Chromosome 1p terminal deletion: report of new findings and confirmation of two characteristic phenotypes

We report three unrelated patients with small terminal deletions involving 1p36.22-->pter that occurred de novo and compare our patients to the 10 previously reported cases. Although our patients have an identical cytogenetic deletion, patients 1 and 2 share similar clinical features that differ substantially from patient 3. Our patients confirm the existence of two characteristic phenotypes in 1p36.22-->pter deletion. Both phenotypes share some dysmorphic features, but are differentiated by characteristics of growth failure versus macrosomia. In addition, we report the new finding of cardiomyopathy and hydrocephalus in the phenotype associated with growth failure. It is possible that different phenotypic subgroups may exist because of differences in the parental origins of the deleted chromosome or of variations in undetectable amounts of genetic material.     

Is ambulatory electrocardiography useful in the evaluation of patients with recent stroke?

This study was designed to determine whether ambulatory electrocardiography in patients with recent stroke would lead to a change in clinical management or outcome and to express these findings in terms of cost benefit. A prospective, consecutive sample of patients (n = 100) with recent stroke referred from the neurology or medical services for ambulatory electrocardiography was identified. Ambulatory electrocardiograms were reviewed to identify patients with potentially important bradyarrhythmias, tachyarrhythmias, or atrial fibrillation. Patients were then followed up without interference with ongoing care to determine whether these findings led to changes in clinical management that might influence patient outcome. Of the 100 patients, 16 had an index "important" arrhythmia. No significant bradyarrhythmias were noted. Nonsustained ventricular tachycardia (> or = 6 complexes) in two patients and supraventricular tachycardia (> or = 10 complexes) in seven patients did not lead to management changes. Four patients had a history of atrial fibrillation who were in sinus rhythm; anticoagulation had been addressed in three; the fourth patient died before the issue could be addressed. Of three patients in atrial fibrillation, there was a history of atrial fibrillation and a decision regarding anticoagulation in each before monitoring. The cost of these 100 ambulatory electrocardiograms was about $55,000. In conclusion, these findings do not support the routine use of ambulatory electrocardiography in the evaluation of patients with stroke.     

Thymocyte activation induces the association of phosphatidylinositol 3-kinase and pp120 with CD5

Specific anions in tubular fluid, including uropontin (UP), the urinary form of human osteopontin (OPN), block adhesion to renal tubular cells of the most common crystal in kidney stones, calcium oxalate monohydrate (COM). In this study, monkey renal epithelial cells (BSC-1 line) in monolayer culture constitutively secreted UP into the culture medium. COM crystals added to the medium avidly bound previously secreted UP, reducing its concentration by 46% one hour later. However, the net UP content of cultures after a 24-hour exposure to COM crystals was increased by 18%. Northern blotting showed that the constitutively expressed gene encoding human OPN was maximally stimulated in BSC-1 cells after exposure to COM crystals for 12 hours. Two other calcium-containing crystals, hydroxyapatite and brushite, did not alter OPN gene expression or protein production. OPN mRNA expression was enhanced in canine renal epithelial cells (MDCK line) after exposure to COM crystals for six hours, whereas the constitutive expression of murine OPN mRNA by 3T3 fibroblasts was unchanged. In vivo this glycoprotein could defend the cell against adhesion of crystals in tubular fluid, and/or promote renal interstitial fibrosis in subjects with heavy crystalluria.     

Respiratory effects of intravenous midazolam

Thirty-four healthy, young-adult patients receiving intravenous midazolam for third-molar surgery had their respiratory parameters measured by respiratory inductive plethysmography. Tidal volume and minute volume showed significant changes during the initial 5-10 minutes of sedation, the changes being maximal during the first 5 minutes from the completion of injection of midazolam. The measurement of phase angle, an indicator of respiratory asynchrony, showed no significant change from normal, although a few patients showed some asynchrony of breathing, suggesting some amount of respiratory obstruction. A few patients showed a short period of apnoea and a small fall in the oxygen saturation. None of these changes caused any clinical concerns. It is suggested that the absence of stimulation after injection of midazolam, particularly in the initial few minutes, may contribute to the potential onset of respiratory problems.     

