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Androgen receptor (AR) is required for sexual differentiation and is implicated in the development of prostate cancer. Here we describe distinct functions for cofactor proteins and gene regulatory elements in the assembly of AR-mediated transcription complexes. The formation of an activation complex involves AR, coactivators, and RNA polymerase II recruitment to both the enhancer and promoter, whereas the formation of a repression complex involves factors bound only at the promoter and not the enhancer. These results suggest a model for the functional coordination between the promoter and enhancer in which communication between these elements is established through shared coactivators in the AR transcription complex.

These recommendations concern the use of aluminum hydroxide adsorbed cell-free anthrax vaccine (Anthrax Vaccine Adsorbed [AVA], BioPort Corporation, Lansing, MI) in the United States for protection against disease caused by Bacillus anthracis. In addition, information is included regarding the use of chemoprophylaxis against B. anthracis.

The numbers of reported cases of meningococcal disease in 15- to 24-year-olds and outbreaks of meningococcal serogroup C disease, including outbreaks in schools and other institutions, have increased during the past decade. In response to outbreaks on college campuses, the American College Health Association has taken an increasingly proactive role in alerting college students and their parents to the risk of this disease and informing them about the availability of an effective vaccine. Recent epidemiologic studies have demonstrated an increased risk of disease in college students living in dormitories, particularly among freshmen, compared with similarly aged persons in the general population. At least 60% of these cases are potentially preventable by vaccination with the quadrivalent meningococcal A, C, Y, and W-135 polysaccharide vaccine. These findings support immunization of college students, particularly freshmen living in dormitories. Hence, college students and their parents should be informed by health care professionals at routine prematriculation visits and during college matriculation of the risk of meningococcal disease and potential benefits of immunization. Vaccine should be made available to those requesting immunization. College and university health services also should facilitate implementation of educational programs concerning meningococcal disease and availability of immunization services.

Several factors that mediate activation by nuclear receptors also modify the chemical and structural composition of chromatin. Prominent in this diverse group is the steroid receptor coactivator 1 (SRC-1) family, which interact with agonist-bound nuclear receptors, thereby coupling them to multifunctional transcriptional coregulators such as CREB-binding protein (CBP), p300, and PCAF, all of which have potent histone acetyltransferase activity. Additionally factors including the Brahma-related gene 1 (BRG-1) that are involved in the structural remodeling of chromatin also mediate hormone-dependent transcriptional activation by nuclear receptors. Here, we provide evidence that these two distinct mechanisms of coactivation may operate in a collaborative manner. We demonstrate that transcriptional activation by the estrogen receptor (ER) requires functional BRG-1 and that the coactivation of estrogen signaling by either SRC-1 or CBP is BRG-1 dependent. We find that in response to estrogen, ER recruits BRG-1, thereby targeting BRG-1 to the promoters of estrogen-responsive genes in a manner that occurs simultaneous to histone acetylation. Finally, we demonstrate that BRG-1-mediated coactivation of ER signaling is regulated by the state of histone acetylation within a cell. Inhibition of histone deacetylation by trichostatin A dramatically increases BRG-1-mediated coactivation of ER signaling, and this increase is reversed by overexpression of histone deacetylase 1. These studies support a critical role for BRG-1 in ER action in which estrogen stimulates an ER–BRG-1 association coupling BRG-1 to regions of chromatin at the sites of estrogen-responsive promoters and promotes the activity of other recruited factors that alter the acetylation state of chromatin.

Heptavalent pneumococcal conjugate vaccine (PCV7) is recommended for universal use in children 23 months and younger, to be given concurrently with other recommended childhood vaccines at 2, 4, 6, and 12 to 15 months of age. For children 7 to 23 months old who have not received previous doses of PCV7, administration of a reduced number of doses is recommended. Two doses of PCV7 are recommended for children 24 to 59 months old at high risk of invasive pneumococcal infection—including children with functional, anatomic, or congenital asplenia; infection with human immunodeficiency virus; and other predisposing conditions—who have not been immunized previously with PCV7. Recommendations have been made for use of 23-valent pneumococcal polysaccharide (23PS) vaccine in high-risk children to expand serotype coverage. High-risk children should be given vaccines at the earliest possible opportunity. Use of antibiotic prophylaxis in children younger than 5 years with functional or anatomic asplenia, including children with sickle cell disease, continues to be recommended. Children who have not experienced invasive pneumococcal infection and have received recommended pneumococcal immunizations may discontinue prophylaxis after 5 years of age. The safety and efficacy of PCV7 and 23PS in children 24 months or older at moderate or lower risk of invasive pneumococcal infection remain under investigation. Current US Food and Drug Administration indications are for administration of PCV7 only to children younger than 24 months. Data are insufficient to recommend routine administration of PCV7 for children at moderate risk of pneumococcal invasive infection, including all children 24 to 35 months old, children 36 to 59 months old who attend out-of-home care, and children 36 to 59 months old who are of Native American (American Indian and Alaska Native) or African American descent. However, all children 24 to 59 months old, regardless of whether they are at low or moderate risk, may benefit from the administration of pneumococcal immunizations. Therefore, a single dose of PCV7 or 23PS vaccine may be given to children 24 months or older. The 23PS is an acceptable alternative to PCV7, although an enhanced immune response and probable reduction of nasopharyngeal carriage favor the use of PCV7 whenever possible.

Infection control is an integral part of pediatric practice in outpatient settings as well as in hospitals. All employees should be educated regarding the routes of transmission and techniques used to prevent transmission of infectious agents. Policies for infection control and prevention should be written, readily available, updated annually, and enforced. The Centers for Disease Control and Prevention standard precautions for hospitalized patients with modifications from the American Academy of Pediatrics are appropriate for most patient encounters. As employers, pediatricians are required by the Occupational Safety and Health Administration (OSHA) to take precautions to protect staff likely to be exposed to blood or other potentially infectious materials while on the job. Key principles of infection control include the following: hand-washing before and after every patient contact, separation of infected, contagious children from uninfected children, safe handling and disposal of needles and other sharp medical devices, appropriate use of personal protection equipment such as gloves, appropriate sterilization, disinfection and antisepsis, and judicious use of antibiotics.

There is an increasing threat that chemical and biological weapons will be used on a civilian population in an act of domestic terrorism. Casualties among adults and children could be significant in such an event. Federal, state, and local authorities have begun extensive planning to meet a chemical-biological incident by developing methods of rapid identification of potential agents and protocols for management of victims without injury to health care personnel. Because children would be disproportionately affected by a chemical or biological weapons release, pediatricians must assist in planning for a domestic chemical-biological incident. Government agencies should seek input from pediatricians and pediatric subspecialists to ensure that the situations created by multiple pediatric casualties after a chemical-biological incident are considered. This statement reviews key aspects of chemical-biological agents, the consequences of their use, the potential impact of a chemical-biological attack on children, and issues to consider in disaster planning and management for pediatric patients.

Current recommendations of the American Academy of Pediatrics (AAP) for infection control practices to prevent transmission of blood-borne pathogens, including human immunodeficiency virus (HIV) in hospitals, other medical settings, schools, and child care facilities, are reviewed and explained. Hand-washing is essential, whether or not gloves are used, and gloves should be used when contact with blood or blood-containing body fluids may occur. In hospitalized children, the 1996 recommendations of the Centers for Disease Control and Prevention (CDC) should be implemented as modified in the 1997 Red Book. The generic principles of Standard Precautions in the CDC guidelines generally are applicable to children in all health care settings, schools, child care facilities, and the home. However, gloves are not required for routine changing of diapers or for wiping nasal secretions of children in most circumstances. This AAP recommendation differs from that in the CDC guidelines. Current US Public Health Service guidelines for the management of potential occupational exposures of health care workers to HIV are summarized. As previously recommended by the AAP, HIV-infected children should be admitted without restriction to child care centers and schools and allowed to participate in all activities to the extent that their health and other recommendations for management of contagious diseases permit. Because it is not required that the school be notified of HIV infection, it may be helpful if the pediatrician notify the school that he or she is operating under a policy of nondisclosure of infection with blood-borne pathogens. Thus, it is possible that the pediatrician will not report the presence of such infections on the form. Because HIV infection occurs in persons throughout the United States, these recommendations for prevention of HIV transmission should be applied universally.

