A series of structurally novel heterotricyclic alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptor-selective antagonists.

BACKGROUND AND PURPOSE: A new class of heterotricyclic glutamate analogues recently was generated by incorporating structural elements of two excitotoxic marine compounds, kainic acid and neodysiherbaine A. Rather than acting as convulsants, several of these 'IKM' compounds markedly depressed CNS activity in mice. Here, we characterize the pharmacological profile of the series with a focus on the most potent of these molecules, IKM-159. EXPERIMENTAL APPROACH: The pharmacological activity and specificity of IKM compounds were characterized using whole-cell patch clamp recording from neurons and heterologous receptor expression systems, in combination with radioligand binding techniques. KEY RESULTS: The majority of the IKM compounds tested reduced excitatory synaptic transmission in neuronal cultures, and IKM-159 inhibited synaptic currents from CA1 pyramidal neurons in hippocampal slices. IKM-159 inhibited glutamate-evoked whole-cell currents from recombinant GluA2- and GluA4-containing alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) receptors most potently, whereas kainate and NMDA receptor currents were not reduced by IKM-159. Antagonism of steady-state currents was agonist concentration dependent, suggesting that its mechanism of action was competitive, although it paradoxically did not displace [(3)H]-AMPA from receptor binding sites. IKM-159 reduced spontaneous action potential firing in both cultured hippocampal neurons in control conditions and during hyperactive states in an in vitro model of status epilepticus. CONCLUSIONS AND IMPLICATIONS: IKM-159 is an AMPA receptor-selective antagonist. IKM-159 and related nitrogen heterocycles represent structurally novel AMPA receptor antagonists with accessible synthetic pathways and potentially unique pharmacology, which could be of use in exploring the role of specific populations of receptors in neurophysiological and neuropathological processes.

Chronic ethanol consumption reduces delta-and mu-opioid receptor-stimulated G-protein coupling in rat brain.

BACKGROUND: Ethanol consumption is thought to enhance the release of endogenous opioids acting at opioid receptors (ORs) in the central nervous system. Prior studies have shown that chronic ethanol consumption in alcohol-preferring rats uncouples mu-ORs from Gi proteins. The purpose of this study was to investigate the potential for uncoupling of the delta- and the mu-OR after chronic ethanol consumption in a nonpreferring rat strain. METHODS: We used radiohistochemical methods to study mu- and delta-OR-stimulated G-protein coupling in brain tissue of rats ingesting liquid diets containing 6.7% ethanol (v/v) for 16 days, as compared with 0% ethanol pair-fed control rats. Sections of brain from pair-fed and ethanol-treated rats were incubated with guanylyl 5'-[gamma-[35S]-thio]-triphosphate ([35S]-GTPgammaS) in the absence and presence of d-Pen2,d-Pen5 enkephalin (DPDPE), a delta-OR agonist, or Tyr-d-Ala-Gly-N(me)Phe-Gly-ol-enkephalin (DAMGO), a mu-OR agonist. RESULTS: DPDPE significantly stimulated [35S]-GTPgammaS binding in the hippocampal dentate gyrus (DG), CA1, cerebellum, and inferior colliculus of untreated pair-fed controls. By contrast, DPDPE-stimulated [35S]-GTPgammaS binding was reduced significantly in those brain regions in the ethanol-consuming group. DAMGO stimulated [35S]-GTPgammaS binding in cortex, caudate, nucleus accumbens, DG, CA1, and superior and inferior colliculi, whereas the DG, CA1, and colliculi showed a significant reduction of binding after chronic ethanol. Basal [35S]-GTPgammaS binding was not different between the two diet groups. CONCLUSIONS These data are the first to demonstrate functional uncoupling of delta-ORs from G proteins after chronic ethanol consumption. Uncoupling may result from modulation of receptors, possibly by internalization or phosphorylation. Alterations in functional coupling of both delta- and mu-ORs and subsequent effects may contribute to continued ethanol consumption.

Risk factors for Candida species colonization of neonatal intensive care unit patients.

