Lipoprotein(a), Cardiovascular Disease,and Contemporary Management

Elevated lipoprotein(a) (Lp[a]) is a causal genetic risk factor for cardiovascular disease. To determine if current evidence supports both screening and treatment for elevated Lp(a) in high-risk patients, an English-language search of PubMed and MEDLINE was conducted. In population studies, there is a continuous association between Lp(a) concentrations and cardiovascular risk, with synergistic effects when low-density lipoprotein (LDL) is also elevated. Candidates for Lp(a) screening include patients with a personal or family history of premature cardiovascular disease, familial hypercholesterolemia, recurrent cardiovascular events, or inadequate LDL cholesterol (LDL-C) responses to statins. Given the comparative strength of clinical evidence, reducing LDL-C to the lowest attainable value with a high-potency statin should be the primary focus of lipid-modifying therapies. If the Lp(a) level is 30 mg/dL or higher in a patient who has the aforementioned characteristics plus residual LDL-C elevations (≥70-100 mg/dL) despite maximum-potency statins or combination statin therapy, the clinician may consider adding niacin (up to 2 g/d). If, after these interventions, the patient has progressive coronary heart disease (CHD) or LDL-C levels of 160-200 mg/dL or higher, LDL apheresis should be contemplated. Although Lp(a) is a major causal risk factor for CHD, no currently available controlled studies have suggested that lowering it through either pharmacotherapy or LDL apheresis specifically and significantly reduces coronary risk. Further research is needed to (1) optimize management in order to reduce CHD risk associated with elevated Lp(a) and (2) determine what other intermediate- or high-risk groups might benefit from Lp(a) screening.     

Serum calcium and phosphorus associate with the occurrence and severity of angiographically documented coronary heart disease, possibly through correlation with atherogenic (apo)lipoproteins.

The associations of serum calcium and phosphorus concentrations as well as other cardiovascular risk factors were investigated in relation to the existence and severity of coronary heart disease (CHD) in 260 clinically stable, angiographically defined CHD patients aged 40-70 years. The subjects were classified as CHD(+) cases if one or more coronary arteries had a significant stenosis (> or =70%) and CHD(-) controls if there was no stenosis (< or =10%) in any artery. The severity of coronary occlusion was scored on the basis of the number and extent of lesions, as normal, mild, moderate or severe. Fasting serum concentrations of electrolytes, lipids and (apo)lipoproteins were determined. The concentrations of serum total calcium (2.41 +/-0.14 vs. 2.33 +/- 0.22 mmol/L, p < or = 0.05), albumin-corrected calcium (2.33 +/- 0.25 vs. 2.23 +/- 0.25 mmol/L, p < or = 0.01), phosphorus (1.32 +/-0.21 vs. 1.25 +/- 0.17 mmol/L, p < or = 0.007) and the ion product of calcium and phosphorus (3.16 +/- 0.58 vs. 2.91 +/- 0.50, p < or =0.0001) were significantly higher in the CHD(+) compared to the CHD(-) group. Patients with CHD compared with controls had increased serum levels of triglyceride, total cholesterol, low-density lipoprotein-cholesterol (LDL-C), apolipoprotein B (apoB), lipoprotein(a) [Lp(a)] and decreased serum levels of high-density lipoprotein (HDL)-C and apoAI. Multiple logistic regression analysis showed strong and significant association between diabetes mellitus (odds ratio, OR = 5.24, p < or = 0.0001), male gender (OR = 8.84, p < or =0.0001), Lp(a) (OR = 1.014, p < or =0.006), hypertension (OR = 2.61, p < or =0.02), apoB (OR = 1.031, p < or =0.001), age (OR = 1.055, p < or =0.003), phosphorus (OR = 2.438, p < or =0.01), albumin-adjusted calcium (OR = 1.532, p < or =0.05), cholesterol (OR = 1.009, p < or =0.05) and the occurrence of CHD. On the basis of bivariate correlation analysis, serum-adjusted calcium was positively correlated with the levels of cholesterol (r = 0.285, p < or =0.0001), LDL-C (r = 0.320, p < or =0.0001), Lp(a) (r = 0.173, p < or = 0.005), apoB (r = 0.237, p < or =0.0001), LDL-C/apoB ratio (r = 0.180, p < or= 0.007), apoAI (r = 0.181, p < or =0.003) and inversely to HDL-C (r = -0.146, p < or =0.02) and HDL-C/apoAI ratio (r = -0.263, p < or =0.0001). Serum phosphorus concentration was a significant correlate of triglyceride (r = 0.199, p < or =0.001) and Lp(a) (r = 0.129, p < or =0.04). The results demonstrated that serum calcium and phosphorus are associated with the prevalence and severity of CHD, probably through correlation with atherogenic lipids and (apo)lipoproteins. Serum calcium and phosphorus and their ion product were also independent risk factors for CHD.     