We have previously shown that phosphatidylinositol (PtdIns) 3'-kinase is activated by the binding of proteins or peptides containing the phosphorylated motif Y(P)XXM. In the present study, we examine interactions between PtdIns 3'-kinase and the human insulin receptor, which contains a C-terminal phosphorylation site in the sequence Y1322THM. Partially purified insulin receptors bound tightly to bacterial fusion proteins containing the N- or C-terminal SH2 domains from PtdIns 3'-kinase regulatory subunit (p85). In contrast, a mutant insulin receptor, truncated by 43 amino acids at the C terminus (IR delta CT), bound poorly to the SH2 domains; these mutant receptors have normal kinase activity but lack the Y1322THM motif. Similarly, incubation with wild-type receptors increased the activity of immunopurified PtdIns 3'-kinase, whereas incubation with IR delta CT receptors did not affect PtdIns 3'-kinase activity. Activation of PtdIns 3'-kinase by the wild-type receptor was mimicked by a tyrosyl phosphopeptide derived from the insulin receptor C terminus and containing the Y1322THM motif; non-phosphorylated peptide did not affect activity. Thus, the insulin receptor C terminus activates PtdIns 3'-kinase in vitro by binding to the SH2 domains of the 85-kDa regulatory subunit. These data support the hypothesis that binding of tyrosyl-phosphorylated receptors to p85 SH2 domains is a general mechanism for PtdIns 3'-kinase activation, and they suggest that direct interactions between the insulin receptor and PtdIns 3'-kinase may provide an alternative pathway for the activation of this enzyme by insulin.

A new condition called the “I-never-took-pills-before” syndrome has been developed to describe hypertensive patients who react adversely to a variety of medications with different side-effect profiles. The typical individual who manifests this syndrome readily admits to a dislike of taking medication in general, has rarely taken drugs before a diagnosis of hypertension was made, and tends to develop the same constellation of side-effects in response to completely different classes of drugs. Various features of this syndrome are outlined and suggestions offered to help physicians identify and treat patients with this condition.

A review of the literature on the cardiovascular effects of caffeine indicates that moderate caffeine consumption does not cause cardiac arrhythmias, hypertension, or an increased incidence of coronary heart disease. Caffeine use is often associated with atherogenic behavior, such as cigarette smoking. Failure to take into account covariables for cardiovascular disease could be responsible for commonly held misconceptions about caffeine and heart disease.

Field studies were conducted near Beechwood, WI in 1986 and Sturgeon Bay, WI in 1987 and 1988 to evaluate herbicide treatments for control of triazine-resistant common lambsquarters (TR-CHEAL) in corn. All PRE and many early postemergence (EP) and POST treatments were less effective in 1988 than in 1986 or 1987 due to drought. Atrazine, cyanazine, and metolachlor PRE controlled less than 15% TR-CHEAL late-season over the three years. Dicamba or pendimethalin applied PRE controlled 88 to 99% late-season TR-CHEAL in 1986 and 1987. Lateseason TR-CHEAL control in 1986 and 1987 from acetochlor plus atrazine, alachlor plus atrazine, and metolachlor plus linuron applied PRE ranged from 58 to 86%. Pendimethalin plus cyanazine or atrazine applied EP controlled TR-CHEAL 97% or more late-season in 1986 and 1987, while pendimethalin plus dicamba plus atrazine applied EP controlled TR-CHEAL 97% or more each year. Late-season TR-CHEAL control from tridiphane plus cyanazine or atrazine EP was less than 58%. Late-season TR-CHEAL control from dicamba, 2,4-D amine, pyridate, and thifensulfuron applied POST was 87 to 99% each year, and was 94 to 99% in 1986 and 1987 from bromoxynil or bentazon applied POST. Dicamba, thifensulfuron, pendimethalin, pyridate, and 2,4-D amine were most effective in controlling TR-CHEAL in corn. Nomenclature: Acetochlor, 2-chloro-N-(ethoxymethyl)-N-(2-ethyl-6-methylphenyl)acetamide; alachlor, 2-chloro-N-(2,6-diethylphenyl)-N-(methoxymethyl)acetamide; atrazine, 6-chloro-N-ethyl-N'-(1-methylethyl)-1,3,5-triazine-2,4-diamine; bentazon, 3-(1-methylethyl)-(1H)-2,1,3-benzothiadiazin-4(3H)-one 2,2-dioxide; bromoxynil, 3,5dibromo-4-hydroxybenzonitrile; cyanazine, 2-[[4-chloro-6-(ethylamino)1,3,5-triazin-2-yl]amino]2-methylpropanenitrile; dicamba, 3,6-dichloro-2-methoxybenzoic acid; linuron, N'-(3,4-dichlorophenyl)-N-methoxy-N-methylurea; metolachlor, 2-chloro-N-(2-ethyl-6-methylphenyl)-N-(2methoxy1 -methylethyl)acetamide; pendimethalin, N-( 1 -ethylpropyl)-3,4-dimethyl-2,6dinitrobezenamine; pyridate, 0-(6-chloro-3-phenyl-4-pyridazinyl)-S-octyl-carbonothioate; thifensulfuron, methyl ester of 3-[[[[(4-methoxy-6-methyl1,3,5-triazin-2-yl)amino]carbonyl]amino]sulfonyl]-2-thiophenecarboxylic acid; tridiphane, 2-(3,5-dichlorophenyl)-2-(2,2,2-trichloroethyl)oxirane; 2,4-D amine, amine salt of 2,4-dichlorophenoxyacetic acid; corn, Zea mays L.; common lambsquarters, Chenopodium album L. #3 CHEAL. Additional index words: CHEAL, atrazine.

Insulin and insulin-like growth factor I (IGF-I) initiate cellular functions by activating their homologous tyrosine kinase receptors. In most mammalian cell types, this results in rapid tyrosine phosphorylation of a high-molecular-weight substrate termed insulin receptor substrate 1 (IRS-1). Previous studies suggest that IRS-1 may act as a "docking" protein that noncovalently associates with certain signal-transducing molecules containing src homology 2 domains; however, direct evidence for the role of IRS-1 in the final biological actions of these hormones is still lacking. We have developed a reconstitution system to study the role of IRS-1 in insulin and IGF-I signaling, taking advantage of the fact that Xenopus oocytes possess endogenous IGF-I receptors but have little or no IRS-1, as determined by immunoblotting with anti-IRS-1 and antiphosphotyrosine antibodies. After microinjection of IRS-1 protein produced in a baculovirus expression system, tyrosyl phosphorylation of injected IRS-1 is stimulated by both insulin and IGF-I in a concentration-dependent manner, with IGF-I more potent than insulin. Furthermore, after IRS-1 injection, both hormones induce a maturation response that correlates well with the amount of injected IRS-1. By contrast, overexpression of human insulin receptors in the Xenopus oocytes does not enhance either IRS-1 phosphorylation or oocyte maturation response upon insulin stimulation. These results demonstrate that IRS-1 serves a critical role in linking IGF-I and insulin to their final cellular responses.

