Menkes disease. New ocular and electroretinographic findings

OBJECTIVE: The authors describe new ocular and electroretinographic (ERG) features in Menkes disease. DESIGN: The study design is a case report. PARTICIPANTS: The authors studied two patients with Menkes disease. INTERVENTION: The authors performed complete ophthalmologic and ERG evaluations in both patients. MAIN OUTCOME MEASURES: The parameters used were slit-lamp biomicroscopy and ERG recordings. RESULTS: Aberrant lashes and anterior stromal hypoplasia of the iris are new findings, and profound delays in b-wave implicit time in well-developed photopic responses may be added as new ERG features. CONCLUSIONS: Patients with Menkes disease may have aberrant lashes, anterior stromal hypoplasia, and retinal degeneration.     

Outcome of the depressed elderly living in the community in Liverpool: a 5-year follow-up

BACKGROUND: Comparatively little is known about the long-term natural history of depressive disorders in the elderly living in the community. This is a follow-up of a subsample of the Continuing Health in the Community study random sample of the elderly population living in Liverpool. METHODS: The investigators followed up 120 cases of depression identified by a semi-structured interview schedule (GMS) for a period of 5 years. A similar number of other subjects defined as subcases of depression, other cases of mental illness and a random selection of non-cases were also included. RESULTS: The 5-year outcome for the cases of depression was worse than the outcome of the non-cases (relative mortality risk of 2.1, 95% confidence interval 1.1 to 3.9). Thirty-four per cent of the cases of depression died and 28% had dropped out during the follow-up. Of the 46 cases of depression who had a complete follow-up, 22% recovered from their symptoms, 30% were found to be AGECAT cases at one of the three follow-up waves, 24% were AGECAT cases at two of the three follow-up waves and the remaining 24% were AGECAT cases at each follow-up wave. Fifteen per cent of the surviving cases of depression were organic cases at the follow-up. Their anxiety comorbid state and depression score were identified as predictors of poor outcome. CONCLUSION: The findings of this study indicate that depressive disorders (most of which were untreated) found in the elderly community have a poor prognosis.     

The impact of Helicobacter pylori eradication on peptic ulcer healing

OBJECTIVE: Current literature was reviewed analyzing the outcome of peptic ulcer healing in relation to the results of the posttherapeutic Helicobacter pylori (HP) status. METHODS: Literature was reviewed along with an analysis of 60 studies, comprising a total of 4329 patients. RESULTS: Successful Helicobacter pylori eradication was found to induce a better response in peptic ulcer healing, regardless of diagnosis: gastric ulcer 88% vs 73% (odds ratio [OR] 2.7, p < 0.01), duodenal ulcer 95% vs 76% (OR 5.6, p < 0.0001), and peptic ulcer 95% vs 76% (OR 6.6, p < 0.0001), for patients having their HP infection successfully cured versus those remaining HP-positive, respectively (Fisher's exact test). For all evaluated time points (< or = 6, 7-8, and 10-12 wk after beginning treatment), HP-negative patients had higher healing rates than HP-positive patients (95% vs 82%, 94% vs 69%, and 96% vs 78% with corresponding OR of 4.2, 6.5, and 7.4, all p < 0.0001, Fisher's exact test). The use of concomitant acid suppression therapy during initial HP eradication provided a benefit on peptic ulcer healing only for patients with persistent HP infection (improved healing rates of 78% vs 67%; otherwise rates were 94-96%). Likewise, prolonged acid inhibition in HP treatment failures after the initial HP treatment phase resulted in 7-20% improved healing rates, whereas patients becoming HP-negative did not profit. CONCLUSION: Successful HP eradication therapy accelerates peptic ulcer healing even without concomitant acid suppression.     

Immunohistochemical analysis of transferrin receptor: regional and cellular distribution in the hypotransferrinemic (hpx) mouse brain