T cell receptor recognition of MHC class II-bound peptide flanking residues enhances immunogenicity and results in altered TCR V region usage

Naturally processed MHC class II-bound peptides possess ragged NH2 and COOH termini. It is not known whether these peptide flanking residues (PFRs), which lie outside the MHC anchor residues, are recognized by the TCR or influence immunogenicity. Here we analyzed T cell responses to the COOH-terminal PFR of the H-2A(k) immunodominant epitope of hen egg lysozyme (HEL) 52-61. Surprisingly, the majority of T cells were completely dependent on, and specific for, the COOH-terminal PFR of the immunogen. In addition, there were striking correlations between TCR V beta usage and PFR dependence. We hypothesize that the V alpha CDR1 region recognizes NH2-terminal PFRs, while the V beta CDR1 region recognizes COOH-terminal PFRs. Last, peptides containing PFRs were considerably more immunogenic and mediated a greater recall response to the HEL protein. These results demonstrate that PFRs, which are a unique characteristic of peptides bound to MHC class II molecules, can have a profound effect on TCR recognition and T cell function. These data may have important implications for peptide-based immunotherapy and vaccine development.     

Cloning and expression of a rat Smad1: regulation by TGFbeta and modulation by the Ras/MEK pathway

A mouse model of Rubinstein-Taybi syndrome (RTS) was generated by an insertional mutation into the cyclic AMP response element-binding protein (CREB)-binding protein (CBP) gene. Heterozygous CBP-deficient mice, which had truncated CBP protein (residues 1-1084) containing the CREB-binding domain (residues 462-661), showed clinical features of RTS, such as growth retardation (100%), retarded osseous maturation (100%), hypoplastic maxilla with narrow palate (100%), cardiac anomalies (15%) and skeletal abnormalities (7%). Truncated CBP is considered to have been acting during development as a dominant-negative inhibitor to lead to the phenotypes of RTS in mice. Our studies with step-through-type passive avoidance tests and with fear conditioning test showed that mice were deficient in long-term memory (LTM). In contrast, short-term memory (STM) appeared to be normal. These results implicate a crucial role for CBP in mammalian LTM. Our CBP +/- mice would be an excellent model for the study of the role of CBP in development and memory storage mechanisms.     

Psoriasiform eruption triggered by recombinant granulocyte-macrophage colony stimulating factor (rGM-CSF) and exacerbated by granulocyte colony stimulating factor (rG-CSF) in a patient with breast cancer

Colony-stimulating factors (CSFs) are commonly used for the treatment of neutropenia following chemotherapy and for the mobilization of peripheral blood stem cells (PBSC). We recently experienced a rare case of a new onset of psoriasiform eruption by GM-CSF (granulocyte-macrophage colony-stimulating factor) which was exacerbated by G-CSF (granulocyte colony-stimulating factor) in a patient with breast cancer. A 36-year-old woman had received neoadjuvant chemotherapy (cyclophosphamide, epirubicin and 5-fluorouracil), modified radical mastectomy and adjuvant chemotherapy with paclitaxel and mitoxantrone followed by GM-CSF administration for the treatment of locally advanced breast cancer. She had developed a psoriatic skin lesion on face and both upper arms during leukocyte recovery in spite of no previous history of psoriasis. Next, the chemotherapy course was complicated by a flare of mild psoriatic skin lesion, although CSF was changed into G-CSF due to GM-CSF-associated psoriasis. Subsequently, she had had high-dose chemotherapy and autologous peripheral blood stem cell transplantation for consolidation therapy. GM-CSF was administered for the mobilization of PBSC and post-transplant period, but psoriatic skin lesion did not appear. During 6 months after PBSCT, psoriasiform eruption did not appear.     