Efficacy of phosphonylmethoxyalkyl derivatives of adenine in experimental herpes simplex virus and vaccinia virus infections in vivo.

The phosphonylmethoxyalkyl derivatives (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine [(S)-HPMPA], 9-(2-phosphonylmethoxyethyl)adenine (PMEA), and 9-(2-phosphonylmethoxyethyl)-2,6-diaminopurine (PMEDAP) were evaluated for their in vivo efficacies in several animal model infections, i.e., mice infected intravenously with vaccinia virus and mice infected intracutaneously, intraperitoneally, or intracerebrally with herpes simplex virus type 1 (HSV-1) or type 2 (HSV-2) or thymidine kinase-deficient (TK-) HSV-1. (S)-HPMPA inhibited the development of tail lesions caused by vaccinia virus if it was administered intraperitoneally or subcutaneously at a dosage as low as 5 mg/kg per day. All three compounds completely suppressed the development of skin lesions and the mortality associated therewith in hairless or athymic nude mice inoculated intracutaneously with HSV-1 or TK- HSV-1, if they were administered topically at a concentration as low as 0.1%; when (S)-HPMPA was applied topically at a concentration of greater than or equal to 0.3%, it completely abrogated mortality resulting from intracutaneous HSV-2 infection. Most dramatic were the effects shown by the compounds in mice inoculated intracerebrally with HSV-1, HSV-2, or TK- HSV-1, in which all three compounds given intraperitoneally at a dose of 50 or 100 mg/kg per day effected a significant reduction in the mortality rate of HSV-1-infected mice. The mortality of mice infected intracerebrally with HSV-2 or TK- HSV-1 was significantly reduced even when (S)-HPMPA was given at doses as low as 10 mg/kg per day. These data point to the great potential of the phosphonylmethoxyalkylpurines for both topical and parenteral treatment of HSV-1, HSV-2, and TK- HSV-1 infections.     

Accurate placement of central venous catheters using a 16-cm catheter

We determine if use of 16-cm central venous catheters (CVC) minimizes dangerous intracardiac catheter placements. We conducted a prospective study in a large community teaching hospital. Consecutive patients (n = 127) who required a CVC via either the internal jugular (IJV) or the subclavian vein (SCV) were assessed using 16 (n = 102) or 20-cm (n = 25) catheters. The main outcome measurements were (1) intracardiac placement of central venous catheters, and (2) relationship of right- or left-sided internal jugular or subclavian vein insertions to intracardiac catheter placement. Use of a 20-cm CVC resulted in 14 of 25 (56%) intracardiac placements compared with 11 of 102 (11%) using a 16-cm catheter (p < 0.0001). All intracardiac placements with the 16-cm CVC were from right-sided approaches: IJV 7 of 38 (16%), SCV 4 of 18 (18%). Use of a 16-cm CVC to access the central circulation from either the SCV or the IJV results in a significantly greater proportion of safe catheter placements than using longer CVCs, and it should become the standard of care.     

The ratio of apoB/apoAI, apoB and lipoprotein(a) are the best predictors of stable coronary artery disease.

