Transferring the C-terminus of the chemokine CCL21 to CCL19 confers enhanced heparin binding.

Chemokines direct the migration of cells during various immune processes and are involved in many disease states. For example, CCL19 and CCL21, through activation of the CCR7 receptor, recruit dendritic cells and naïve T-cells to the secondary lymphoid organs aiding in balancing immune response and tolerance. However, CCL19 and CCL21 can also direct the metastasis of CCR7 expressing cancers. Chemokine binding to glycosaminoglycans, such as heparin, is as important to chemokine function as receptor activation. CCL21 is unique in that it contains an extended C-terminus not found in other chemokines like CCL19. Deletion of this extended C-terminus reduces CCL21's affinity for heparin and transferring the CCL21 C-terminus to CCL19 enhances heparin binding mainly through non-specific, electrostatic interactions.

Search for the rare decays K(L)→π0π0µ+µ- and K(L)→π0π0X0→π0π0µ+µ-.

The KTeV E799 experiment has conducted a search for the rare decays, K(L)→π(0)π(0)µ(+)µ(-) and K(L)→π(0)π(0)X(0)→π(0)π(0)µ(+)µ(-), where the X(0) is a possible new neutral boson that was reported by the HyperCP experiment with a mass of (214.3 ± 0.5) MeV/c(2). We find no evidence for either decay. We obtain upper limits of Br(K(L)→π(0)π(0)X(0)→π(0)π(0)µ(+)µ(-)) < 1.0 × 10(-10) and Br(K(L)→π(0)π(0)µ(+)µ(-)) < 9.2 × 10(-11) at the 90% confidence level. This result rules out the pseudoscalar X(0) as an explanation of the HyperCP result under the scenario that the dsX(0) coupling is completely real.

Measurements of the decay KL-->e+ e- gamma.

The E799-II (KTeV) experiment at Fermilab has collected 83 262 K(L)-->e+ e- gamma(gamma) events above a background of 79 events. We measure a decay width, normalized to the K(L)-->pi0pi0pi(D)0 (pi0-->gammagamma, pi0-->gammagamma, pi(D0-->e+ e- gamma(gamma)) decay width, of Gamma(K(L)-->e+e-gamma(gamma))/Gamma(K(L)-->pi0pi0pi(D)0)=(1.3302+/-0.0046(stat)+/-0.0102(syst)) x 10(-3). We also measure parameters of two K(L)gamma*gamma form factor models. In the Bergström-Massó-Singer parametrization, we find Calpha(K*)= -0.517 +/- 0.030(stat) +/- 0.022(syst). We separately fit for the first parameter of the D'Ambrosio-Isidori-Portolés model and find alpha(DIP)= -1.729 +/- 0.043(stat) +/- 0.028(syst).

The nature and course of depression following myocardial infarction.

Two hundred eighty-three patients admitted to cardiac care units for myocardial infarction at two urban teaching hospitals were interviewed 8 to 10 days after infarction and 171 were reinterviewed 3 to 4 months later. Initially, 45% met diagnostic criteria for minor or major depression, including 18% with major depressive syndromes. Depression was not associated with the severity of cardiac illness but was associated with the presence of noncardiac medical illnesses. Three to 4 months after infarction, 33% of patients met criteria for minor or major depression. The large majority of patients who initially met criteria for major but not minor depression showed evidence of depression at 3 months and most patients with major depression had not returned to work by 3 months. Treatment of major depressive syndromes after myocardial infarction may reduce chronicity and disability, while minor depressive syndromes may be similar to normal grief and tend to be self-limited.

Luteinizing hormone (LH) receptor aggregation: modification of ferritin-LH binding and aggregation by prostaglandin F2 alpha and ferritin-LH.

The interaction of LH and its receptor was investigated by ultrastructural analysis of ferritin-LH (FELH) binding to isolated rat luteal cells in the absence and presence of prostaglandin F2 alpha (PGF2 alpha), an inhibitor of LH-stimulated cAMP production. FELH, with a molar ratio of FE to LH of 1:1, bound specifically to LH receptors, either singly or in small groups (microaggregates), at intervals on luteal cell surfaces. FELH elicited a dose-dependent increase in progesterone production, and its binding increased with increased FELH concentration. The number of LH receptors per cell, estimated from particle counts, was about 6.2 +/- 0.6 X 10(4), similar to estimates from Scatchard analysis of [125I]iodo-hCG binding. Microaggregate size increased in parallel with FELH binding. Only partial aggregation was seen at concentrations of FELH that elicited near-maximal progesterone secretion. Aggregation continued to increase at FELH concentrations beyond that required to elicit maximal progesterone secretion. In the presence of PGF2 alpha, FELH-stimulated progesterone production was attenuated, and FELH binding decreased from 2.9 +/- 0.4 X 10(4) to 2.1 +/- 0.3 X 10(4) receptors/cell. PGF2 alpha did not alter microaggregate size on cells labeled with FELH at 4 C when membrane fluidity was already reduced, but did substantially reduce microaggregate size at 37 C. We conclude that FELH binds initially at random sites on membranes of isolated luteal cells and that as binding increases, receptors aggregate into small groups. Furthermore, microaggregates are related in part to receptor occupancy and possibly also to levels of cAMP or activation of the adenylate cyclase mechanism.