BACKGROUND: Candida spp. are increasingly important pathogens in neonatal intensive care units (NICU). Prior colonization is a major risk factor for candidemia, but few studies have focused on risk factors for colonization, particularly in NICU patients. METHODS: A prospective, multicenter cohort study was performed in six NICUs to determine risk factors for Candida colonization. Infant gastrointestinal tracts were cultured on admission and weekly until NICU discharge and health care worker hands were cultured monthly for Candida spp. RESULTS: The prevalence of Candida spp. colonization was 23% (486 of 2157 infants); 299 (14%), 151 (7%) and 74 (3%) were colonized with Candida albicans, Candida parapsilosis and other Candida spp., respectively. Multiple logistic regression analysis adjusting for length of stay, birth weight < or = 1000 g and gestational age < 32 weeks revealed that use of third generation cephalosporins was associated with either C. albicans (155 incident cases) or C. parapsilosis (104 incident cases) colonization. Use of central venous catheters or intravenous lipids were risk factors for C. albicans, whereas delivery by cesarean section was protective. Use of H2 blockers was an independent risk factor for C. parapsilosis. Of 2989 cultures from health care workers' hands, 150 (5%) were positive for C. albicans and 575 (19%) for C. parapsilosis, but carriage rates did not correlate with NICU site-specific rates for infant colonization. CONCLUSIONS: We speculate that NICU patients acquire Candida spp., particularly C. parapsilosis, from the hands of health care workers. H2 blockers, third generation cephalosporins and delayed enteral feedings alter gastrointestinal tract ecology, thereby facilitating colonization.

Ionotropic glutamate receptor subunit expression in the rat hippocampus: lack of an effect of a long-term ethanol exposure paradigm.

BACKGROUND: Studies have shown that acute ethanol exposure inhibits ionotropic glutamate receptor function and that long-term ethanol exposure results in maladaptive increases in the expression of some of these receptors in neurons. It has been postulated that these changes, when unopposed by ethanol, contribute, in part, to the hyperexcitability associated with ethanol withdrawal. In this study, we compared the effect of long-term ethanol exposure on the hippocampal expression levels of subunits belonging to the three families of ionotropic glutamate receptors. METHODS: Adult male Sprague-Dawley rats were fed an ethanol-containing diet for 16 days. This diet contained 0% ethanol on days 1 and 2, 3% on days 3 and 4, 5% on days 5 to 7, and 6.7% on days 8 to 16. Control rats received an equivalent amount of an isocaloric diet without ethanol. Rats were killed on day 16 at the peak of ethanol consumption. Hippocampal homogenates were prepared by sonication and analyzed by Western immunoblotting techniques. On a separate group of rats, we measured withdrawal scores and audiogenic seizures on day 17. RESULTS: Ethanol-exposed rats had significantly higher withdrawal scores, and a significantly higher percentage of them developed audiogenic seizures; this indicates that the 16-day ethanol diet induces ethanol dependence. Unexpectedly, we found that expression of NR1 (including the expression of NR1 subunits containing the N1, C1, and C2 inserts), NR2A, NR2B, NR2C, GluR1, GluR2/3, GluR5, GluR6/7, and KA2 subunits was not altered in hippocampal homogenates from ethanol-exposed rats. CONCLUSIONS: These results indicate that maladaptive changes in the hippocampal expression levels of ionotropic glutamate receptor subunits do not always occur in ethanol-dependent rats. Consequently, other mechanisms must mediate the hyperexcitability state associated with ethanol withdrawal in these animals.

Effect of the quality of health care on permanent inability secondary to femoral fractures due to occupational accidents.