Studies were conducted for 3 yr to evaluate herbicides and herbicide combinations for triazine-resistant smooth pigweed (TR-AMACH) control in field corn. Of the PRE treatments, combinations of atrazine plus acetochlor, metolachlor plus dicamba, and atrazine plus alachlor provided the most complete control of this weed (77 to 81%). The best early postemergence (EP) combination was pendimethalin plus atrazine plus dicamba (93% control). Pyridate plus atrazine applied POST provided a four-site average of 98% control. The most effective sequential herbicide treatments consisted of either metolachlor or pendimethalin PRE followed by POST treatments containing either pyridate, thifensulfuron, bromoxynil, or dicamba. Nomenclature: Acetochlor, 2-chloro-N-(ethoxymethyl)-N-(2-ethyl-6-methylphenyl)acetamide; alachlor, 2-chloro-N-(2,6-diethylphenyl)-N-(methoxymethyl)acetamide; atrazine, 6-chloro-N-ethyl-N'-(1-methylethyl)-1,3,5-triazine2,4-diamine; bentazon, 3-(1 -methylethyl)-( 1H)-2, 1 ,3-benzothiadiazin-4(3H)-one 2,2-dioxide; bromoxynil, 3,5-dibromo-4-hydroxybenzonitrile; cyanazine, 2-[[4-chloro-6-(ethylamino)-1,3,5-triazin-2-yl]amino]-2-methylpropanenitrile; dicamba, 3,6-dichloro-2-methoxybenzoic acid; linuron, N'(3,4-dichlorophenyl)-N-methoxy-N-methylurea; metolachlor, 2-chloro-N-(2-ethyl-6-methylphenyl)N-(2-methoxy-1-methylethyl)acetamide; metribuzin, 4-amino-6-(1,1-dimethylethyl)-3-(methylthio)1 ,2,4-triazin-5(4H)-one; pendimethalin, N-( 1-ethylpropyl)-3,4-dimethyl-2,6-dinitrobenzenamine; pyridate, 0-(6-chloro-3-phenyl-4-pyridazinyl)-S-octyl-carbonothioate; simazine, 6-chloro-N,N'diethyl1 ,3,5-triazine-2,4,diamine; thifensulfuron, 3[ [[[(4-methoxy-6-methyl1,3 ,5-triazin-2yl)amino]carbonyl]amino]sulfonyl]-2-thiophenecarboxylic acid; tridiphane, 2-(3,5-dichlorophenyl)2-(2,2,2-trichloroethyl)oxirane; 2,4-D amine, dimethylamine salt of (2,4-dichlorophenoxy)acetic acid; corn, Zea mays L.; smooth pigweed, Amaranthus hybridus L. #3 AMACH. Additional index words: AMACH, atrazine, metribuzin.

Insulin stimulates the formation of binary and ternary signaling complexes between the phosphatidylinositol (PtdIns) 3'-kinase, IRS-1, and the insulin receptor in vivo. Binary complex formation between IRS-1 and the PtdIns 3'-kinase occurs in intact cells and requires the tyrosyl phosphorylation IRS-1, as mutant insulin receptors which weakly phosphorylate IRS-1 in vivo do not mediate formation of IRS-1/PtdIns 3'-kinase complexes in transfected CHO cells. Association with IRS-1 involves as much as 70% of total cellular PtdIns 3'-kinase activity. Insulin also stimulates the formation of ternary signaling complexes, as both IRS-1 and the PtdIns 3'-kinase are present in anti-insulin receptor immunoprecipitates from insulin-stimulated cells. Overexpression of IRS-1 in CHO cells increases the amount of PtdIns 3'-kinase activity in alpha IR immunoprecipitates, and IRS-1 markedly increases the in vitro binding of p85 alpha and PtdIns 3-kinase activity to anti-receptor immunoprecipitates. The mechanism for this association is unknown, but appears to involve the binding of IRS-1/PtdIns 3'-kinase complexes to the insulin receptor. The formation of binary and ternary complexes between the insulin receptor, IRS-1 and the PtdIns 3'-kinase may play a critical role in transmission of the insulin signal.

Blood pressure (BP) measurements taken outside the routine office context may be a useful adjunct strategy to monitor BP. Community-based BP data can also provide estimates of the prevalence of elevated BP. We compared multiple readings taken on different days in pharmacies using an automated BpTRU device during a cardiovascular health programme targeting community-dwelling older adults. Mean systolic (S) and diastolic (D) BP values were compared over time using repeated measures analysis of variance for all participants with at least three separate sets of readings (n=317). BP variability was then examined among four subgroups based on report of antihypertensive medication or no treatment, and normal or elevated SBP at the initial visit (oror=140, or 130 if diabetes reported). Prevalence of elevated BP was compared across visits. Overall, mean SBP decreased between visits 1 and 2 (140.4 vs 137.1 mm Hg; P0.001). Among participants with normal SBP at the initial visit, SBP did not vary significantly, whether or not antihypertensive treatment was reported. Those with initially elevated SBP experienced a significant decrease between visits 1 and 2, also regardless of treatment status. Prevalence of elevated BP decreased from visits 1 to 2 (55.8 vs 48.9%; P=0.026) and from visits 1 to 3 (55.8 vs 42.9%; P0.001). Analyses of BP data from a community-based programme using an accurate device showed that initial readings may inflate the population estimate of elevated BP. Findings suggest that more than one set of BP readings measured on different occasions are needed, particularly if the first set is elevated.

We studied the structure and function of the human insulin receptor (IR) and a mutant which lacked the last 43 amino acids of the beta-subunit (IR delta ct). This deletion removed tyrosine (Tyr1322, Tyr1316) and threonine (Thr1336) phosphorylation sites. In Chinese hamster ovary (CHO) cells, insulin binding to the mutant receptor was normal, and [35S]methionine labeling indicated that both the IR and IR delta ct were processed normally; however, the beta-subunit of IR delta ct was 5 kDa smaller than that of the IR. The time course of insulin-stimulated autophosphorylation of the partially purified IR delta ct was normal, but the maximum autophosphorylation was reduced 20-30%. Tryptic phosphopeptide mapping confirmed the absence of the C-terminal phosphorylation sites and indicated that phosphorylation of the regulatory region (Tyr1146, Tyr1150, Tyr1151) occurred normally; kinase activity of the IR and IR delta ct was activated normally by insulin-stimulated autophosphorylation. In the intact CHO cells, insulin-stimulated serine and threonine phosphorylation of the IR delta ct was reduced 20%, suggesting that most Ser/Thr phosphorylation sites are located outside of the C terminus. During insulin stimulation, the wild-type and mutant insulin receptor activated the phosphatidylinositol 3-kinase. Moreover, insulin itself or human-specific anti-insulin receptor antibodies stimulated glycogen and DNA synthesis equally in both CHO/IR and CHO/IR delta ct cells. These data suggest that the C terminus plays a minimal role in IR function and signal transmission in CHO cells.