BACKGROUND: The ratio of low- to high-density lipoprotein-cholesterol (LDL-C/HDL-C) conventionally represents the balance of proatherogenic and anti-atherogenic lipids. However, growing evidence supports the idea that the ratio of apolipoprotein (apo) B/apoAI is a better index for risk assessment of coronary artery disease (CAD). The aim of this study was to evaluate the efficiency of advanced profile of serum (apo)lipoproteins for predicting stable CAD in secondary prevention. METHODS: The study subjects, 138 men and 126 women aged 40-70 years, were classified as CAD cases or controls, according to the results of coronary angiography. The severity of CAD was scored on the basis of the number and extent of lesions in coronary arteries. Serum (apo)lipoproteins were measured by immunoturbidometric and electrophoresis methods. RESULTS: Patients with CAD compared with controls had increased serum levels of triglycerides (2.6+/-2.0 vs. 2.0+/-1.2 mmol/L, p< or =0.005), apoB (1.36+/-0.31 vs. 1.19+/-0.24 g/L, p< or =0.0001), lipoprotein(a) [Lp(a)] (0.69+/-0.60 vs. 0.43+/-0.31 g/L, p< or =0.0001) and apoB/apoAI ratio (1.07+/-0.32 vs. 0.87+/-0.18, p< or =0.0001), and decreased serum levels of HDL-C (1.02+/-0.29 vs. 1.11+/-0.34 mmol/L, p< or =0.03), apoAI (1.32+/-0.22 vs. 1.37+/-0.19 g/L, p< or =0.04) and LDL-C/apoB ratio (0.91+/-0.32 vs. 1.02+/-0.25 mmol/g, p< or =0.01). Multiple logistic regression analysis after adjusting for major risk factors showed that the apoB/apoAI ratio, apoB and Lp(a) were among seven significant and independent determinants of CAD. The area under the receiver operating characteristic (ROC) curves (AUC) as a relative measure of test efficiency was highest and significant for the apoB/apoAI ratio (AUC=0.71, p< or =0.0001), apoB (0.67, p< or =0.0001), Lp(a) (0.63, p< or =0.001), the LDL-C/apoB ratio (0.62, p< or =0.006), triglycerides (0.62, p< or =0.004) and apoAI (0.58, p< or =0.05). ANOVA analysis showed significant association for the apoB/apoAI ratio, apoB, Lp(a) and triglycerides, and moderate association for total cholesterol and its subfractions, with the severity of CAD. CONCLUSIONS: The results indicate that the apoB/apoAI ratio, apoB and Lp(a) are independent risk factors for CAD and are superior to any of the cholesterol ratios. We suggest using the apoB/apoAI ratio as the best marker of CAD in clinical practice.     

Modulation of human lymphocyte function by C3a and C3a(70-77)

Human C3a and the synthetic octapeptide C3a (70-77), which retains the activities of an anaphylatoxin, inhibit in a concentration-dependent manner the generation of leukocyte inhibitory factor (LIF) activity by human mononuclear leukocytes and T lymphocytes cultured with the mitogens phytohemagglutinin (PHA) or concanavalin A (Con A) or the antigen streptokinase-streptodornase (SK-SD). The generation of LIF activity was inhibited by 50% by 10(-8) M C3a or C3a(70-77) with PHA or Con A as the stimulus, whereas a more than 10-fold higher concentration of C3a(70-77) than C3a was required to achieve the same level of suppression with SK-SD as the stimulus. Similar concentrations of C3a(70-77) inhibited to the same extent the migration of T lymphocytes stimulated by alpha-thioglycerol of Con A. Neither C3a nor C3a(70-77) altered significantly the uptake of [3H]thymidine by human mononuclear cells exposed to PHA, Con A, or SK-SD. The capacity of C3a(70-77)- Sepharose,m but not Sepharose alone, to adsorb or inactivate mononuclear leukocytes required for the generation of LIF activity established a direct interaction. Analysis of the lymphocytes in the effluent from C3a(70-77)-Sepharose columns, using monoclonal antibodies to surface antigens, showed a selective depletion of the helper/inducer population of lymphocytes. C3a might represent an important mediator of the functionally selective regulation of human T lymphocyte activities by the complement system.     

Nitric oxide and its metabolites mediate ethanol-induced microtubule disruption and intestinal barrier dysfunction