OBJECTIVE: To construct and validate an indicator for evaluating the quality of care for femoral fractures, and to assess the contribution of the quality of health care as a determinant of partial permanent inability secondary to femoral fractures due to occupational accidents. MATERIALS AND METHODS: The study was conducted from January to December 1995 at Mexican Institute of Social Security. The instrument was designed with experts' contribution along different stages and validated using implicit criteria and factorial analysis. A case-control study was then conducted to evaluate the contribution of the quality of care to inability secondary to femoral fractures. Cases were 108 active workers with permanent inability secondary to femoral fracture; controls were 94 active workers with fracture of femur but no permanent inability. Logistic regression modeling was used to establish the association between quality of care and partial permanent inability, adjusting by relevant variables. RESULTS: The ultimate indicator of quality of care consisted of the following: Timely care, presurgical management, surgical management, and fracture complications. A final score over 229 points meant that the worker had received good quality of care. Workers getting 229 or less points had received poor quality of care. Forty-eight (44%) cases and 66 (70%) controls received good quality of medical care. The likelihood of partial permanent inability was almost three times higher among workers given poor quality of care (OR 2.95; 95% CI 1.5-5.5). According to the multivariate model, predictors of partial permanent inability were: Having exposed or epiphysiary fractures, being re-submitted to surgery, having less than 90 days of rehabilitation care, and receiving deficient medical care. CONCLUSIONS: The constructed instrument was validated. The level of the quality of care received by workers is a determining factor for the generation of partial permanent inability. In workers having femoral fractures, it is important to consider timely medical care and early rehabilitation, to reduce the high incidence and prevalence of this medical problem in Mexico. The English version of this paper is available too at: http://www.insp.mx/salud/index.html.

Pragmatic randomized trial of home visits by a nurse to elderly people with hypertension in Mexico.

BACKGROUND: In Mexico, hypertension is a major cause of disability and death in the elderly, but the most effective way to promote behaviour change in old people is unknown. Low resource interventions that are effective in normal healthcare settings are urgently needed. We report the results of a randomized trial of nurse-provided health and lifestyle advice during home visits to elderly people with hypertension in Mexico City. METHODS: Subjects were 718 people with hypertension aged > or =60 years, who were residents of Mexico City and were registered with the Family Medicine Clinics of the Mexican Institute of Social Security (IMSS). A randomized controlled trial was carried out in which the intervention group was offered nurse visits over 6 months with blood pressure checks and negotiated lifestyle changes. The control group continued to receive usual care. RESULTS: After 6 months, 36.5% of the intervention versus 6.8% of the control group had a blood pressure of <160/90 mmHg. The difference in the mean change in systolic blood pressure was 3.31 mmHg (P = 0.03, 95% CI : 6.32, 0.29) and the same difference in diastolic blood pressure was 3.67 mmHg (P = 0.00, 95% CI : 5.22, 2.12). Weight and sodium excretion fell more in the intervention group, but the difference was not significant. CONCLUSIONS: Nurse home visits are effective in reducing blood pressure in hypertensive patients aged > or =60 years.

Fetal alcohol exposure alters neurosteroid modulation of hippocampal N-methyl-D-aspartate receptors.

The actions of ethanol on brain ligand-gated ion channels have important roles in the pathophysiology of alcohol-related neurodevelopmental disorders and fetal alcohol syndrome. Studies have shown that N-methyl-d-aspartate (NMDA) receptors are among the ligand-gated ion channels affected by prenatal ethanol exposure. We exposed pregnant dams to an ethanol-containing liquid diet that results in blood ethanol levels near the legal intoxication limit in most states (0.08%). Primary cultures of hippocampal neurons were prepared from the neonatal offspring of these dams, and NMDA receptor function was assessed by patch clamp electrophysiological techniques after 6-7 days in culture in ethanol-free media. Unexpectedly, we did not detect any changes in hippocampal NMDA receptor function at either the whole-cell or single-channel levels. However, we determined that fetal alcohol exposure alters the actions of the neurosteroids pregnenolone sulfate and pregnenolone hemisuccinate, which potentiate NMDA receptor function. Western immunoblot analyses demonstrated that this alteration is not due to a change in the expression levels of NMDA receptor subunits. Importantly, in utero ethanol exposure did not affect the actions of neurosteroids that inhibit NMDA receptor function. Moreover, the actions of pregnenolone sulfate on type A gamma-aminobutyric acid and non-NMDA receptor function were unaltered by ethanol exposure in utero, which suggests that the alteration is specific to NMDA receptors. These findings are significant because they provide, at least in part, a plausible mechanistic explanation for the alterations in the behavioral responses to neurosteroids found in neonatal rats prenatally exposed to ethanol and to other forms of maternal stress (Zimmerberg, B., and McDonald, B. C. (1996) Pharmacol. Biochem. Behav. 55, 541-547).

Family physician job satisfaction in different medical care organization models.