The specific immune alterations associated with HSV recurrences are ill defined although it appears that alterations in cell-mediated immune mechanisms are more likely associated with recurrent disease than humoral immunity. Immunization with HSV glycoproteins B and D (gBgD) after primary HSV infection has reportedly reduced the frequency of recurrences but the mechanisms remain unidentified. We therefore evaluated the effects of immunization with cloned gBgD on selected cell-mediated immune responses and their relationship to recurrent disease by using the guinea pig model of genital HSV-2 infection. In two experiments, immunization with gBgD + CFA on days 21 and 42 after HSV-2 inoculation significantly decreased the number of subsequent recurrent lesion days observed whereas CFA alone had no effect. Immunization with gBgD + CFA increased the lymphoproliferative and in vitro IL-2 response to gBgD more than to whole HSV-2 Ag preparations. Peak responses were observed 2 wk after the second immunization. The HSV-specific cytolytic response was also persistently increased beginning 1 wk after the first immunization. Analysis including both untreated and gBgD-immunized animals revealed that recurrent lesion days were inversely correlated to the IL-2 response to whole HSV-2 Ag (p less than 0.0001), the IL-2 response to gBgD (p = 0.0004), and the HSV-specific cytolytic response (p = 0.005 and 0.003 in two experiments, respectively). When the untreated group was analyzed separately, only the IL-2 response to whole HSV-2 Ag correlated to recurrences (p = 0.007). HSV glycoprotein immunization may increase IL-2 or other cytokines secreted by HSV-sensitized T cells increasing critical immune responses, such as NK- or lymphokine-activated killer-mediated cytolysis, that could eliminate the reactivated virus before the development of clinically apparent lesions.

The adipose tissue-derived hormone, leptin, acts via its receptor (LRb) in the brain to regulate energy balance and neuroendocrine function. In order to understand leptin action we have explored the physiological function of LRb signalling pathways, defining important roles for signal transducer and activator of transcription-3 (STAT3) in positive signalling and for LRbTyr(985)-mediated feedback inhibition in leptin signal attenuation. As the cells on which leptin acts are not homogeneous, but rather represent a broadly distributed network of neurones with divergent projections and functions, it is also crucial to consider how each of these populations responds to LRb signals to contribute to leptin action. While well-known LRb-expressing neurones within the arcuate nucleus of the hypothalamus mediate crucial effects on satiety and energy expenditure, other populations of LRb-expressing neurones in the ventral tegmental area and elsewhere likely control the mesolimbic dopamine system. Additional populations of LRb-expressing neurones likely contribute to other aspects of neuroendocrine regulation. It will be important to define the molecular mechanisms by which leptin acts to regulate neurophysiology in each of these LRb-expressing neural populations in order to understand the totality of leptin action.

To provide updated, evidence-based recommendations for the diagnosis and assessment of high blood pressure in adults.For people with high blood pressure, the assignment of a diagnosis of hypertension depends on the appropriate measurement of blood pressure, the level of the blood pressure elevation, the duration of follow-up and the presence of concomitant vascular risk factors, target organ damage and established atherosclerotic diseases. For people diagnosed with hypertension, defining the overall risk of adverse cardiovascular outcomes requires laboratory testing, a search for target organ damage and an assessment of the modifiable causes of hypertension. Out-of-clinic blood pressure assessment and echocardiography are options for selected patients.People at increased risk of adverse cardiovascular outcomes and were identified and quantified.Medline searches were conducted from the period of the last revision of the Canadian recommendations for the management of hypertension (May 1998 to October 2000). Reference lists were scanned, experts were polled, and the personal files of the subgroup members and authors were used to identify other studies. All relevant articles were reviewed and appraised, using prespecified levels of evidence, by content experts and methodological experts.A high value was placed on the identification of people at increased risk of cardiovascular morbidity and mortality.The identification of people at higher risk of cardiovascular disease will permit counselling for lifestyle manoeuvres and the introduction of antihypertensive drugs to reduce blood pressure for patients with sustained hypertension. In certain settings, and for specific classes of drugs, blood pressure lowering has been associated with reduced cardiovascular morbidity and/or mortality.The present document contains detailed recommendations pertaining to aspects of the diagnosis and assessment of patients with hypertension, including the accurate measurement of blood pressure, criteria for the diagnosis of hypertension and recommendations for follow-up, routine and optional laboratory testing, assessment for renovascular hypertension, home and ambulatory blood pressure monitoring, and the role of echocardiography in hypertension.All recommendations were graded according to strength of the evidence and voted on by the Canadian Hypertension Recommendations Working Group. Only the recommendations achieving high levels of consensus are reported here. These guidelines will be updated annually.These recommendations are endorsed by the Canadian Hypertension Society, The Canadian Coalition for High Blood Pressure Prevention and Control, The College of Family Physicians of Canada, The Heart and Stroke Foundation of Canada, The Adult Disease Division and Bureau of Cardio-Respiratory Diseases and Diabetes at the Centre for Chronic Disease Prevention and Control of Health Canada.

The sixth report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of Hypertension report has recommended long-acting, once-daily drugs as preferred therapy for the management of hypertension. The duration of action of an antihypertensive agent can be assessed in several ways. The decrease in clinical blood pressure at the end of the dosing interval has traditionally been the method for determining antihypertensive efficacy. However, this approach does not provide information about a drug's effects over the remainder of the 24-hour dosing interval. The trough-to-peak ratio has been proposed as an arithmetic index of a compound's maximum and minimum antihypertensive effects. This ratio can be obtained from multiple readings in an office setting or using data from 24-hour ambulatory blood-pressure monitoring. A simplified approach has been to compare a single office reading at the time of a drug's known maximum antihypertensive effect (peak) with the reduction in blood pressure at 24 hours (trough). Office readings have also been used to show that the same dose of a drug given once daily versus twice daily results in a similar trough blood pressure, confirming that once-daily therapy is appropriate. The 24-hour ambulatory blood pressure can be used to determine mean changes in daytime, evening, and night-time blood pressure to demonstrate the antihypertensive profile over the entire dosing interval. Finally, the finding of a persistent reduction in ambulatory blood pressure following substitution of placebo for an antihypertensive drug during chronic therapy (missed-dose technique) suggests that a compound decreases blood pressure for 48 hours or longer. Thus, it should be possible to demonstrate the effectiveness of once-daily antihypertensive therapy using one or more of the aforementioned methods.

Ambulatory blood pressure (ABP) monitoring has become increasingly more available in routine clinical practice in Canada. The ABP is more reliable and more reproducible than office readings, and is a better predictor of target organ damage. Normal values for ABP have been established using both cross-sectional and longitudinal outcome data. Abnormal mean 24 h and awake ABP values should exceed 135/85 mmHg and 140/90 mmHg, respectively. ABP recordings are useful in making a diagnosis of hypertension by identifying people with high office but normal ABP values. ABP monitoring can also be performed in patients already receiving antihypertensive therapy to determine the extent of any white coat effect that may be increasing office readings. The interpretation of the ABP should take into account cardiac risk factors, any target organ damage that may be present or coexisting conditions such as diabetes mellitus.

Pancreatic beta-cell mitogenesis is increased by insulin-like growth factor I (IGF-I) in a glucose-dependent manner. In this study it was found that alternative beta-cell nutrient fuels to glucose, pyruvate, and glutamine/leucine independently induced and provided a platform for IGF-I to induce INS-1 cell DNA synthesis in the absence of serum. In contrast, long chain FFA (/=C(12)) inhibited 15 mM glucose-induced [(3)H]thymidine incorporation (+/-10 nM IGF-I) by 95% or more within 24 h above 0.2 mM FFA complexed to 1% BSA (K(0.5) for palmitate/1% BSA = 65-85 microM for 24 h; t(0.5) for 0.2 mM palmitate/1% BSA = approximately 6 h). FFA-mediated inhibition of glucose/IGF-I-induced ss-cell DNA synthesis was reversible, and FFA oxidation did not appear to be required, nor did FFA interfere with glucose metabolism in INS-1 cells. An examination of mitogenic signal transduction pathways in INS-1 cells revealed that glucose/IGF-I induction of early signaling elements in SH2-containing protein (Shc)- and insulin receptor substrate-1/2-mediated pathways leading to downstream mitogen-activated protein kinase and phosphoinositol 3'-kinase activation, were unaffected by FFA. However, glucose-/IGF-I-induced activation of protein kinase B (PKB) was significantly inhibited, and protein kinase Czeta was chronically activated by FFA. It is possible that FFA-mediated inhibition of ss-cell mitogenesis contributes to the reduction of beta-cell mass and the subsequent failure to compensate for peripheral insulin resistance in vivo that is key to the pathogenesis of obesity-linked diabetes.