Imipramine inhibiton of ragweed allergic conjunctivitis.

Twenty-seven patients sensitive to ragweed pollen were treated with topical imipramine 0.05% in one eye and vehicle in the other in a double-masked fashion. The eyes treated with imipramine showed significantly less redness, tearing, and discomfort after exposure to pollen extract. Imipramine, a tricyclic antidepressant, appears to be an effective antihistamine in the eye.

Clinical predictors of arrhythmia worsening by antiarrhythmic drugs.

Aggravation of ventricular arrhythmia is a serious, potentially lethal, side effect that can occur with all antiarrhythmic agents. The purpose of this retrospective case-controlled study was to identify clinically useful parameters that would predict aggravation of arrhythmia. Patients in whom arrhythmia worsened while taking either quinidine, mexiletine or encainide were selected and matched to 2 similar patients who never developed this drug complication with any antiarrhythmic tested. A number of hemodynamic, electrophysiologic and pharmacologic parameters were compared. Only the presenting arrhythmia and a left ventricular ejection fraction less than 35% identified patients at risk for drug-induced aggravation of arrhythmia. Patients who presented with either sustained ventricular tachycardia or ventricular fibrillation were 3.4 times more likely to have arrhythmia aggravation compared with patients presenting with nonsustained ventricular tachycardia or ventricular premature beats. Patients with a left ventricular ejection fraction less than 35% were 2.2 times more likely to develop this drug complication compared with patients with an ejection fraction greater than 35%. There was no association between other clinical parameters, electrocardiographic intervals, ventricular arrhythmia density, drug dose or drug levels and aggravation of arrhythmia. In addition, drug aggravation to 1 drug did not predict its occurrence with another drug of the same class. Patients with a history of a sustained ventricular arrhythmia, especially when left ventricular dysfunction is present, are at high risk for the development of aggravation of arrhythmia.

SCH 38057: a picornavirus capsid-binding molecule with antiviral activity after the initial stage of viral uncoating.

The activity of a new water-soluble molecule, SCH 38057, against picornaviruses is described. SCH 38057 inhibited plaque formation of selected entero- and rhinoviruses in a range of 10.2 to 29.1 microM (50% endpoint) and had a therapeutic index of 10 against poliovirus type 2 (polio 2) in HeLa cells. When administered orally or subcutaneously, SCH 38057 protected mice infected with either coxsackievirus B3 (CVB3) or echovirus-9 from mortality. The molecule provided a low level of protection against thermal inactivation of virus, indicating that SCH 38057 interacts with the picornavirus capsid. Binding studies with [3H]SCH 38057 revealed that the molecule binds to CVB3 and human rhinovirus 14 (HRV14) in a ratio of 29 and 19 molecules per viral particle, respectively. The affinity constant for SCH 38057 binding to CVB3 was 7.0 x 10(-4) M. When added to cultures of infected cells at 3 h after infection, SCH 38057 markedly inhibited viral RNA synthesis. This finding with lack of inhibition of attachment and loss of infectious virus after attachment were interpreted to indicate that, although SCH 38057 binds to the viral capsid, the molecule exerts its antiviral effect after the initial stage of picornavirus uncoating, i.e., after conversion of the 156S infectious viral particle to smaller subviral species.

Antimicrobial activity of merocyanine 540: a photosensitizing dye.

The antimicrobial activity of merocyanine 540 (MC 540), a photosensitizing dye previously used to purge malignant cells from autologous bone marrow grafts, was evaluated against a panel of Gram-positive and Gram-negative bacteria and Candida albicans in the presence and absence of light. In the absence of light, MC 540 demonstrated no antibacterial activity against any of the organisms tested. When combined with increasing intervals of photoillumination, growth inhibition was observed with all Gram-positive organisms tested except Mycobacterium fortuitum. Photosensitizing growth inhibition was also observed with Moraxella catarrhalis but not with any other Gram-negative bacilli including members of the Enterobacteriaceae, Pseudomonas aeruginosa, Acinetobacter baumannii, Stenotrophomonas maltophila, or Burkhoderia cepacia. These results suggested that differences in cell wall structure confer resistance to the photodamaging effects of the dye. MC 540 exhibited no antimicrobial activity against C. albicans in the presence or absence of light.

A prospective evaluation of the electrocardiographic manifestations of hypothermia.