OBJECTIVES: The aim of the present study was to estimate physician job satisfaction at the Mexican Institute of Social Security (IMSS), the Ministry of Health (SSA) and in the private sector, and to measure the association between these different family medical care organization models. METHODS: A comparative cross-sectional design was used to investigate the job satisfaction of family physicians in private and institutional family medicine clinics. Satisfaction was measured with a previously constructed and validated instrument. The instrument measures the satisfaction in four areas: 'global satisfaction', 'institution where the physician works', 'the patients' and 'themselves as physicians'. RESULTS: One hundred and seven IMSS physicians, 106 SSA physicians and 97 private physicians were selected randomly from a census according to the sample size. The sample was weighted. Fifty-one percent of IMSS and SSA physicians were dissatisfied, against 25% in the private sector, in the first three areas. Comparing the private model and the IMSS, differences were found (P < 0.0001) in the area of 'global satisfaction' [odds ratio (OR) = 2.47, 95% confidence interval (CI) 1.69-3.67], 'institution where the physician works' (OR = 2.12, CI 1. 45-3.13) and 'themselves as physicians' (OR = 1.84, CI 1.28-2.65). When the private/SSA groups were compared, the differences were similar (P < 0.0001). No differences were found in terms of 'the patients'. When stratifying, the risks increased in females, in the group aged 31-40 years and in specialists in family medicine. CONCLUSIONS: The organization model is associated with dissatisfaction in all areas, except in 'the patients'.

Risk factors for candidemia in Neonatal Intensive Care Unit patients. The National Epidemiology of Mycosis Survey study group.

BACKGROUND: Candida species are important nosocomial pathogens in neonatal intensive care unit (NICU) patients. METHODS: A prospective cohort study was performed in six geographically diverse NICUs from 1993 to 1995 to determine the incidence of and risk factors for candidemia, including the role of gastrointestinal (GI) tract colonization. Study procedures included rectal swabs to detect fungal colonization and active surveillance to identify risk factors for candidemia. Candida strains obtained from the GI tract and blood were analyzed by pulsed field gel electrophoresis to determine whether colonizing strains caused candidemia. RESULTS: In all, 2,847 infants were enrolled and 35 (1.2%) developed candidemia (12.3 cases per 1,000 patient discharges or 0.63 case per 1,000 catheter days) including 23 of 421 (5.5%) babies < or =1,000 g. After adjusting for birth weight and abdominal surgery, forward multivariate logistic regression analysis demonstrated significant risk factors, including gestational age <32 weeks, 5-min Apgar <5; shock, disseminated intravascular coagulopathy, prior use of intralipid, parenteral nutrition, central venous catheters, H2 blockers, intubation or length of stay > 7 days before candidemia (P < 0.05). Catheters, steroids and GI tract colonization were not independent risk factors, but GI tract colonization preceded candidemia in 15 of 35 (43%) case patients. CONCLUSIONS: Candida spp. are an important cause of late onset sepsis in NICU patients. The incidence of candidemia might be decreased by the judicious use of treatments identified as risk factors and avoiding H2 blockers.

Multicenter evaluation of the efficacy and safety of gatifloxacin in Mexican adult outpatients with respiratory tract infections.

Respiratory tract infections (RTIs), the most common indication for outpatient antimicrobial therapy, impose a heavy medical and societal burden and present a difficult therapeutic challenge in the face of increasing pathogen resistance worldwide. Gatifloxacin is a new broad-spectrum fluoroquinolone with excellent activity against prevalent respiratory bacteria, including penicillin-resistant Streptococcus pneumoniae and atypical pathogens. A multicenter, open-label, noncomparative surveillance study carried out in Mexico evaluated the safety and efficacy of oral gatifloxacin 400 mg once daily in 17,923 adult outpatients with community-acquired pneumonia (CAP) (n = 3322), acute exacerbations of chronic bronchitis (AECB) (n = 5885), and acute bacterial sinusitis (n = 8716). Voluntary, unpaid physician participation contributed to an unbiased study design. Physician-assessed global rate of cure or improvement was 96.3%; efficacy was 95.8% in CAP, 96.1% in AECB, and 96.4% in sinusitis. The incidences of relapse (1.5%) and therapeutic failure (0.7%) were low. The most commonly reported adverse events, nausea (2.76%), headache (2.20%), and dizziness (1.33%), were generally mild and self-limited. Oral gatifloxacin 400 mg once daily is effective and safe for patients with CAP, AECB, and acute sinusitis.