Loss of gastrointestinal (GI) barrier integrity has been implicated in a wide range of inflammatory illnesses, including alcoholic cirrhosis. Using monolayers of Caco-2 (intestinal) cells as a model, we showed that the ability of ethanol (EtOH) to disrupt intestinal barrier integrity depends on damage to the microtubule (MT) cytoskeleton, especially oxidative injury. One drug that prevented both the MT damage and barrier disruption was L-N(6)-1-iminoethyl-lysine, a selective inhibitor of the inducible form of nitric-oxide synthase (iNOS). Because of this finding and because overproduction of nitric oxide (NO) and generation of peroxynitrite (ONOO(-)) have been proposed to be responsible for mucosal injury in other GI disorders, we sought to determine whether NO overproduction and ONOO(-) formation mediates EtOH-induced MT damage and loss of intestinal barrier function. To this end, Caco-2 monolayers were exposed to EtOH or to authentic ONOO(-) or ONOO(-) generators with or without pretreatment with iNOS inhibitors or antioxidants. We found that EtOH caused 1) iNOS activation, 2) NO overproduction, 3) increases in oxidative stress and superoxide anion production (superoxide dismutase quenchable fluorescence of dichlorofluorescein), 4) nitration and oxidation of tubulin (immunoblotting), 5) decreased levels of stable polymerized tubulin, and 6) increased levels of disassembled tubulin. EtOH also 7) extensively damaged the MT cytoskeleton and 8) disrupted barrier function. Authentic ONOO(-) or ONOO(-) donors had similar effects. Pretreatment with a selective iNOS inhibitor, L-N(6)-1-iminoethyl-lysine, or with antioxidants (ONOO(-) scavengers urate or L-cysteine; superoxide anion scavenger superoxide dismutase) attenuated damage due to EtOH or to ONOO(-) generators. We conclude that EtOH-induced MT damage and intestinal barrier dysfunction require iNOS activation followed by NO overproduction and ONOO(-) formation. These findings provide a rationale for the development of novel therapeutic agents for alcohol-induced GI disorders that inhibit this mechanism.     

Unilateral photophobia or phonophobia in migraine compared with trigeminal autonomic cephalalgias

Our objective was to compare the presence of self-reported unilateral photophobia or phonophobia, or both, during headache attacks comparing patients with trigeminal autonomic cephalalgias (TACs)—including cluster headache, short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) and paroxysmal hemicrania—or hemicrania continua, and other headache types. We conducted a prospective study in patients attending a referral out-patient clinic over 5 months and those admitted for an intramuscular indomethacin test. Two hundred and six patients were included. In episodic migraine patients, two of 54 (4%) reported unilateral photophobia or phonophobia, or both. In chronic migraine patients, six of 48 (13%) complained of unilateral photophobia or phonophobia, or both, whereas none of the 24 patients with medication-overuse headache reported these unilateral symptoms, although these patients all had clinical symptoms suggesting the diagnosis of migraine. Only three of 22 patients (14%) suffering from new daily persistent headache (NDPH) experienced unilateral photophobia or phonophobia. In chronic cluster headache 10 of 21 patients (48%) had unilateral photophobia or phonophobia, or both, and this symptom appeared in four of five patients (80%) with episodic cluster headache. Unilateral photophobia or phonophobia, or both, were reported by six of 11 patients (55%) with hemicrania continua, five of nine (56%) with SUNCT, and four of six (67%) with chronic paroxysmal hemicrania. Unilateral phonophobia or photophobia, or both, are more frequent in TACs and hemicrania continua than in migraine and NDPH. The presence of these unilateral symptoms may be clinically useful in the differential diagnosis of primary headaches.     

Time course characteristics of tolerance development to continuously infused antinociceptive agents in rat spinal cord

By using a constant-rate, fixed concentration intrathecal infusion model, the time course of change in hot plate (HP) response latencies over a 7-day period was examined in rats receiving constant infusion of saline (vehicle), morphine (MOR (2, 6 or 20 nmol/hr), sufentanil (SUF) (0.06, 0.2 or 0.6 nmol/hr), D-Ala2-MePhe4-Gly-ol5-enkephalin (DAMGO) (0.1, 0.3 or 1.0 nmol/hr) (mu opioids), D-Ala2-D-Leu5-enkephalin (DADLE) (2,6 or 20 nmol/hr) (delta opioid), ST-91 (3, 10 or 30 nmol/hr) (alpha-2 agonist) or the combination of ST-91 + MOR. Three important observations were made: 1) A concentration-dependent elevation in HP latency was observed on day 1 (order of potency: DAMGO = SUF greater than MOR greater than or equal to DADLE greater than or equal to ST-91 + MOR greater than or equal to ST-91) with a gradual return to saline-infused values observed for all concentrations of all drugs by 3 to 5 days. 2) The rate of tolerance development, estimated by calculation of the exponential decay half-life from peak day 1 HP, was not different as a function of drug dose. The area under the 7-day tolerance curve (response latency x day) was directly proportional to infusion concentration and to peak HP effect on day 1. These two calculations both suggest that the rate at which the tolerance adaptation of drug occurs to agonist effects is similar for agents acting upon mu, delta and alpha-2 receptors in rat spinal cord.(ABSTRACT TRUNCATED AT 250 WORDS)     

Clinical significance of uterine artery blood flow velocity waveforms during provoked uterine contractions in high-risk pregnancy.

