormalities that appear to result in neocortical tubers.

Concern has been raised regarding the quality and engraftment potential of peripheral stem cells obtained from mobilizing regimens containing BCNU. We compared the mononuclear cell (MNC) yields and engraftment times of neutrophils and platelets in twenty-nine patients who received autologous peripheral blood stem cell transplants at our institution. Sixteen patients with either refractory or resistant Hodgkin's disease or non-Hodgkin's lymphoma, were mobilized with a BCNU-containing regimen, mini-BEAM (BCNU 60 mg/m(2) on day 1, etoposide 100 mg/m(2) on days 1-3, cytarabine 150 mg/m(2)q12h on days 1-3, and melphalan 30 mg/m(2) on day 3). Thirteen patients with various malignancies were mobilized with non-BCNU containing priming regimens. All patients received rhGM-CSF (Leukine, Immunex, Seattle, WA) 250μg/m(2) subcutaneously daily from 24 hours after completion of mobilizing chemotherapy through the completion of leukapheresis. The mean mononuclear cell yields in the BCNU versus non-BCNU containing regimens were 2.15 and 1.97 × 10(8) MNC/kg [95% CI -.32 to.68] after a median of 3 and 3 leukaphereses respectively. The median time post-stem cell infusion to an absolute neutrophil count (ANC) of ≥0.5 × 10(9)/1 were 11 days and 13 days [mean 11.7 and 12.2, p = 0.99, 95% CI -2.5, 1.6], days to an ANC of ≥1.0 x 10(9)/1 were 13 and 13 [mean 13.8 and 13.1, p = 0.47, 95% CI-1.8, 3.3], days to a platelet count of ≥20 × 10(9)/1 were 9 and 9 days [mean 11.4 and 9.8, p = 0.10, CI -0.6, 4.0], and days to a platelet count of ≥50 × 10(9)/1 were 14 and 15 days (p = 0.14) respectively. Mini-BEAM, as a mobilizing regimen, is easily administered as an outpatient. Stem cells mobilized with this regimen produces similar mononuclear cell yields as compared to non-BCNU containing regimens. There was no difference in the engraftment times for ANC or platelets from stem cells mobilized with BCNU versus non-BCNU containing regimens.

TSC2 is a gene on chromosome 16p13.3 associated with the autosomal dominant neurocutaneous disorder, tuberous sclerosis complex (TSC). By using a partial nucleotide sequence from the cloned TSC2 and polymerase chain reaction methodology, we constructed a digoxigenin-labeled complementary DNA probe to examine TSC2 gene expression in autopsy- or biopsy-derived human tissues by in situ hybridization. TSC2 messenger RNA was widely expressed in various cell types throughout the body, including epithelia, lymphocytes, and cells with endocrine functions, e.g., adrenal cortex and anterior pituitary. It was prominently and selectively (within the central nervous system) expressed in pyramidal cells of the cerebral cortex and other motor neurons, e.g., in spinal cord and brainstem nuclei. Visceral TSC2 expression was comparable in autopsy tissues from patients with and without TSC; TSC2 messenger RNA expression was most prominent in cells with a rapid mitotic rate and turnover, e.g., epithelia and lymphocytes, with central nervous system pyramidal cells and other neurons being an obvious exception, and/or in cells with important secretory/transport functions. This widespread expression of the TSC2 gene supports the view that it encodes a protein vital to cell growth and metabolism or one that functions as a tumor/growth suppressor.

Background: Though earlier investigations have demonstrated the efficacy of autologous blood transfusion in reducing allogeneic blood exposure in patients undergoing heart or lung transplantation, questions remain regarding the safety of blood donation by patients with severe heart or lung disease., Methods: Response to autologous blood donation by candidates for heart and lung transplantation and a group of age- and gender-matched control subjects was studied. Heart rate, blood pressure, oxygen saturation, and cardiac rhythm were examined before and after phlebotomy, and response to orthostatic challenge was evaluated. Patients were also questioned regarding impressions of changes in subjective sense of well being. Differences between patients and control subjects were evaluated by the paired t test and Fisher's exact test. An alpha of 0.05 was used in all testing to determine statistical significance., Results: Eighteen candidates for heart transplantation, 16 candidates for lung transplantation, and their matched control subjects were studied. Though patients and control subjects differed with respect to baseline hemodynamic measurements, significant differences between the groups' responses to phlebotomy were not observed. After whole blood donation, orthostatic challenge resulted in a mean change in mean arterial pressure of -2.1 mm Hg in candidates for heart transplantation compared with a mean of +3.6 mm Hg in their control subjects (p = 0.062). In candidates for lung transplantation there was a mean change of +2.2 mm Hg after orthostatic challenge versus a mean change of +8.5 mm Hg in their control subjects (p = 0.052). Furthermore, no changes in cardiac rhythm or arterial oxygen saturation were detected., Conclusions: The hemodynamic effects of autologous blood donation in a group of patients with significant cardiac or pulmonary disease were not different from those observed in patients considered acceptable candidates for autologous blood collection. On the basis of these objective findings, we believe that patients with less severe degrees of heart or lung disease should not be excluded from participation in autologous blood donation programs.