Dietary calcium, calcium supplementation, and blood pressure in African American adolescents

BACKGROUND: Intake of calcium from the diet is inversely associated with blood pressure in observational studies and animal models but randomized trials in humans have found only small effects of calcium supplementation on blood pressure. A blood pressure-lowering effect of calcium supplementation may thus be restricted to persons with a low intake of calcium from the diet and specific genetic or other characteristics. OBJECTIVE: A randomized trial was conducted to assess the effect of calcium supplementation on blood pressure in African American adolescents. Rapid growth during adolescence may increase calcium requirements, and avoidance of milk and milk products by some African Americans can result in low intake of calcium. DESIGN: One hundred sixteen adolescents (65 girls, 51 boys; mean age: 15.8 y) were given calcium (1.5 g/d) or placebo for 8 wk in a randomized, double-blind, crossover design. Blood pressure was measured after 2, 4, and 8 wk. Dietary calcium was determined with a validated food-frequency questionnaire. RESULTS: The net effect (+/-SE) of calcium supplementation on diastolic blood pressure was a reduction of 1.9 +/- 1.1 mm Hg (P = 0.04, one-tailed t test). Blood pressure reduction was greater in adolescents with lower intake of calcium from the diet (P = 0.003, one-tailed t test for interaction): -4.9 +/- 1.6, -2.3 +/- 1.6, and 1.4 +/- 1.8 mm Hg for change in the lower (0.024-0.067 g Ca/MJ), middle (0.069-0.091 g Ca/MJ), and upper (0.093-0.217 g Ca/MJ) tertiles, respectively. No main effect on systolic blood pressure was detected. CONCLUSION: These findings suggest that calcium supplementation may lower diastolic blood pressure in African American adolescents with low dietary intakes of calcium.     

Improved mineral balance and skeletal metabolism in postmenopausal women treated with potassium bicarbonate

BACKGROUND: In normal subjects, a low level of metabolic acidosis and positive acid balance (the production of more acid than is excreted) are typically present and correlate in degree with the amount of endogenous acid produced by the metabolism of foods in ordinary diets abundant in protein. Over a lifetime, the counteraction of retained endogenous acid by base mobilized from the skeleton may contribute to the decrease in bone mass that occurs normally with aging. METHODS: To test that possibility, we administered potassium bicarbonate to 18 postmenopausal women who were given a constant diet (652 mg [16 mmol] of calcium and 96 g of protein per 60 kg of body weight). The potassium bicarbonate was given orally for 18 days in doses (60 to 120 mmol per day) that nearly completely neutralized the endogenous acid. RESULTS: During the administration of potassium bicarbonate, the calcium and phosphorus balance became less negative or more positive--that is, less was excreted in comparison with the amount ingested (mean [+/- SD] change in calcium balance, +56 +/- 76 mg [1.4 +/- 1.9 mmol] per day per 60 kg; P = 0.009; change in phosphorus balance, +47 +/- 64 mg [1.5 +/- 2.1 mmol] per day per 60 kg; P = 0.007) because of reductions in urinary calcium and phosphorus excretion. The changes in calcium and phosphorus balance were positively correlated (P < 0.001). Serum osteocalcin concentrations increased from 5.5 +/- 2.8 to 6.1 +/- 2.8 ng per milliliter (P < 0.001), and urinary hydroxyproline excretion decreased from 28.9 +/- 12.3 to 26.7 +/- 10.8 mg per day (220 +/- 94 to 204 +/- 82 mumol per day; P = 0.05). Net renal acid excretion decreased from 70.9 +/- 10.1 to 12.8 +/- 21.8 mmol per day, indicating nearly complete neutralization of endogenous acid. CONCLUSIONS: In postmenopausal women, the oral administration of potassium bicarbonate at a dose sufficient to neutralize endogenous acid improves calcium and phosphorus balance, reduces bone resorption, and increases the rate of bone formation.