OBJECTIVE: To determine whether, in a group of high-risk pregnancies undergoing an oxytocin challenge test (OCT), uterine artery Doppler velocimetry will identify fetuses at risk of distress during the provoked contractions. METHODS: Bilateral uterine artery Doppler velocimetry was performed simultaneously with electronic fetal heart rate (FHR) recordings in 67 high-risk pregnancies subjected to an OCT. Flow velocity waveforms (FVWs) were classified according to pulsatility index (PI), presence of diastolic notching and a novel classification of FVW shapes. The OCT was classified as negative (normal) or positive (late FHR decelerations). Only OCT-negative cases were allowed a trial of vaginal delivery. Non-parametric statistical methods were used to test for differences between the OCT groups. RESULTS: There was no difference in prevalence of high PI or diastolic notching in OCT-positive (n = 10) and OCT-negative (n = 57) cases at basal (resting) measurements or between uterine contractions in either uterine artery (P > or = 0.3). During contractions the PI could not be used for assessment due to the biphasic shape of the FVWs, but there was no difference in distribution of FVW classes between the groups in either the placental side (P > or = 0.3) or contraplacental side (P > or = 0.6) uterine artery. No significant associations between PI or FVW class distribution and birth asphyxia or operative delivery for fetal distress in labor were found (P > or = 0.1). CONCLUSIONS: During uterine contractions there is no difference in uterine artery FVW pattern between OCT-positive and OCT-negative cases. Recording of uterine artery FVWs during the OCT seems to be of limited clinical relevance.     

Permanent Pacemaker Placement in Chronic Atrial Fibrillation Associated with Intermittent AV Block and Cerebral Symptoms

We examined the hypothesis that a greater than or equal to 2 second pause detected on 24-hour Holter monitoring in patients with persistent atrial fibrillation and complaints of syncope or dizziness lacked sufficient specificity to warrant implantation of a permanent pacemaker. We retrospectively reviewed cases from our 24-hour electrocardiographic (Holter) monitoring data base. A total of 411 consecutive Holter monitoring records demonstrating persistent atrial fibrillation obtained during a 5-year period (1982 to 1987) were examined. One hundred and five (26%) patients had cerebral symptoms (dizziness or syncope) as a primary indication for monitoring 80 (76%) patients were identified with documented ventricular pauses of greater than or equal to 2 seconds. Three hundred and six patients (74%) underwent 24-hour monitoring without cerebral symptoms as an indication and 209 (68%) patients had greater than or equal to 2-second pauses. Clinical information was available in 164 (50 symptomatic and 114 asymptomatic) patients. There were no significant differences in the clinical or Holter findings between the two groups. Of the 50 symptomatic patients, 15 (30%) underwent permanent pacemaker placement and the remaining 35 (70%) were managed conservatively during a mean follow-up of 23 +/- 5 months. Eleven of 15 paced (73%) and 31 of 35 (89%) nonpaced patients experienced resolution of their cerebral symptoms (NS). The sensitivity of Holter monitoring in detecting pauses of greater than or equal to 2 seconds in patients with cerebral symptoms was high (76%), but the specificity (32%) and positive predictive values (28%) were low.(ABSTRACT TRUNCATED AT 250 WORDS)     

Initial Experience with Mode Switching in a Dual Sensor, Dual Chamher Pacemaker in Patients with Paroxysmal Atrial Tachyarrhythmias