The hypotransferrinemic (hpx) mouse mutant produces <1% of the normal circulating level of transferrin (Tf). Heterozygote animals of this strain (hpx/+) have approximately 50% of normal plasma Tf levels. In this study we examine the cellular and regional distribution of Tf receptor (Tf-R) in the brain of wild type, hpx/+ and mutant (hpx/hpx) mice. Also, using slot-blot (immunoblot) analysis, we describe the relative amount of Tf-R in brain microvessels of hpx/+ animals compared with wild type. Tf-R was seen primarily in neurons throughout the brains of wild type, hpx/+ and hpx/hpx animals. Gray matter areas immunoreacted more robustly than white matter areas. Oligodendrocytes and third ventricle tanycytes, both of which we have previously described as iron-positive, did not immunoreact for Tf-R. Tf-R immunohistochemical reaction in wild type, hpx/+ and hpx/hpx brains appeared similar. Immunoblot analysis of isolated cortical microvessels from wild type and hpx/+ animals revealed no upregulation of Tf-R expression in hpx/+ (relative to normal) despite a 50% decrease in circulating Tf levels. These results indicate that Tf-R is primarily expressed by neurons and that half normal levels of Tf (hpx/+) or transferrin supplementation (hpx/hpx) are apparently sufficient for normal expression and distribution of Tf-R. Because of the lack of circulating Tf, but unaltered Tf-R expression, hpx mice could serve as a model for delivery of therapeutic agents via the Tf/Tf-R system.     

The metabolic anatomy of tremor in Parkinson's disease

OBJECTIVE: To identify regional metabolic brain networks related specifically to the presence of tremor in PD. BACKGROUND: The pathophysiology of parkinsonian tremor is unknown. Because tremor in PD occurs mainly in repose, we used resting state PET with 18F-fluorodeoxyglucose (FDG) to identify specific metabolic brain networks associated with this clinical manifestation. METHODS: We studied two discrete groups of eight PD patients with and without tremor using FDG/PET. Both patient groups were matched for gender, age, and Unified Parkinson Disease Rating Scale ratings for akinesia and rigidity. Ten normal volunteer subjects served as controls. RESULTS: Network analysis with the Scaled Subprofile Model was performed in two steps. 1) We computed the expression of the PD-related pattern (PDRP) identified by us previously in each of the PD patients and control subjects. Although PDRP subject scores were abnormally elevated in the combined PD cohort (p < 0.005), these values did not differ in the PD patient groups with and without tremor (p = 0.36). 2) We used SSM to analyze the data from the combined PD cohort comprising both patient groups. We found that PD patients with tremor were characterized by increased expression of a metabolic network comprising the thalamus, pons, and premotor cortical regions. Subject scores for this pattern were elevated in the tremor group compared with the atremulous patient group and the normal control group (p < 0.005). CONCLUSIONS: The findings suggest that PD patients with tremor are characterized by distinct increases in the functional activity of thalamo-motor cortical projections. Modulation of this functional anatomic pathway is likely to be the mechanism for successful interventions for the relief of parkinsonian tremor.     

Long term changes in brain cholinergic markers and nerve growth factor levels after partial immunolesion

The pathophysiology of central nervous system (CNS) inflammatory disease is dependent, in part, on leukocyte recruitment across the blood-brain barrier. The expression of cytokines and chemokines by astrocytes may contribute to this process. Astrocytes express monocyte chemoattractant protein-1 (MCP-1), an activator of monocytes and a chemoattractant for monocytes and activated T cells. We examined the regulation of MCP-1 expression in human fetal astrocytes following cytokine treatment in the presence and absence of transforming growth factor beta (TGF-beta). TGF-beta, TNFalpha and IL-1beta, but not IFNgamma, induced MCP-1 mRNA and protein. TGF-beta, in cotreatment with TNFalpha caused an additive increase in MCP-1 mRNA, but not protein. In combination with IFNgamma, TGF-beta significantly increased MCP-1 mRNA and protein, as compared to either untreated, TGF-beta- or IFNgamma-treated astrocytes. However, TGF-gamma in cotreatment with IL-1beta decreased MCP-1 mRNA and protein, as compared to IL-1beta alone. Treatment of astrocytes with TGF-beta prior to TNFalpha, IFNgamma or IL-1beta treatment significantly increased MCP-1 expression. The kinetics of cytokine expression in the CNS may differentially regulate astrocyte-derived MCP-1 expression and subsequent recruitment and activation of leukocytes.     

Acute cyanide toxicity caused by apricot kernel ingestion

A 41-year-old woman ingested apricot kernels purchased at a health food store and became weak and dyspneic within 20 minutes. The patient was comatose and hypothermic on presentation but responded promptly to antidotal therapy for cyanide poisoning. She was later treated with a continuous thiosulfate infusion for persistent metabolic acidosis. This is the first reported case of cyanide toxicity from apricot kernel ingestion in the United States since 1979.     