A common recommendation for youth treated for substance abuse is to attend 12-step groups. However, little is known regarding the effects of this adult-derived prescription on substance use outcomes for teens. This study examined (a) the relation between 12-step attendance and substance use outcome in the 6 months postdischarge from inpatient care and (b) a process model of how 12-step attendance during the first 3 months postdischarge affects proximal outcomes of motivation, coping, and self-efficacy, measured at 3 months, and how these, in turn, affect ultimate substance use outcome in the following 3 months. Adolescent inpatients (N = 99) were assessed during treatment and 3 and 6 months postdischarge. Results revealed modest beneficial effects of 12-step attendance, which were mediated by motivation but not by coping or self-efficacy. Findings suggest that closer attention be paid to motivational factors in the treatment of adolescent substance abuse.

To provide updated, evidence-based recommendations for health care professionals on the management of hypertension in adults.For patients with hypertension, there are both lifestyle options and pharmacological therapy options that may control blood pressure. For those patients who are using pharmacological therapy, a range of antihypertensive drugs is available. The choice of a specific antihypertensive drug is dependent upon the severity of the hypertension and the presence of other cardiovascular risk factors and concurrent diseases.The health outcomes considered were changes in blood pressure and in morbidity and mortality rates. Because of insufficient evidence, no economic outcomes were considered.MEDLINE searches were conducted from the period of the last revision of the Canadian Recommendations for the Management of Hypertension (January 1993 to May 1998). Reference lists were scanned, experts were polled and the personal files of the authors were used to identify other studies. All relevant articles were reviewed, classified according to study design and graded according to levels of evidence.A high value was placed on the avoidance of cardiovascular morbidity and premature death caused by untreated hypertension.Harms and costs: The diagnosis and treatment of hypertension with pharmacological therapy will reduce the blood pressure of patients with sustained hypertension. In certain settings, and for specific drugs, blood pressure lowering has been associated with reduced cardiovascular morbidity and mortality.This document contains detailed recommendations pertaining to all aspects of the diagnosis and pharmacological therapy of hypertensive patients. With respect to diagnosis, the recommendations endorse the greater use of non-office-based measures of blood pressure control (i.e., using home blood pressure and automatic ambulatory blood pressure monitoring equipment) and greater emphasis on the identification of other cardiovascular risk factors, both in the assessment of prognosis in hypertension and in the choice of therapy. On the treatment side, lower targets for blood pressure control are advocated for some subgroups of hypertensive patients, in particular, those with diabetes and renal disease. Implicit in the recommendations for therapy is the principle that for the vast majority of hypertensive patients treated pharmacologically, practitioners should not follow a stepped-care approach. Instead, therapy should be individualized, based on consideration of concurrent diseases, both cardiovascular and noncardiovascular.All recommendations were graded according to the strength of the evidence and the consensus of all relevant stakeholders.The Canadian Hypertension Society and the Canadian Coalition for High Blood Pressure Prevention and Control.

Mitogenic signal-transduction pathways have not been well defined in pancreatic beta-cells. In the glucose-sensitive rat beta-cell line, INS-1, glucose (6-18 mM) increased INS-1 cell proliferation (>20-fold at 15 mM glucose). Rat growth hormone (rGH) also induced INS-1 cell proliferation, but this was glucose-dependent in the physiologically relevant concentration range (6-18 mM glucose). The combination of rGH (10 nM) and glucose (15 mM) was synergistic, maximally increasing INS-1 cell proliferation by >50-fold. Moreover, glucose-dependent rGH-induced INS-1 cell proliferation was increased further by addition of insulin-like growth factor 1 (IGF-1; 10 nM) to >90-fold at 12 mM glucose. Glucose metabolism and phosphatidylinositol-3'-kinase (PI3'K) activation were necessary for both glucose- and rGH-stimulated INS-1 cell proliferation. Glucose (>3 mM) independently increased tyrosine-phosphorylation-mediated recruitment of growth-factor-bound protein 2 (Grb2)/murine sons of sevenless-1 protein (mSOS) and PI3'K to insulin receptor substrate (IRS)-1 and IRS-2, as well as SH2-containing protein (Shc) association with Grb2/mSOS and downstream activation of mitogen-activated protein kinase and 70 kDa S6 kinase. Glucose-induced IRS- and Shc-mediated signal transduction was enhanced further by the addition of IGF-1, but not rGH. In contrast, rGH was able to activate Janus kinase 2 (JAK2)/signal transducer and activator of transcription 5 (STAT5) signal transduction at glucose concentrations above 3 mM, but neither glucose independently, nor glucose with added IGF-1, were able to activate the JAK2/STAT5 signalling pathway. Thus rGH-mediated proliferation of beta-cells is directly via the JAK2/STAT5 pathway without engaging the Shc or IRS signal-transduction pathways, although activation of PI3'K may play an important permissive role in the glucose-dependent aspect of rGH-induced beta-cell mitogensis. The additive effect of rGH and IGF-1 on glucose-dependent beta-cell proliferation is therefore reflective of rGH and IGF-1 activating distinctly different mitogenic signalling pathways in beta-cells with minimal crosstalk between them.

Episiotomy continues to be a frequently used procedure in obstetrics despite little scientific support for its routine use. Although episiotomy does decrease the occurrence of anterior lacerations, it fails to accomplish the majority of goals stated as reasons for its use. Episiotomy does not decrease damage to the perineum but rather increases it. The midline episiotomy increases the risk for third-degree and fourth-degree lacerations. Episiotomy fails to prevent the development of pelvic relaxation and its attendant complications. Rather than decreasing maternal morbidity, episiotomy increases blood loss and is related to greater initial postpartum pain and dyspareunia. It has been associated with a more difficult and lengthy repair as measured by the need for suture material and operating room time. The claims of a protective effect on the fetus in shortening the second stage of labor, improving Apgar scores, and preventing perinatal asphyxia have not been borne out. The value of episiotomy use on a routine basis bears scientific examination in prospective, randomized, controlled trials. These types of trials are certainly achievable, ethically correct, and much needed. Until these trials are completed and published, obstetricians should not routinely perform the procedure but rather determine the need for episiotomy on a case-by-case basis.

To provide background information on the scientific basis for new Canadian guidelines on ambulatory blood pressure monitoring and the process for developing recommendations for clinical practice.A comprehensive review of the literature on ambulatory blood pressure monitoring was conducted using a computerized literature search and a bibliography of key scientific articles.Studies of the highest scientific quality were used to support recommendations based on established rules for grading evidence.A series of recommendations for the use of ambulatory blood pressure monitoring in routine clinical practice directed towards both untreated patients with a diagnosis of possible hypertension and treated patients with a suspected 'white coat' component to their office readings have been proposed for consideration by the Canadian Hypertension Society.There are now sufficient data available to support the use of ambulatory blood pressure monitoring in accordance with specific clinical practice guidelines.