Mode switching algorithms have been developed to avoid tracking of atrial fibrillation (AF) or flutter (AFL) during DDD(R) pacing. Upon recognition of AF or AFL, the mode is switched to a nontracking, sensor driven mode. The Vitatron Diamond model 800 pacemaker does this on a beat-to-beat basis. Atrial events occurring within a “physiological range” (± 15 beats/min) calculated from a running average of the atrial rate are tracked. When atrial events are not tracked the escape interval is either determined by the sensor(s) or by a fallback algorithm thereby preventing large increases in V-V interval during mode switching. Loss of atrioventricular (AV) synchrony by atrial premature beats and after an episode of AF or AFL is prevented by atrial synchronization pulses (ASP), which are delivered after a safe interval (timed out from the sensed premature atrial event) has expired and before delivery of the next ventricular stimulus. We implanted 26 such devices in 18 men and 8 women with symptomatic second- or third-degree AV block and paroxysmal AF or AFL. Their ages ranged from 18–84 years (mean 60), and the follow-up ranged from 2–13 months (mean 8). During pacemaker check-up, exercise testing or 24-hour Holter monitoring one or more episodes of mode switching was documented in 8 patients. In these 8 patients a smooth transition (ventricular rate) from sinus rhythm to AF or AFL was documented on one or more occasions, without inappropriate increase in ventricular rate in the DDDR mode. None of the patients complained of palpitations. Appropriate rate response was seen in all patients during Holter monitoring and exercise. Restoration of AV synchrony with ASP was documented many times. In 2 patients the DDIR mode was programmed due to intermittent synchronization of ventricular stimuli to near incessant supraventricular tachycardia, which sometimes gave rise to asymptomatic slightly irregular ventricular paced rhythms below WO beats/min. Recognition of AF or AFL was reliable. No inappropriate increases in ventricular pacing rate were seen at the onset of or during AF or AFL. ASP is an effective method of maintaining AV synchrony and avoiding competitive atrial pacing.     

Amino acid influences on seizures elicited within the inferior colliculus

Using a model in which seizure activity was elicited electrically from the inferior colliculus, the influence of both inhibitory and excitatory putative neurotransmitter amino acids on this seizure activity was assessed by manipulating neurotransmitter amino acid function. It was found that i.c.v. administration of the inhibitory amino acids taurine (2.5 micrograms) or glycine (30 micrograms), or the gamma-aminobutyric acidA agonist, muscimol (300 ng), significantly elevated the threshold current necessary to initiate seizure activity from the inferior collicular cortex. Similarly, the microinjection of muscimol (10 or 30 ng) or racemic baclofen (20 or 60 ng), a gamma-aminobutyric acidB agonist, into the inferior collicular cortex significantly elevated the seizure threshold current, but inferior collicular microinjections of taurine (1 microgram) or glycine (1 microgram) exerted no effect on the seizure threshold current. When excitatory amino acid influences were assessed on seizure production, neither ventricular administration of glutamate or aspartate (100 micrograms) nor inferior collicular administration of glutamate (1 or 10 micrograms) or aspartate (10 micrograms) changed the seizure initiation threshold. Although the site administration of 30 or 100 ng of N-methyl-D-aspartic acid did not alter the seizure initiation threshold, 300 ng of N-methyl-D-aspartic acid significantly lowered the amount of electrical stimulation necessary to elicit the seizure activity. Conversely, blockade of N-methyl-D-aspartic acid receptors in the inferior colliculus with L-3-amino-7-phosphonoheptanoic acid (100 ng) or gamma-glutamylglycine (200 ng) significantly elevated the threshold current for seizure production, whereas microinjection of DL-3-amino-phosphonobutyric acid (200 ng) or glutamic acid diethyl ester (1 microgram) had no effect.(ABSTRACT TRUNCATED AT 250 WORDS)     

Secretory carcinoma of the breast: sonographic features.

OBJECTIVE: The purpose of this series was to evaluate the sonographic features of secretory carcinoma of the breast. METHODS: Between 1994 and 2006, 9 patients had histologically confirmed secretory carcinoma of the breast in our institution, and 6 of them underwent breast sonography. We retrospectively evaluated the sonographic findings of the patients in correlation with other available images and reviewed the clinical records. RESULTS: Clinical manifestations were a palpable mass (n=3), a bloody nipple discharge (n=1), and screening-detected abnormalities (n=2). Breast sonograms showed masses with a round or oval (n=5) or tubular (n=1) shape, with relatively well-circumscribed (n=2) or partially microlobulated (n=4) margins, and with a hypoechoic (n=4) or an isoechoic (n=2) internal echo texture. Most lesions were single nodules (n=3) or groups of nodules (n=2) measuring 1 cm or smaller, except 1 mass measuring 3.5 cm with axillary lymph node metastasis. Two cases had associated ductectasia. Sonographic assessments were classified as Breast Imaging Reporting and Data System category 3 in 2 cases, category 4A in 3 cases, and category 4B in 1 case. CONCLUSIONS: Secretory carcinoma of the breast is frequently shown as a small benign-looking nodule or group of nodules or sometimes as an intraductal lesion with a low clinical stage on sonography. Although secretory carcinoma is a rare breast malignancy, awareness of its sonographic features will be helpful for the differential diagnosis.     

