Successful treatment of advanced retinopathy of prematurity

Thirty-nine eyes of 20 premature infants, mean birthweight 922 g, mean gestational age 27 weeks, with active retinopathy of prematurity (ROP), were treated. Thirty-one eyes with stage 3+ ROP and 180 degrees to 360 degrees of preretinal neovascularization received cryotherapy to ablate the zone of peripheral avascular retina. All underwent complete regression of active disease. Eight of these eyes subsequently developed retinal detachments due to ongoing vitreous traction. One detachment was inoperable. Six eyes were successfully reattached following scleral buckling surgery. One of these six redetached and became inoperable after 20 months. Pars plicata vitrectomy was not successful in reattaching the eighth case. Twenty-eight of these 31 eyes retain useful visual acuity with follow-up of 15 to 70 months (mean 41 months). There have been no complications resulting from cryotherapy. Eight other eyes with stage 4 ROP (traction retinal detachment) were treated with cryotherapy and scleral buckling surgery. All were initially reattached, but ongoing vitreoretinal traction caused redetachment in five. One was inoperable. "Open sky" vitrectomy was successful in reattaching three of the other four. Of the six cases that remained reattached with follow-up of 6 to 51 months, only two retain useful vision.     

Interethnic studies of TNF polymorphisms confirm the likely presence of a second MHC susceptibility locus in ankylosing spondylitis

The objective of this study was to investigate TNF promoter region polymorphisms for association with susceptibility to ankylosing spondylitis (AS). The TNF -238 and -308 polymorphisms were genotyped in 306 English AS cases and 204 ethnically matched healthy B27-positive controls, and 96 southern German AS cases, 58 B27-positive and 251 B27-negative ethnically matched controls. Additionally, the TNF -376 polymorphism was genotyped in the southern German cases and controls. In the southern German AS patients a significant reduction in TNF -308.2 alleles was seen, compared with B27 positive controls (odds ratio 0.4, P = 0.03, 95% confidence interval 0.2-0.9), but no difference in allele frequencies was observed at TNF -238. Significant association between AS and both TNF -238 and TNF -308 was excluded in the English cases. These results confirm previous observations in the southern German population of association between TNF promoter region polymorphisms and AS, but the lack of association in the English population suggests that these polymorphisms themselves are unlikely to be directly involved. More likely, a second, non-HLA-B, MHC locus is involved in susceptibility to AS in these two populations.     

Mature eosinophils stimulated to develop in human-cord blood mononuclear cell cultures supplemented with recombinant human interleukin-5. II. Vesicular transport of specific granule matrix peroxidase, a mechanism for effecting piecemeal degranulation.

The mechanism of piecemeal degranulation by human eosinophils was investigated. Mature eosinophils that developed in rhIL-5-containing conditioned media from cultured human cord blood mononuclear cells were prepared for ultrastructural studies using a combined technique to image eosinophil peroxidase by cytochemistry in the same sections on which postembedding immunogold was used to demonstrate Charcot-Leyden crystal protein. Vesicular transport of eosinophil peroxidase from the specific granule matrix compartment to the cell surface was associated with piecemeal degranulation. This process involved budding of eosinophil peroxidase-loaded vesicles and tubules from specific granules. Some eosinophil peroxidase that was released from eosinophils remained bound to the cell surface; some was free among the cultured cells. Macrophages and basophils bound the released eosinophil peroxidase to their plasma membranes, internalized it in endocytotic vesicles, and stored it in their respective phagolysosomes and secretory granules. Charcot-Leyden crystal protein was diffusely present in the nucleus and cytoplasm of IL-5-stimulated mature eosinophils. Extensive amounts were generally present in granule-poor and subplasma membrane areas of the cytoplasm in contrast to eosinophil peroxidase, which was secreted and bound to the external surface of eosinophil plasma membranes. These studies establish vesicular transport as a mechanism for emptying the specific eosinophil granule matrix compartment during IL-5-associated piecemeal degranulation.     

Immunodepression during Trypanosoma brucei gambiense infections in the field vole, Microtus montanus.

The effects of Trypanosoma brucei gambiense infections upon immune responses were examined in an outbred laboratory colony of field voles. Microtus montanus. Antibody levels to challenge with heterologous erythrocytes and bovine serum albumin were significantly depressed in infected animals. Trypanosome infections impaired both primary and secondary humoral responses, although previously established specific antibody levels were not affected by infection. Specific antibody-producing capabilities of previously infected, trypanoicidal drug-treated voles were found to be comparable to uninfected controls, within 3 days following chemotherapy. Cell-mediated hypersensitivity responses to oxazolone were also significantly depressed by trypanosome infection; responses to the initial sensitization of oxazolone and to secondary challenge treatments were depressed compared to uninfected controls. Possible mechanisms of trypanosome-induced immunodepression are discussed.     

Thyroid function, metabolic regulation, and depression

Evidence suggests that alterations in thyroid function are associated with depression. Thyroid hormones also play an essential role in regulating metabolism. They influence the balance between metabolic rate and caloric intake and thus affect body weight changes. Appetite and weight disturbances are common in the syndrome of depression. There may be changes in resting metabolic rate in depression as well. Hence an interrelationship between thyroid function, metabolic regulation, and depression is suggested. A basic model of metabolic regulation is presented and linked to changes in mood and various indices of thyroid function. The model is offered as an initial framework for studying endocrine and metabolic components of depression. Testable hypotheses are generated through the use of the model, and research strategies are discussed.     