Performance of advanced resuscitation skills by pediatric housestaff

OBJECTIVE: To describe pediatric housestaff resuscitation experience and their ability to perform key resuscitation skills. DESIGN: Cohort study of 63 pediatric residents in a university-based training program. PARTICIPANTS AND METHODS: Investigators observed, scored, and timed resident performance on 4 key resuscitation skills. Cognitive ability was tested with 4 written scenarios. Housestaff provided self-reports of the number of months since their last American Heart Association Pediatric Advanced Life Support course, number of mock and actual codes attended, number of times skills were performed, and self-confidence with respect to resuscitation. RESULTS: A total of 45 pediatric residents (71%) participated. Median cognitive score was 5 (range, 1-5). Of all residents, 44 (97%) successfully bag mask-ventilated the mannequin; 24 (53%) and 36 (80%) used the correct bag and mask size, respectively. Thirty-nine residents (87%) placed a tube in the mannequin trachea, 12 (27%) checked that suction was working prior to intubation, and 30 (67%) chose the correct endotracheal tube size. Forty residents (89%) discharged the defibrillator, and 25 (56%) and 32 (71%) correctly chose asynchronous mode and infant paddles, respectively. Thirty-eight residents (84%) inserted an intraosseous line; 35 (78%) had correct placement. Median times for successful skill completion were 83 seconds for bag mask ventilation, 136 seconds for intubation, 149 seconds for defibrillation, and 68 seconds for intraosseous line placement. CONCLUSION: Pediatric housestaff previously trained in pediatric advanced life support were generally able to reach the end point of 4 key resuscitation skills but less frequently performed the specific subcomponents of each skill. This poor performance and the prolonged time to skill completion suggest the need for greater attention to detail during training.     

Posttranscriptional regulation of urokinase plasminogen activator receptor messenger RNA levels by leukocyte integrin engagement

As an adhesion receptor, the beta2 integrin lymphocyte function-associated antigen-1 (LFA-1) contributes a strong adhesive force to promote T lymphocyte recirculation and interaction with antigen-presenting cells. As a signaling molecule, LFA-1-mediates transmembrane signaling, which leads to the generation of second messengers and costimulation resulting in T cell activation. We recently have demonstrated that, in costimulatory fashion, LFA-1 activation promotes the induction of T cell membrane urokinase plasminogen activator receptor (uPAR) and that this induced uPAR is functional. To investigate the mechanism(s) of this induction, we used the RNA polymerase II inhibitor 5, 6-dichloro-1-beta-D-ribobenzimidazole and determined that uPAR mRNA degradation is delayed by LFA-1 activation. Cloning of the wild-type, deleted and mutated 3'-untranslated region of the uPAR cDNA into a serum-inducible rabbit beta-globin cDNA reporter construct revealed that the AU-rich elements and, in particular the nonameric UUAUUUAUU sequence, are crucial cis-acting elements in uPAR mRNA degradation. Experiments in which Jurkat T cells were transfected with reporter constructs demonstrated that LFA-1 engagement was able to stabilize the unstable reporter mRNA containing the uPAR 3'-untranslated region. Our study reveals a consequence of adhesion receptor-mediated signaling in T cells, which is potentially important in the regulation of T cell activation, including production of cytokines and expression of proto-oncogenes, many of which are controlled through 3' AU-rich elements.     

A comparison of descriptive characteristics of male outpatients and inpatients with affective disorders

Recent studies of patients with affective disorders have found that there are biological differences between inpatients and outpatients. Concerned by these findings, we compared individuals admitted to our inpatient and outpatient affective disorders clinical research center who met criteria for major depression. We hypothesized that inpatients would be more severely ill, more suicidal, more functionally impaired, and have more co-morbid disorders and higher ratings of depression and mood state dysfunction. The demographic profiles, lifetime co-morbid Axis I diagnoses, consumption histories, symptom profiles, global assessment of functioning, and severity of current stressors (Axis IV) were compared and contrasted for the two groups. Inpatients had more severe current psychosocial stressors, lower current levels of functioning, increased lifetime co-morbid Axis I diagnoses, and increased rates of psychiatric hospitalizations, however, they did not have higher depression symptom ratings. In conclusion, inpatients and outpatients differed significantly in the severity of their stressors, coping abilities and history of previous hospitalizations, but not in most demographic variables or their current symptoms of depression.