Serum levels of stem cell factor in patients during transplantation of bone marrow or peripheral blood stem cells

Stem cell factor (SCF) synergizes with other cytokines in vitro to stimulate the proliferation and differentiation of cells of the myeloid, megakaryocytic, erythroid, and lymphoid lineages. In vivo, it may play a role in engraftment after transplantation of bone marrow (BM) or peripheral blood stem cells (PBSC). Serum levels of SCF were closely monitored in 82 patients before and after allogeneic (n = 38), autologous (n = 6), or syngeneic (n = 1) BM transplantation (BMT) or autologous PBSC transplantation (PBSCT) (n = 37), respectively. SCF serum levels fluctuated around a mean in patients after allogeneic or autologous BMT or after PBSCT. In two patient subgroups (5 patients with acute myeloid leukemia [AML] and 6 patients with chronic myelogenous leukemia [CML]) with identical pretransplant conditioning regimen followed by allogeneic BMT, serum IL-6 levels significantly increased up to day +14 (p < 0.05). Correlation was not found between SCF serum levels and leukocyte or thrombocyte counts or the day of engraftment of these cell types. These data are a basis for further studies and constitute a further mosaic stone in understanding the changes in the complex cytokine network during engraftment.     

The immigrant patient having widespread pain. Clinical findings by physicians in Swedish primary care

AIM. Do the clinical findings explain the complaints of longstanding demonstrated widespread pain (DWP) in a group of immigrant patients, or not? SUBJECTS. Consecutive immigrant patients, on long-term sick leave, aged 18 - 45, at a primary healthcare centre in Stockholm, Sweden. METHODS. Interpreters were available. Two primary care physicians jointly, made a somatic status and diagnosed tender-structure locations (> or =3 tender-structure locations or less) and depression (yes or no), and assessed psychosocial stressors (little or much) and pain-related anxiety (yes or no). The patients pointed at their pain parts. This was transferred by one of the doctors to a pain drawing with 18 fields. Five or more fields were defined as DWP. Non-parametric tests were used to detect significant differences between the DWP and non-DWP groups. Cumulative frequencies of the following four categories of explanatory variables of DWP were counted: > or =3 tender-structure locations (could also include the other variables), much psychosocial stress (could include depression and pain-related anxiety), depression (could include pain-related anxiety), or pain-related anxiety alone. RESULTS. Many of the 49 men and 100 women, on average 38 years, spoke little or no Swedish. A fifth of the men (n = 10) and half (n = 56) of the women had DWP. These men often had much stress (p < 0.01) while the women had > or =3 tender-structure locations (p < 0.001). DWP among men was explained to 100% by: > or =3 tender-structure locations (30%), much psychosocial stress (60%), or depression alone (10%). DWP among the women was explained to 96 cum. % by: > or =3 tender-structure locations (59%), much psychosocial stress (25%), or pain-related anxiety alone (13%). CONCLUSION. Demonstrated widespread pain was nearly always explained by clinical findings, and especially by numerous tender-structure locations in women. There is a need for more studies among men.     

Essential requirement for c-kit and common gamma chain in thymocyte development cannot be overruled by enforced expression of Bcl-2.

The thymus in mice lacking both the receptor tyrosine kinase c-kit and the common cytokine receptor gamma chain (gamma(c)) is alymphoid because these receptors provide essential signals at the earliest stages of thymocyte development. The signals transduced by these receptors potentially regulate proliferation, survival, or differentiation, but the contribution of each receptor to distinct intracellular signaling cascades is only poorly defined. Here, we have examined whether enforced expression of Bcl-2 can rescue thymocyte development in c-kit and gamma(c) single or double mutant mice. A bcl-2 transgene (E(mu)-bcl-2-25; expressed in the T cell lineage) was introduced into (a) c-kit and gamma(c) wild-type (c-kit+gamma(c)+bcl+), (b) c-kit-deficient (c-kit(-)gamma(c)+bcl+), (c) gamma(c)-deficient (c-kit+gamma(c)-bcl+), or (d) c-kit and gamma(c) double-deficient mice (c-kit-gamma(c)-bcl+). The bcl-2 transgene was functionally active in wild-type and c-kit or gamma(c) single mutants, as it promoted survival of ex vivo isolated thymocytes, including pro-T cells. In vivo, however, transgenic Bcl-2 did not release T cell precursors from their phenotypic block and failed to increase progenitor or total thymocyte cellularity in c-kit or gamma(c) single or double mutants. These data argue strongly against a role for Bcl-2 as a key mediator in signaling pathways linked to cytokine and growth factor receptors driving early thymocyte development.     

