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Biomedical subjects

J Lynch

Publications and source records attributed to J Lynch.

At least 55 records · Page 3Linked to original sources
PubMed2001

Women's exposure to early and later life socioeconomic disadvantage and coronary heart disease risk: the Stockholm Female Coronary Risk Study.

BACKGROUND: Measures of low socioeconomic position have been associated with increased risk for coronary heart disease (CHD) among women. A more complete understanding of this association is gained when socioeconomic position is conceptualized from a life course perspective where socioeconomic position is measured both in early and later life. We examined various life course socioeconomic indicators in relation to CHD risk among women. METHODS: The Stockholm Female Coronary Risk Study is a population-based case-control study, in which 292 women with CHD aged < or =65 years and 292 age-matched controls were investigated using a wide range of socioeconomic, behavioural, psychosocial and physiological risk factors. Socioeconomic disadvantage in early life (large family size in childhood, being born last, low education), and in later life (housewife or blue-collar occupation at labour force entry, blue-collar occupation at examination, economic hardships prior to examination) was assessed. RESULTS: Exposure to early (OR = 2.65, 95% CI : 1.12-6.54) or later (OR = 5.38, 95% CI : 2.01-11.43) life socioeconomic disadvantage was associated with increased CHD risk as compared to not being exposed. After simultaneous adjustment for marital status and traditional CHD risk factors, early and later socioeconomic disadvantage, exposure to three instances of socioeconomic disadvantage in early life was associated with an increased CHD risk of 2.48 (95% CI : 0.90-6.83) as compared to not being exposed to any disadvantage. The corresponding adjusted risk associated with exposure to later life disadvantage was 3.22 (95% CI : 1.02-10.53). Further analyses did not show statistical evidence of interaction effects between early and later life exposures (P = 0.12), although being exposed to both resulted in a 4.2-fold (95% CI : 1.4-12.1) increased CHD risk. Exposure to cumulative socioeconomic disadvantage (combining both early and later life), across all stages in the life course showed strong, graded associations with CHD risk after adjusting for traditional CHD risk factors. Stratification of cumulative disadvantage by body height showed that exposure to more than three periods of cumulative socioeconomic disadvantage had a 1.7- (95% CI : 0.9-3.2) and 1.9- (95% CI : 1.0-7.7) fold increased CHD risk for taller and shorter women, respectively. The combination of both short stature and more than two periods of cumulative socioeconomic disadvantage resulted in a 4.4-fold (95% CI : 1.7-9.3) increased CHD risk. CONCLUSIONS: Both early and later exposure to socioeconomic disadvantage were associated with increased CHD risk in women. Later life exposure seems to be more harmful for women's cardiovascular health than early life exposure to socioeconomic disadvantage. However, being exposed to socioeconomic disadvantage in both early and later life magnified the risk for CHD in women. Cumulative exposure to socioeconomic disadvantage resulted in greater likelihood of CHD risk, even among women who were above median height. In terms of better understanding health inequalities among women, measures of socioeconomic disadvantage over the life course are both conceptually and empirically superior to using socioeconomic indicators from one point in time.

Adult↗
PubMed2001

Glutamine administration reduces Gram-negative bacteremia in severely burned patients: a prospective, randomized, double-blind trial versus isonitrogenous control.

OBJECTIVE: To determine the effect of intravenous glutamine supplementation vs. an isonitrogenous control on infectious morbidity in severely burned patients. Previous clinical studies in seriously ill patients suggest a beneficial effect of glutamine on infectious morbidity, but no trials have examined possible clinical benefits in severely burned patients. DESIGN: Prospective, double-blind, randomized trial. SETTING: Burn intensive care unit of a university hospital. PATIENTS: Twenty-six severe burn patients with total burn surface area of 25% to 90% and presence of full-thickness burns. Patients were evaluated for occurrence of bacteremia and antibiotic use during the first 30 days of their burn unit admission. Nutritional status and overall inflammation were also measured. INTERVENTION: Either intravenous glutamine or an isonitrogenous control amino acid solution was administered as a continuous infusion during burn intensive care unit stay. MEASUREMENTS AND MAIN RESULTS: The incidence of Gram-negative bacteremia was significantly reduced in the glutamine-supplemented group (8%) vs. control (43%; p <.04). No difference was seen in the incidence of Gram-positive bacteremia or fungemia. Average number of positive blood cultures, antibiotic usage, and mortality rates also were reduced but did not reach statistical significance. Significant improvements in serum transferrin and prealbumin were observed in glutamine-supplemented patients at 14 days after burn injury (p <.01 and.04, respectively). C-reactive protein was also significantly reduced at 14 days after burn injury in the glutamine group (p <.01). CONCLUSIONS: Significantly fewer bacteremic episodes with Gram-negative organisms occurred in the glutamine-supplemented patients. Glutamine supplementation improved measures of nutrition and decreased measures of overall inflammation. In addition, a trend toward lower mortality rate, decreased overall bacteremia incidence, and antibiotic usage in the glutamine group was observed. Glutamine's beneficial effects may be a result of improved gut integrity or immune function, but the precise mechanism of glutamine's protection is unknown.