Recent increases in adolescent cigarette smoking have provided an impetus for developing effective youth smoking-cessation interventions. Adolescents treated for substance abuse are a particularly important target for tobacco use intervention given the high prevalence and persistence of smoking among this subgroup of youth. The few studies to date of adolescent smoking cessation have demonstrated little success in effecting change in tobacco use. In the absence of empirical evidence, recommendations for tobacco intervention with substance-abusing adolescents are proposed based on information from several sources: studies of adolescent smoking cessation, adolescent developmental considerations, issues specific to substance abusers, motivational concerns, and adult smoking-cessation techniques. An outline is provided of components to consider for inclusion in a substance-abusing adolescent smoking intervention. It is suggested that tobacco-focused interventions be incorporated as a routine part of treatment for adolescent substance abuse.

Adolescent alcohol and other drug abuse is an important public health concern, and the past two decades has seen a dramatic increase in the demand for interventions to address substance use problems among teenagers. This demand has led to the development of multiple primary, secondary, and tertiary substance abuse prevention programs, some of which have little theoretical basis and most of which currently operate in the absence of data supporting their effectiveness. Very recently, there has been increased emphasis on the goal of developing and testing theoretically based and empirically supported intervention approaches for adolescent substance abuse. We describe five ongoing research programs devoted to meeting this goal. The background and rationale for each research program are discussed, and preliminary efficacy data concerning the specific interventions are presented.

Atrial fibrillation (AF) is a common complication of coronary artery bypass surgery (CABS). Because conventional antiarrhythmic therapy may cause proarrhythmia, a rate control approach to AF was evaluated in 59 patients post-CABS. The use of digoxin with or without verapamil for AF was associated with spontaneous conversion to normal sinus rhythm in 55 of 59 patients. Two to four weeks later, all patients were on digoxin and 12% were on verapamil, with two of four AF patients having converted to normal sinus rhythm and two others previously in normal sinus rhythm now in AF. A rate control approach to treating AF post-CABS resulted in over 90% of patients being in normal sinus rhythm for two to four weeks after the onset of the arrhythmia.

The increasing availability of ambulatory blood pressure monitoring has shifted interest in blood pressure measurement from the doctor's office to the entire 24-h period. Routine office blood pressure recordings correlate poorly with left ventricular mass, a sign of early target-organ damage. In contrast, ambulatory blood pressure or estimates of 24-h blood pressure load show a good correlation with left ventricular mass.Circadian blood pressure rhythms may be important in determining future cardiovascular events. For example, patients who maintain high nocturnal blood pressures (non-dippers) experience more cardiovascular sequelae than do nocturnal dippers, with women non-dippers having the greatest risk. Longer-acting antihypertensive drugs may return circadian blood pressure rhythms to normal by converting non-dippers to dippers. Adequate control of blood pressure toward the end of each 24-h cycle may reduce the early morning rise in cardiovascular events associated with awakening and ambulation.Recent improvements in the estimation of trough to peak ratio have provided a useful arithmetic index for comparing the antihypertensive effects of different compounds over 24-h dosing intervals. Long-acting agents have now been identified in each of the major classes of antihypertensive drugs, making it now possible to maximize target-organ protection by achieving good 24-h blood pressure control in most hypertensive patients.

To examine the dose-response characteristics of perindopril at the time of its peak and trough antihypertensive effects, with the primary outcome measure being changes in diastolic blood pressure.After a four-week, single-blind placebo run-in, patients were randomly allocated to four doses of perindopril or placebo using a parallel group design.Sixteen specialist centres in the United States.Of 483 patients entered into the run-in phase, 293 were eligible for randomization to perindopril or placebo therapy, with 260 patients included in the final efficacy analysis.Eligible patients were randomized to 12 weeks of therapy with perindopril 2, 4, 8 or 16 mg or placebo.At the final visit, all doses of perindopril significantly (P0.05) lowered diastolic blood pressure compared with placebo. The ratio of changes in placebo-corrected diastolic blood pressure at 24 versus 6 h for perindopril 2, 4 and 8 mg was 1.0, 1.0 and 0.97, respectively. The maximum antihypertensive effect was seen with perindopril 8 mg, with the 16 mg dose providing no additional response. Changes in systolic and diastolic blood pressure were similar.Perindopril is most effective at doses of 4 and 8 mg once daily, with similar reductions in diastolic blood pressure present at 6 and 24 h after dosing.

OBJECTIVE: To examine the long-term benefits and safety of aerobic training in patients with chronic heart failure. DESIGN: Non-randomised control trial with 52 weeks follow up. SETTING: Outpatient cardiac rehabilitation referral centre. PATIENTS: Patients with compensated chronic heart failure (mean (SD) age 62 (6) years, New York Heart Association stage III, initial resting ejection fraction 22 (7)%). Experimental group of 17 men, 4 women; control group 8 men, 1 woman. INTERVENTIONS: Experimental group: progressive, supervised aerobic walking programme for 52 weeks. Control group: standard medical treatment. MAIN OUTCOME MEASURES: Six-minute walk distance, progressive cycle ergometer test to subjective exhaustion, disease-specific quality of life questionnaire, and standard gamble test, all measured at entry, 4, 8, 12, 16, 26, and 52 weeks. RESULTS: Control data showed no changes except a small trend to improved emotional function (P = 0.02 at 12 weeks only). Fifteen of the 21 patients completed all 52 weeks of aerobic training; two withdrew for non-cardiac reasons (16, 52 weeks). Three were withdrawn because of worsening cardiac failure unrelated to their exercise participation (4, 4, 8 weeks), and one had a non-fatal cardiac arrest while shopping (16 weeks). Gains of cardiorespiratory function plateaued at 16-26 weeks, with 10-15% improvement in six-minute walk, peak power output, and peak oxygen intake linked to gains in oxygen pulse and ventilatory threshold and reductions in resting heart rate. Marked improvements in quality of life followed a parallel course. CONCLUSIONS: Aerobic training is safe and beneficial in compensated chronic heart failure. Gains in aerobic function and quality of life persisted over a programme lasting 52 weeks.

The morbidity and mortality of neonatal herpes simplex virus infection remains unacceptably high despite antiviral therapy. A better understanding of factors that might contribute to this poor outcome is needed but has been hindered by a lack of a good animal model. The recently described guinea pig model of neonatal HSV-2 infection was used to explore the effect of age and route of inoculation on the outcome of infection. After intranasal inoculation the onset, extent, and severity of the primary disease, as well as the number of recurrent lesion days, varied inversely with age. The route of inoculation also affected the outcome. Newborn animals were inoculated either intradermally on the scalp or by the intranasal, oral or corneal route. Animals inoculated on the scalp had the best outcome with no deaths or evidence of neurologic disease while the intranasal route produced the most severe disease, 88% mortality. Neurologic disease was common after oral (41%) and corneal (56%) inoculation but resolved spontaneously whereas following intranasal (39%) inoculation all animals with neurologic disease died. Recurrent disease manifest by cutaneous lesions was observed in all survivors of each group but also differed by the route of inoculation. The guinea pig model of neonatal HSV-2 disease appears to mimic human disease. The studies presented here show that the outcome of infection is influenced by the age and route of inoculation.