OBJECTIVE: To determine the effects of body temperature, ethanol use, electrolyte status, and acid-base status on the electrocardiograms (ECGs) of hypothermic patients. METHODS: Prospective, two-year, observational study of patients presenting to an urban ED with temperature < or =95 degrees F (< or =35 degrees C). All patients had at least one ECG obtained. Electrocardiograms were interpreted by a cardiologist blinded to the patient's temperature. J-point elevations known as Osborn waves were defined as present if they were at least 1 mm in height in two consecutive complexes. RESULTS: 100 ECGs were obtained in 43 patients. Presenting temperatures ranged between 74 degrees F and 95 degrees F (23.3 degrees C-35 degrees C). Initial rhythms included normal sinus (n = 34), atrial fibrillation (n = 8), and junctional (n = 1). Osborn waves were present in 37 of 43 initial ECGs. Of the six initial ECGs that did not have Osborn waves present, all were obtained in patients whose temperatures were > or =90 degrees F > or =32.2 degrees C). For the entire group, the Osborn wave was significantly larger as temperature decreased (p = 0.0001, r = -0.441). The correlation between temperature and size of the Osborn wave was strongest in six patients with four or more ECGs (range r = -0.644 to r = -0.956, p = 0.001). No correlation could be demonstrated between the height of the Osborn waves and the serum electrolytes, including sodium, chloride, potassium, bicarbonate, BUN, creatinine, glucose, anion gap, and blood ethanol levels. CONCLUSIONS: The presence and size of the Osborn waves in hypothermic patients appear to be a function of temperature. The magnitude of the Osborn waves is inversely correlated with the temperature.

Variations in the electrocardiograms of young adults: are revised criteria for thrombolysis needed?

OBJECTIVE: The evaluation of chest pain in young adults has changed with the recognition of cocaine-induced myocardial ischemia. The high frequency of abnormal electrocardiograms (56-84%) in the cocaine-user population is largely due to "normal" electrocardiographic variants (early repolarization). The authors sought to determine the frequency of these "normal" variants in a young population, and whether these findings can be confused with acute ischemia. METHODS: A prospective convenience sample of subjects aged 18 to 35 without known heart disease was interviewed and had 12-lead electrocardiographic tracings performed. An emergency physician (physician 1) and a cardiologist (physician 2) read the tracings while blinded to patient history, age, and race. When the physicians disagreed, another physician adjudicated the diagnosis. RESULTS: Four hundred fourteen subjects (127 black, 175 Hispanic, and 112 Caucasian) were enrolled. Overall, 154 tracings (37%) were normal, 245 (59%) were abnormal but nondiagnostic for ischemia, and 15 (4%) were consistent with ischemia. Frequencies of repolarization "abnormalities" as determined by physicians 1 and 2, respectively, were: blacks, 32%, 51%; Hispanics, 26%, 35%; Caucasians, 17%, 27%; chi-squared, p = 0.02 and 0.0004. Patients with ischemic electrocardiograms according to physician 1 had a high frequency of repolarization "abnormalities" according to physician 2, and vice versa (100%, 61%). Electrocardiographic criteria for thrombolytic use per physician 2 were present in 31 patients (7%): blacks, 9%; Hispanics, 10%; and Caucasians, 2%; chi-squared, p = 0.03.

Community-acquired pneumonia in Christchurch and Waikato 1999-2000: microbiology and epidemiology.

AIMS: To prospectively record current epidemiology and microbiology of community-acquired pneumonia in two New Zealand centres. METHODS: Between July 1999 and 2000 all adults admitted to Christchurch and Waikato Hospitals with community-acquired pneumonia were screened for study inclusion. All those enrolled had their medical history, clinical variables, inpatient management and clinical outcomes recorded and standardised microbial diagnostic testing carried out. RESULTS: 474 participants were enrolled with a mean age of 64 years and a microbial diagnosis was made in 197 cases (42%). Streptococcus pneumoniae (14%), Haemophilus influenzae (10%) and Influenza A virus (7%), Legionella spp (4%) and Mycoplasma pneumoniae (3%) were the most commonly isolated organisms. An 'atypical' organism was diagnosed in 8% of cases compared to 30% and 23% in previous Christchurch and Waikato studies respectively. Fourteen of the 67 S pneumoniae isolates (21%) had reduced susceptibility to penicillin, all with a MIC < or = 2 microg/mL, a level of reduced susceptibility not associated with worse patient outcomes. Clinical outcome included a mean hospital stay of 6.7 days and a 6 week mortality of 6%. CONCLUSION: Although S pneumoniae was the most commonly isolated organism in this study there have been significant changes in the prevalence of atypical organisms since previous surveys. Ongoing surveillance of antibiotic resistance and variations in the prevalence of organisms causing community-acquired pneumonia is required to guide clinicians' empiric antibiotic use.