Delta CK-MB outperforms delta troponin I at 2 hours during the ED rule out of acute myocardial infarction

It has been shown that a rise in creatine kinase MB bank (CK-MB) of > or = + 1.6 ng/mL in 2 hours is more sensitive and equally specific for detection of acute myocardial infarction (AMI) as compared with a 2-hour CK-MB > or = 6 ng/mL during the emergency department (ED) evaluation of chest pain. Because cardiac specific troponin I (cTnI) is thought to have similar early release kinetics as compared with CK-MB mass, we undertook a retrospective cohort study in 578 chest pain patients whose baseline CK-MB and cTnI was less than two times the hospital's upper limits of normal and who underwent a 2-hour CK-MB and cTnI to compare sensitivities and specificities of the 2-hour delta CK-MB (deltaCK-MB) and delta cTnI (delta cTnI) for AMI and 30-day Adverse Outcome (AO). Thirty day AO was defined as AMI, life-threatening complication, death, or percutaneous transluminal coronary angioplasty (PTCA)/coronary artery bypass graft (CABG) within 30 days of ED presentation. Optimum delta values were determined by choosing the smallest cutoff value greater than the assay precision where the deltaCK-MB and delta cTnI had a positive likelihood ratio for 30-day AO of > or = 15. A deltaCK-MB > or = +1.5 ng/mL was more sensitive than a deltaTnI > or = +0.2 ng/mL for AMI (87.7% versus 61.4%; P < .0005) and 30-day AO (56.7% versus 42.3%; P < .005). There were no differences in specificities for AMI and 30-day AO. Combining the two tests (MBdelta > or = +1.5 ng/mL and/or a deltaTnI > or = +0.2 ng/mL) resulted in an incremental increase in sensitivity of 89.5% for AMI and 61.9% for AO (P < .005). Patients with either a rise in CK-MB of > or = +1.5 ng/mL or rise in cTnI of > or = +0.2 ng/mL in 2 hours should receive consideration for aggressive antiischemic therapy and further diagnostic testing before making an exclusionary diagnosis of nonischemic chest pain.     

Pharmacokinetics in healthy subjects of althiazide and spironolactone in a fixed combination for 2 doses

Pharmacokinetic plasma curves of altizide (ALT), spironolactone (SPI) and two of the main metabolites of spironolactone, 7 alpha-thiomethyl-spirolactone (7TM) and canrenone (CAN) have been established in 12 healthy human volunteers (6 men and 6 women) after unique oral administration of 1 or 2 tablets of a combination of the two diuretic compounds: altizide (15 mg per tablet) and spironolactone (25 mg per tablets). Main pharmacokinetic parameters have been calculated using a biexponential (ALT and SPI) or a triexponential model (7TM and CAN). Spironolactone is rapidly absorbed. Plasma curves show Tmax respectively equal to 1.19 +/- 0.47 hours (1 tablet) or 1.21 +/- 0.46 (2 tablets). Spironolactone is rapidly metabolized as it is shown by the mean Tmax of metabolites: 7TM and CAN Tmax are respectively 1.56 +/- 0.45 hours and 2.54 +/- 1.06 hours after administration of 1 tablet, or 1.58 +/- 0.42 hours and 2.67 +/- 1.13 hours after administration of 2 tablets. The mean residence time (MRT) of ALT [4.94 +/- 1.14 hours (1 tablet) or 5.31 +/- 1.06 hours (2 tablets)] and SPI [1.81 +/- 0.45 hours (1 tablet) or 1.88 +/- 0.50 hours (2 tablets)] shows a rapid elimination of both drugs. SPI metabolites present higher MRT than the unchanged drug. 7TM MRT after administration of 1 or 2 tablets, are 24.51 +/- 15.35 hours and 18.11 +/- 11.87 hours, respectively. CAN MRT are 39.65 +/- 23.58 hours (1 tablet) and 38.93 +/- 24.58 (2 tablets). Statistical analysis shows no significant administration order effect on the different parametres. Student' t test shows a significant sex effect on CAN AUC, for both formulations.(ABSTRACT TRUNCATED AT 250 WORDS)