Mechanisms of MHC class I-restricted antigen processing and cross-presentation

Summary: In this review, we discuss recent data from our laboratory that address two aspects of major histocompatibility complex (MHC) class I‐restricted antigen processing. First, we consider the nature of the peptide‐loading complex, which is the assembly of proteins in the endoplasmic reticulum (ER) into which newly synthesized MHC class I‐β₂ microglobulin (β₂m) heterodimers are incorporated, and the mechanisms involved in MHC class I assembly and peptide loading that are facilitated by the peptide‐loading complex. Second, we discuss mechanisms of cross‐presentation, the phenomenon whereby extracellular and luminal protein antigens can be processed by antigen‐presenting cells, particularly dendritic cells, and presented by MHC class I molecules to CD8⁺ T cells. The focus of the discussion is mainly on the human MHC class I system.     

Acute lung inflammation in rats induced by phorbol myristate acetate (PMA)

Intratracheal administration of PMA produces acute lung injury in part due to the generation of O₂-derived free radicals. This study evaluated the role of the antioxidant enzyme superoxide dismutase (SOD) in PMA-induced lung injury in the rat. PMA was instilled into rats intratracheally (20–60 g/kg), and the lungs were lavaged 4 hr later. Total number of cells recovered from lavage after PMA treatment was not different from the total number recovered from controls; lavagable PMNs increased in a dose-dependent manner. Albumin in lavage fluid (an index of lung vascular permeability) was significantly increased at 60 g/kg PMA. SOD (10,000 U)+PMA (60 g/kg) reduced the albumin level but significantly increased both total number of cells and number of PMNs recovered from lavage fluid. To investigate the possibility that SOD decreases the ability of PMNs to adhere, PMN aggregation was measuredin vitro. The results indicated that 10,000 U SOD can inhibit PMA-induced aggregation by 50%. In contrast, aggregation to other stimuli (e.g., fMet-Leu-Phe, A23187) was unaffected by SOD. We conclude SOD prevents PMA-induced lung permeability and diminishes PMN adherence.     

Postmortem molecular analysis of SCN5A defects in sudden infant death syndrome.

CONTEXT: Fatal arrhythmias from occult long QT syndrome may be responsible for some cases of sudden infant death syndrome (SIDS). Because patients who have long QT syndrome with sodium channel gene (SCN5A) defects have an increased frequency of cardiac events during sleep, and a recent case is reported of a sporadic SCN5A mutation in an infant with near SIDS, SCN5A has emerged as the leading candidate ion channel gene for SIDS. OBJECTIVE: To determine the prevalence and functional properties of SCN5A mutations in SIDS. DESIGN, SETTING, AND SUBJECTS: Postmortem molecular analysis of 93 cases of SIDS or undetermined infant death identified by the Medical Examiner's Office of the Arkansas State Crime Laboratory between September 1997 and August 1999. Genomic DNA was extracted from frozen myocardium and subjected to SCN5A mutational analyses. Missense mutations were incorporated into the human heart sodium channel alpha subunit by mutagenesis, transiently transfected into human embryonic kidney cells, and characterized electrophysiologically. MAIN OUTCOME MEASURES: Molecular and functional characterization of SCN5A defects. RESULTS: Two of the 93 cases of SIDS possessed SCN5A mutations: a 6-week-old white male with an A997S missense mutation in exon 17 and a 1-month old white male with an R1826H mutation in exon 28. These 2 distinct mutations occurred in highly conserved regions of the sodium channel and were absent in 400 control patients (800 alleles). Functionally, the A997S and R1826H mutant channels expressed a sodium current characterized by slower decay and a 2- to 3-fold increase in late sodium current. CONCLUSION: Approximately 2% of this prospective, population-based cohort of SIDS cases had an identifiable SCN5A channel defect, suggesting that mutations in cardiac ion channels may provide a lethal arrhythmogenic substrate in some infants at risk for SIDS.     

Aortocaval compression in the sitting and lateral decubitus positions during extradural catheter placement in the parturient

We prospectively studied the incidence of concealed aortocaval compression in parturients at term during identification of the extradural space. Forty ASA I or II parturients, at term and in active labour, who requested extradural analgesia were randomly allocated to one of two groups. Parturients in the first group (n = 22) were positioned in the left lateral decubitus position and those in the second group (n = 18) were in the sitting position. Cardiac output (CO) was recorded at one-minute intervals for five minutes before extradural catheter placement (supine position with a 15° wedge under the right side), and during and thereafter for five minutes (in the supine wedged position), using the BoMED NCCOM3-R7 thoracic electrical bioimpedance (TEB) monitor. The average of five CO_TEB recordings before positioning the patient were compared with the average of five CO_TEB measurements during and after extradural space identification. A change of >25% CO_TEB was considered beyond machine variability. Upper limb arterial pressure was recorded at one-minute intervals. In the left lateral decubitus position, 17 of 22 patients demonstrated a >25% reduction in CO_TEB compared with five of 18 patients in the sitting position (X²,P <0.01). The percentage change in CO_TEB in the lateral decubitus position (?29.8%, 95% CI ?17% to ?44%) was greater than the sitting position (?9.8%, 95% CI +36% to ?32%) (P <0.01). A decreased incidence of aortocaval compression during identification of the extradural space was demonstrated in the sitting position when compared with the left lateral decubitus position.