To compare the antihypertensive effects and incidence of side effects of two formulations of nifedipine: a prolonged action (PA) tablet bid and a gastrointestinal therapeutic system (GITS) tablet once daily.Patients with controlled hypertension (diastolic blood pressure less than 90 mmHg) on nifedipine-PA 10 mg (n = 74) or 20 mg (n = 99) bid were enrolled into an open label study consisting of six weeks of previous nifedipine-PA followed by six weeks of nifedipine-GITS therapy. Nifedipine-GITS was increased from 30 mg to 60 mg daily if the patient's diastolic blood pressure increased by at least 10 mmHg compared with the value after six weeks of nifedipine-PA.Blood pressure after six weeks of nifedipine-PA 10 mg (142 +/- 1/86 +/- 1 mmHg) decreased (P0.01) after conversion to nifedipine-GITS 30 mg (137 +/- 1/84 +/- 1 mmHg). Blood pressure values for nifedipine-PA 20 mg patients were unchanged after conversion to nifedipine-GITS; 74 patients received nifedipine-GITS 30 mg and 14 patients required titration up to nifedipine-GITS 60 mg daily. Sixteen patients withdrew on nifedipine-PA and five withdrew on nifedipine-GITS, mostly for reasons unrelated to drug therapy. Twenty-three patients experienced adverse events on nifedipine-PA versus 20 patients on nifedipine-GITS therapy.Patients whose hypertension is controlled by nifedipine-PA 10 or 20 mg bid can be successfully converted to nifedipine-GITS with most patients remaining normotensive on 30 mg daily.

Ambulatory blood pressure recordings were performed in patients receiving anti-hypertensive therapy to determine the prevalence of a white coat effect and to evaluate the importance of the sex of the patients with higher office vs. ambulatory blood pressure (BP) readings. A white coat effect (office--ambulatory BPor = 20/10 mm Hg) was present in 106 of 152 treated hypertensive patients who had a mean office BP (mm Hg) of 174 +/- 2/94 +/- 1 compared with a mean awake ambulatory BP of 137 +/- 2/81 +/- 1 (P0.001). A severe white coat effect (office--ambulatory BPor = 40/20 mm Hg) was observed in 49 of 152 patients with office BP (183 +/- 3/96 +/- 2) being higher (P0.001) than mean awake ambulatory BP (134 +/- 2/77 +/- 1). A white coat effect was present in 70 of 87 women but only in 36 of 65 men (P0.001). Similarly, a severe white coat effect was seen in 41 of 87 women but only in 8 of 65 men (P0.001). Female sex and office SBP were significantly (P0.001) correlated with the presence of a white coat or severe white coat effect. Thus, female patients with treated hypertension are more likely than men to have a white coat component to their high office BP readings. These sex differences in white coat effect should be considered in future studies involving patients with hypertension based on high office readings.

To determine the effectiveness of beta-blocker therapy for suppression of supraventricular arrhythmias (SVA) following aortocoronary bypass surgery (ACBS) in routine clinical practice.Prospective data collection and retrospective assessment of the occurrence of SVA following ACBS.Cardiovascular surgery intensive care unit and hospital patient ward with electrocardiogram (ECG) monitoring facilities.Ninety-two consecutive patients without contraindication to beta-blockade admitted for elective ACBS.Patients having persistent SVA requiring drug therapy during a minimum of four days of ECG monitoring were identified, and the use of beta-blocker therapy following ACBS was noted.Persistent SVA developed in 24 of 92 patients. Beta-blockers were taken by 11 of 24 patients with SVA compared with 49 of 68 without SVA (P = 0.02). Characteristics were similar for SVA and non-SVA patients including sex, left ventricular function, number of bypass grafts, preoperation beta-blocker use and postoperation intravenous esmolol therapy. SVA occurred 48 +/- 6 h (mean +/- SD) post-ACBS lasting 47 +/- 11 h. Patients with SVA were older than those without (64 +/- 2 versus 57 +/- 1 years, P = 0.002). Hospital stay after ACBS was increased (P0.001) in SVA versus non-SVA patients (8.7 +/- 0.7 versus 6.5 +/- 0.1 days).Oral beta-blocker prophylaxis is effective in preventing SVA after ACBS when used routinely in unselected patients. Failure to develop standardized approaches to beta-blocker therapy following ACBS may result in prolonged hospitalization.

Insulin receptor substrate-1 (IRS-1) serves as the major immediate substrate of insulin/insulin-like growth factor (IGF)-1 receptors and following tyrosine phosphorylation binds to specific Src homology-2 (SH2) domain-containing proteins including the p85 subunit of phosphatidylinositol (PI) 3-kinase and GRB2, a molecule believed to link IRS-1 to the Ras pathway. To investigate how these SH2-containing signaling molecules interact to regulate insulin/IGF-1 action, IRS-1, glutathione S-transferase (GST)-SH2 domain fusion proteins and Ras proteins were microinjected into Xenopus oocytes. We found that pleiotropic insulin actions are mediated by IRS-1 through two independent, but convergent, pathways involving PI 3-kinase and GRB2. Thus, microinjection of GST-fusion proteins of either p85 or GRB2 inhibited IRS-1-dependent activation of mitogen-activated protein (MAP) and S6 kinases and oocyte maturation, although only the GST-SH2 of p85 reduced insulin-stimulated PI 3-kinase activation. Co-injection of a dominant negative Ras (S17N) with IRS-1 inhibited insulin-stimulated MAP and S6 kinase activation. Micro-injection of activated [Arg12,Thr59]Ras increased basal MAP and S6 kinase activities and sensitized the oocytes to insulin-stimulated maturation without altering insulin-stimulated PI 3-kinase. The Ras-enhanced oocyte maturation response, but not the elevated basal level of MAP and S6 kinase, was partially blocked by the SH2-p85, but not SH2-GRB2. These data strongly suggest that IRS-1 can mediate many of insulin's actions on cellular enzyme activation and cell cycle progression requires binding and activation of multiple different SH2-domain proteins.

The trough:peak ratio (TPR) has been used to describe the extent to which an antihypertensive drug achieves adequate blood pressure control over the entire dosing interval. The TPR represents the net fall in blood pressure just before the next dose of medication is taken divided by the maximum reduction in blood pressure. For dihydropyridine calcium antagonists, the TPR is highly dependent upon the pharmacokinetics of the individual compound since the antihypertensive response correlates with the log drug plasma concentration. Accordingly, longer acting formulations exhibit a TPR close to unity with the maximum fall in blood pressure similar to the reduction at the end of the dosing interval. The application of TPR to angiotensin-converting enzyme inhibitors has unmasked a number of methodological problems associated with this approach to evaluating a drug's antihypertensive profile. The TPR has been calculated with and without subtracting responses to placebo with first doses and after several weeks of chronic therapy, and in responders only versus all subjects. Different approaches have also been taken to calculate the TPR, leading to marked variations in values. A review of the existing literature leads to the conclusion that improvements in the standardization of study design and data analysis are needed before TPR can become an accepted measure of 24 h blood pressure control.

EFFECTS OF SHORTER-ACTING CALCIUM ANTAGONISTS: The antihypertensive effect of the dihydropyridine calcium antagonists is highly correlated with the drug plasma concentration. These agents reduce blood pressure primarily via arteriolar vasodilation. More rapidly absorbed formulations such as the nifedipine capsule quickly produce a marked fall in blood pressure which tends to provoke a reflex increase in sympathetic nervous activity via the baroreceptor mechanism. These shorter-acting formulations are therefore more likely to be associated with vasodilatory side-effects such as flushing, palpitations, ankle edema, headaches and dizziness. ADVANTAGES OF LONGER-ACTING AGENTS: The link between pharmacokinetics, pharmacodynamics and side effects becomes more evident when longer-acting agents such as nifedipine gastrointestinal therapeutic system (GITS) and amlodipine are examined. These drugs have a trough: peak ratio that approaches 1, and thus exert a uniform antihypertensive effect over the dose interval. They are associated with fewer side effects in consequence of less baroreceptor reflex stimulation. The net result is improved efficacy and greater patient tolerability of these compounds.