Development and validation of an inventory to measure satisfaction of users of family medicine clinics in Mexico.

The object of this study was to construct and validate an inventory to measure the satisfaction of users of Family Medicine Clinics. The satisfaction construct was theoretically developed, then the semantic network technique was applied to write 45 items with a dichotomized response. The scale was validated for 4,134 users. Cronbach coefficient alpha was .78. In a factor analysis, 8 factors were obtained, which explained 43.3% of the variance. The content of the first factor referred to the Family Physician dimension, Factors 3, 4, and 5 to the Family Medicine Clinic, and Factors 2, 6, 7, and 8 to Other Services of the Clinic. The questionnaire is being integrated to the Quality of Care Evaluation System to assess satisfaction of users. It may be useful in other venues to assess cultural and organizational aspects of satisfaction with health care.

[Effect of maternal death on family dynamics and infant survival]. / Efecto de la muerte materna sobre la dinámica familiar y la sobrevivencia infantil.

Family adjustments, which are generated by a maternal death, have been analysed previously in Mexico by using a reduced number of cases in rural areas. This study was design in order to establish changes in family dynamic generated b y a maternal death and to analyse child surviving after one year of birth. Family members of maternal deaths cases, which occurred during 1988-89 in the Federal District, were interviewed by first time in order to know information related to family dynamic and women's characteristics. A second interview was made after one year of birth for cases in which the newborn survived hospital discharge. Simple frequencies were calculated and using X2 test compared groups. Main consequences were family disintegration, child acquiring new roles and economic problems when woman was the main or the only one support of the family. Child surviving was higher than we expected considering other national or international reports. Children were mainly integrated to their grandparent's family.

Maternal mortality regionalization and trend in Mexico (1937-1995)

BACKGROUND: The objectives were to establish regions by level of maternal mortality in order to evaluate its trend from 1937-1995 and to analyze characteristics of cases which occurred from 1990-1995. METHODS: Regionalization of the country by maternal mortality level was carried out using Poisson regression. Level and mortality trends were analyzed globally and compared by regions using Poisson and linear regression. Characteristics of cases were analyzed from 1990-1995 using proportions and X2 test. RESULTS: Four well-differentiated and independent regions were established. Low and medium maternal mortality rate regions were found in northern and northwestern Mexico. High and very high maternal mortality regions were found in the South and the Southeast of the country. Even when maternal mortality had descended, the speed of the descent has decreased and in the last few years, maternal mortality has increased. The quality of health care is a challenge for regions with low mortality rates, while the problem of accessibility is present in those with very high mortality rates. CONCLUSION: The employment of this regionalization approach in maternal mortality analysis would be useful to determine specific problems for each region. The establishment of programs according to this analysis could contribute to decrease in maternal mortality cases in Mexico.

[Adequate utilization of prenatal care at the Mexican Institute of Social Security]. / Utilización adecuada de la atención prenatal en el Instituto Mexicano del Seguro Social.

OBJECTIVE: To establish what proportion of women utilize antenatal care adequately and analyze obstetric, economic, social and cultural factors related to the adequacy of antenatal care use at the Mexican Institute of Social Security (IMSS). MATERIAL AND METHODS: This cross-sectional study included 394 women from 12 to 49 years of age at twenty-eight to forty-two weeks of gestation. A questionnaire was applied that collected information on the following: demographic, social economic and cultural variables; knowledge about pregnancy and complications; gyneco-obstetric history, and barriers to use of antenatal health care services. Data were analyzed by using descriptive statistics, odds ratios and logistic regression modelling. RESULTS: Antenatal care was started during the first trimester by 75% of women, 23.8% of these made at least nine antenatal care visits (adequate utilization). Adequate utilization was associated to prenatal care in family medicine units with a computer system, knowledge and behavior regarding complications, parity, care by the same physician at IMSS, and the woman's occupation. CONCLUSIONS: The proportion of women who utilize prenatal care adequately is low at IMSS. Information about related factors could be used in order to improve institutional programs.