Trisomy 22 is commonly found among spontaneous abortions, second in frequency of occurrence only to trisomy 16. Most earlier reports of surviving trisomy 22 cases in the literature are thought to represent the product of unbalanced 11;22 translocations or the result of undetected mosaicism, since this condition is thought to manifest early embryonic or fetal lethality. We present two strikingly similar cases of non-mosaic trisomy 22 surviving to late gestation. In this paper we emphasize the unique phenotype of this trisomy which included intrauterine growth retardation, microcephaly, broad flat nasal bridge with epicanthal folds and ocular hypertelorism, microtia, variable cleft palate, webbed neck, congenital heart defects involving anomalous great vessels, anorectal and renal anomalies, and hypoplastic distal digits with thumb anomalies. We also explore why some cases survive to late gestation. Confined placental mosaicism, a frequent finding in other lethal trisomies, has been ruled out in one of the cases. Molecular studies done to assess the parental origin of the extra chromosome in the other case showed that the non-disjunction originated during maternal meiosis II. Parental origin of the extra chromosome does not seem to play a role in late survival for trisomy 22.

Objective: To retrospectively identify unrecognized human immunodeficiency virus type 1 (HIV-1) infection among a cohort of children transfused as neonates before donated blood was routinely screened for HIV-1 antibody., Methods: Records at a large, private, metropolitan hospital were reviewed to identify children who were transfused as neonates between January 1980 and March 1985 and discharged alive from the hospital. Multiple data sources were used to locate these children. Parents or guardians were contacted, and their children were offered HIV-1 antibody testing and physical examination., Results: Of the 775 children identified as having received transfusions during the project period, 644 (83%) were located, and 443 (69%) were evaluated for HIV-1 infection. Among those evaluated, 33 (7%) had antibody to HIV-1, including 14 whose infections had not been previously diagnosed. At the time of enrollment, 13 children infected with HIV-1 were asymptomatic an average of 63 months after transfusion., Conclusion: HIV-1 antibody testing should be considered for all children, regardless of clinical status, who were transfused before routine blood donor screening was implemented in March 1985, particularly in areas with a high incidence of acquired immunodeficiency syndrome during those years.

We report two cases of mosaic trisomy 16 diagnosed by amniocentesis, with dysmorphic findings in both cases evident upon delivery. Following elective termination, case 1 demonstrated a trisomy 16 cell line in fetal skin (4 per cent) and placental tissue (64 per cent). Molecular studies on the disomic cell line indicated that both chromosome 16s were maternal in origin, suggesting loss of the paternal chromosome 16 from a trisomic zygote (uniparental heterodisomy). At birth, case 2 demonstrated only disomic cells in skin and blood, with trisomy 16 present in 4 per cent of cells from the amnion. Molecular studies confirmed both maternal and paternal contributions of the chromosome 16s. We analysed DNA from one previously reported case of mosaic trisomy 16 (Williams et al., 1992) and failed to find signs of uniparental disomy in this child with congenital heart defects. These cases had distinctive but different dysmorphic features. We suggest that trisomy 16 embryos may revert to disomy during the course of pregnancy, allowing for longer survival with various abnormalities in growth and morphogenesis. The clinical significance of prenatally detected mosaic trisomy 16 may not be completely defined by additional cytogenetic, molecular, and ultrasound studies.

Background: Autoantibody production by the fetus is thought to be extremely unlikely. Only one possible case of in utero autoantibody production against red cells by the fetus has previously been described., Study Design and Methods: A case of apparent red cell IgG autoantibody production in utero is reported., Results: This was established by a positive direct antiglobulin test in a newborn infant without evidence of maternal alloantibodies or autoantibodies. There was no evidence of clinically significant hemolysis at the infant's birth. After 6 weeks, his direct antiglobulin test remained strongly positive. The infant thrived without evidence of hemolysis, and after 6 months the direct antiglobulin test was negative., Conclusion: The production of autoantibodies to red cells in utero is possible, though rare. This did not result in apparent hemolysis in this patient.