To evaluate the antihypertensive effects of cilazapril, a new angiotensin-converting enzyme inhibitor, on clinic and ambulatory blood pressure (ABP) after first and last dose administrations.Four weeks randomized, double-blind, controlled trial of three regimens.Six hypertensive research clinics in Canada.After a two-week placebo run-in period, 130 patients aged 22 to 77 years with mild to moderate essential hypertension were randomized and evaluated. Exclusion criteria were secondary hypertension, childbearing potential and other significant diseases.Patients were assigned to cilazapril 2.5 mg (44 patients), cilazapril 5 mg (42) or placebo (44). Fourteen patients in each group were further evaluated in a substudy by 24 h ABP monitoring.Cilazapril in either dosage induced significant and similar antihypertensive effects on clinic blood pressure shortly after dosing (2 to 4 h), persisting during chronic treatment; however, no relevant effect persisted at the end of dosing (24 h). After four weeks, at the end of dosing, 22, 24 and 38% of patients were clinical responders (decrease in sitting diastolic blood pressure 10 mmHg or greater) on placebo, 2.5 or 5 mg (differences not significant). Conversely, both cilazapril regimens induced similar and significant (P0.01) falls in mean 24 h ABP compared with placebo. Moreover, 7, 50 and 48% of patients exhibited a reduction in mean 24 h diastolic blood pressure 10 mmHg or greater on placebo, cilazapril 2.5 or 5 mg, respectively. Furthermore, both regimens induced adequate trough:peak ratios on ABP.

GRB-2 is a small SH2- and SH3 domain-containing adapter protein that associates with the mammalian SOS homolog to regulate p21ras during growth factor signaling. During insulin stimulation, GRB-2 binds to the phosphorylated Y895VNI motif of IRS-1. Substitution of Tyr-895 with phenylalanine (IRS-1F-895) prevented the IRS-1-GRB-2 association in vivo and in vitro. The myeloid progenitor cell line, 32-D, is insensitive to insulin because it contains few insulin receptors and no IRS-1. Coexpression of IRS-1 or IRS-1F-895 with the insulin receptor was required for insulin-stimulated mitogenesis in 32-D cells, while expression of the insulin receptor alone was sufficient to mediate insulin-stimulated tyrosine phosphorylation of Shc and activation of p21ras and mitogen-activated protein (MAP) kinase. The Shc-GRB-2 complex formed during insulin stimulation is a possible mediator of p21ras and MAP kinase activation in IRS-1-deficient 32-D cells. Interestingly, IRS-1, but not IRS-1F-895, enhanced the stimulation of MAP kinase by insulin in 32-D cells expressing insulin receptors. Thus, IRS-1 contributes to the stimulation of MAP kinase by insulin, probably through formation of the IRS-1-GRB-2 complex at Tyr-895. Our results suggest that the Shc-GRB-2 complex and the activation of p21ras-dependent signaling pathways, including MAP kinase, are insufficient for insulin-stimulated mitogenesis and that the essential function(s) of IRS-1 in proliferative signaling is largely unrelated to IRS-1-GRB-2 complex formation.

To examine the prevalence and persistence of cigarette smoking along with health outcomes in a clinical sample of substance-abusing adolescents.This is a 2-year prospective case series study.Subjects were recruited from two private, hospital-based inpatient adolescent substance abuse treatment facilities.A consecutive sample of 166 adolescents, ages 12 to 18, meeting Diagnostic and Statistical Manual of Mental Disorders (3rd ed, revised) criteria for substance abuse participated in the present investigation. Of the original sample, 154 and 144 were interviewed 12 and 24 months after discharge, respectively.Information regarding cigarette smoking, drug and alcohol use, and respiratory problems was based on self-report by the adolescents and was corroborated by parent interview. The prevalence of smoking in this sample of teens immediately before treatment was 85%. Sixty-one percent of the sample smoked 1/2 pack or more/day and 75% were daily smokers. Although prevalence (74 and 77%) and average daily cigarette consumption (11.1 and 10.7 cigarettes daily) decreased at 12 and 24 months after treatment, rates remained very high. Teens reporting posttreatment respiratory problems smoked more, and heavier smokers at the time of treatment were more likely to report respiratory problems at follow-up than lighter smokers.Substance-abusing teens smoke at rates far and above those of the general adolescent population. Further, these teens appear at increased risk for negative health consequences regardless of posttreatment drug and alcohol use. These findings highlight the importance of preventing adolescent cigarette smoking by substance abuse treatment programs.

We have previously shown that phosphatidylinositol (PtdIns) 3'-kinase is activated by the binding of proteins or peptides containing the phosphorylated motif Y(P)XXM. In the present study, we examine interactions between PtdIns 3'-kinase and the human insulin receptor, which contains a C-terminal phosphorylation site in the sequence Y1322THM. Partially purified insulin receptors bound tightly to bacterial fusion proteins containing the N- or C-terminal SH2 domains from PtdIns 3'-kinase regulatory subunit (p85). In contrast, a mutant insulin receptor, truncated by 43 amino acids at the C terminus (IR delta CT), bound poorly to the SH2 domains; these mutant receptors have normal kinase activity but lack the Y1322THM motif. Similarly, incubation with wild-type receptors increased the activity of immunopurified PtdIns 3'-kinase, whereas incubation with IR delta CT receptors did not affect PtdIns 3'-kinase activity. Activation of PtdIns 3'-kinase by the wild-type receptor was mimicked by a tyrosyl phosphopeptide derived from the insulin receptor C terminus and containing the Y1322THM motif; non-phosphorylated peptide did not affect activity. Thus, the insulin receptor C terminus activates PtdIns 3'-kinase in vitro by binding to the SH2 domains of the 85-kDa regulatory subunit. These data support the hypothesis that binding of tyrosyl-phosphorylated receptors to p85 SH2 domains is a general mechanism for PtdIns 3'-kinase activation, and they suggest that direct interactions between the insulin receptor and PtdIns 3'-kinase may provide an alternative pathway for the activation of this enzyme by insulin.

Xenopus oocytes from unprimed frogs possess insulin-like growth factor I (IGF-I) receptors but lack insulin and IGF-I receptor substrate 1 (IRS-1), the endogenous substrate of this kinase, and fail to show downstream responses to hormonal stimulation. Microinjection of recombinant IRS-1 protein enhances insulin-stimulated phosphatidylinositol (PtdIns) 3-kinase activity and restores the germinal vesicle breakdown response. Activation of PtdIns 3-kinase results from formation of a complex between phosphorylated IRS-1 and the p85 subunit of PtdIns 3-kinase. Microinjection of a phosphonopeptide containing a pYMXM motif with high affinity for the src homology 2 (SH2) domain of PtdIns 3-kinase p85 inhibits IRS-1 association with and activation of the PtdIns 3-kinase. Formation of the IRS-1-PtdIns 3-kinase complex and insulin-stimulated PtdIns 3-kinase activation are also inhibited by microinjection of a glutathione S-transferase fusion protein containing the SH2 domain of p85. This effect occurs in a concentration-dependent fashion and results in a parallel loss of hormone-stimulated oocyte maturation. These inhibitory effects are specific and are not mimicked by glutathione S-transferase fusion proteins expressing the SH2 domains of ras-GAP or phospholipase C gamma. Moreover, injection of the SH2 domains of p85, ras-GAP, and phospholipase C gamma do not interfere with progesterone-induced oocyte maturation. These data demonstrate that phosphorylation of IRS-1 plays an essential role in IGF-I and insulin signaling in oocyte maturation and that this effect occurs through interactions of the phosphorylated YMXM/YXXM motifs of IRS-1 with SH2 domains of PtdIns 3-kinase or some related molecules.