Development and validation of an inventory for measuring job satisfaction among family physicians.

The aim was to develop and validate a measure of job satisfaction among family physicians. The construct of job satisfaction was developed theoretically, then the semantic network technique was used for the construction of the items. 80 semantic differential items in a random order were related by nine physicians. Four dimensions integrated the construct: "job satisfaction," "health institutions where I work," "my patients," and "myself as a doctor." The average Cronbach alpha was .81. In the factor analysis, four factors were obtained in each dimension except that of "my patients," for which two were obtained. These factors accounted for at least 44% of the construct developed. The semantic network technique may be useful.

[Magnitude and causes of maternal mortality in the Federal District (1988-1989)]. / La magnitud y las causas de la mortalidad materna en el Distrito Federal (1988-1989).

Despite the availability of health resources to provide prenatal and delivery care for all pregnant women in the Federal District, the maternal mortality ratio is extremely high. Based on the study of all the maternal deaths which occurred in the Federal District during 1988 and the first semester of 1989 (n = 433), a ratio of 11.4 deaths per 10,000 registered live births was estimated. This is almost twice as high as the ratio reported through vital statistics. The maternal mortality ratio is higher among women delivered in public assistance hospitals as compared with those delivered in social security hospitals. This is due to the high percentage of women arriving with severe complications and to the lower standards of obstetric care in the former. About 75% of the deaths were due to one of the following causes: hypertensive disease of pregnancy, hemorrhage and infection. A detailed study of hospital records undertaken by a maternal mortality committee revealed that 85% of the deaths were preventable with the technology and resources available. The committee identified errors in medical judgment as the main factor involved in the chain of causation leading to potential preventable deaths.

Systemic inflammatory response syndrome, sepsis, severe sepsis and septic shock: incidence, morbidities and outcomes in surgical ICU patients.

OBJECTIVES: To determine the incidence of systemic inflammatory response syndrome (SIRS), sepsis and severe sepsis in surgical ICU patients and define patient characteristics associated with their acquisition and outcome. DESIGN: One-month prospective study of critically ill patients with a 28 day in-hospital follow up. SETTING: Surgical intensive care unit (SICU) at a tertiary care institution. METHODS: All patients (n = 170) admitted to the SICU between April 1 and April 30, 1992 were prospectively followed for 28 days. Daily surveillance was performed by two dedicated, specifically-trained research nurses. Medical and nursing chart reviews were performed, and follow up information at six and twelve months was obtained. RESULTS: The in-hospital surveillance represented 2246 patient-days, including 658 ICU patient-days. Overall, 158 patients (93%) had SIRS for an incidence of 542 episodes/1000 patients-days. The incidence of SIRS in the ICU was even higher (840 episodes/1000 patients-days). A total of 83 patients (49%) had sepsis; among them 28 developed severe sepsis. Importantly, 13 patients had severe sepsis after discharge from the ICU. Patient groups were comparable with respect to age, sex ratio, and type of surgery performed. Apache II score on admission to the ICU and ASA score at time of surgery were significantly higher (p < 0.05) only for patients who subsequently developed severe sepsis. The crude mortality at 28 days was 8.2% (14/170); it markedly differed among patient groups: 6% for those with SIRS vs. 35% for patients with severe sepsis. Patients with sepsis and severe sepsis had a longer mean length of ICU stay (2.1 +/- 0.2 and 7.5 +/- 1.5, respectively) than those with SIRS (1.45 +/- 0.1) or control patients (1.16 +/- 0.1). Total length of hospital stay also markedly differed among groups (35 +/- 9 (severe sepsis), 24 +/- 2 (sepsis), 11 +/- 0.8 (SIRS), and 9 +/- 0.1 (controls, respectively). CONCLUSIONS: Almost everyone in the SICU had SIRS. Therefore, because of its poor specificity, SIRS was not helpful predicting severe sepsis and septic shock. Patients who developed sepsis or severe sepsis had higher crude mortality and length of stay than those who did not. Studies designed to identify those who develop complications of SIRS would be very useful.