Adult↗
PubMed2001

Cerebral blood flow velocity response to magnesium sulfate in patients after subarachnoid hemorrhage.

Magnesium sulfate therapy, standard in preventing seizures in preeclampsia, is under active investigation as a neuroprotective agent. The authors studied the effect of magnesium as a cerebral vasodilator by measuring the cerebral blood flow velocity (CBFV) response to a 5g intravenous bolus of MgSO4 compared with a saline placebo after subarachnoid hemorrhage (SAH). Transcranial Doppler ultrasonography of the middle cerebral artery (MCA) was measured after each infusion. Patients were studied up to three times after SAH at prescribed time intervals. Fourteen patients (11 women, 3 men; mean age 58 years) underwent 29 studies. All patients underwent hypertensive, hypervolemic therapy. Four patients developed cerebral vasospasm. Doubling serum magnesium levels did not affect MCA CBFV but slightly lowered mean arterial blood pressure and systemic vascular resistance. Intravenous magnesium bolus did not reduce elevated CBFV in the subset of SAH patients with clinical vasospasm. The role of magnesium sulfate as a cerebral vasodilator in patients with SAH requires further study.

Adult↗
PubMed2001

Mutational analysis of the repeated open reading frames, ORFs 63 and 70 and ORFs 64 and 69, of varicella-zoster virus.

Varicella-zoster virus (VZV) open reading frame 63 (ORF63), located between nucleotides 110581 and 111417 in the internal repeat region, encodes a nuclear phosphoprotein which is homologous to herpes simplex virus type 1 (HSV-1) ICP22 and is duplicated in the terminal repeat region as ORF70 (nucleotides 118480 to 119316). We evaluated the role of ORFs 63 and 70 in VZV replication, using recombinant VZV cosmids and PCR-based mutagenesis to make single and dual deletions of these ORFs. VZV was recovered within 8 to 10 days when cosmids with single deletions were transfected into melanoma cells along with the three intact VZV cosmids. In contrast, VZV was not detected in transfections carried out with a dual deletion cosmid. Infectious virus was recovered when ORF63 was cloned into a nonnative AvrII site in this cosmid, confirming that failure to generate virus was due to the dual ORF63/70 deletion and that replication required at least one gene copy. This requirement may be related to our observation that ORF63 interacts directly with ORF62, the major immediate-early transactivating protein of VZV. ORF64 is located within the inverted repeat region between nucleotides 111565 and 112107; it has some homology to the HSV-1 Us10 gene and is duplicated as ORF69 (nucleotides 117790 to 118332). ORF64 and ORF69 were deleted individually or simultaneously using the VZV cosmid system. Single deletions of ORF64 or ORF69 yielded viral plaques with the same kinetics and morphology as viruses generated with the parental cosmids. The dual deletion of ORF64 and ORF69 was associated with an abnormal plaque phenotype characterized by very large, multinucleated syncytia. Finally, all of the deletion mutants that yielded recombinants retained infectivity for human T cells in vitro and replicated efficiently in human skin in the SCIDhu mouse model of VZV pathogenesis.

Animals↗
PubMed2001

Varicella-zoster virus ORF47 protein serine kinase: characterization of a cloned, biologically active phosphotransferase and two viral substrates, ORF62 and ORF63.

Varicella-zoster virus (VZV) codes for a protein serine kinase called ORF47; the herpes simplex virus (HSV) homolog is UL13. No recombinant alphaherpesvirus serine kinase has been biologically active in vitro. We discovered that preservation of the intrinsic kinase activity of recombinant VZV ORF47 required unusually stringent in vitro conditions, including physiological concentrations of polyamines. In this assay, ORF47 phosphorylated two VZV regulatory proteins: the ORF62 protein (homolog of HSV ICP4) and the ORF63 protein (homolog of HSV ICP22). Of interest, ORF47 kinase also coprecipitated ORF63 protein from the kinase assay supernatant.

Aspartic Acid↗
PubMed2001

Social capital, disorganized communities, and the third way: understanding the retreat from structural inequalities in epidemiology and public health.

The construct of social capital has recently captured the interest of researchers in social epidemiology and public health. The authors review current hypotheses on the social capital and health link, and examine the empirical evidence and its implications for health policy. The construct of social capital employed in the public health literature lacks depth compared with its uses in social science. It presents itself as an alternative to materialist structural inequalities (class, gender, and race) and invokes a romanticized view of communities without social conflict that favors an idealist psychology over a psychology connected to material resources and social structure. The evidence on social capital as a determinant of better health is scant or ambiguous. Even if confirmed, such hypotheses call for attention to social determinants beyond the proximal realm of individualized sociopsychological infrastructure. Social capital is used in public health as an alternative to both state-centered economic redistribution and party politics, and represents a potential privatization of both economics and politics. Such uses of social capital mirror recent "third way" policies in Germany, the United Kingdom, and United States. If third way policies lose support in Europe, the prominence of social capital there might be short lived. In the United States, where the working class is less likely to influence social policy, interest in social capital could be longer lived or could drift into academic limbo like other psychosocial constructs once heralded as the next big idea.

Community Health Planning↗
PubMed2000

COUP-TF1 antagonizes Nkx2.5-mediated activation of the calreticulin gene during cardiac development.

Calreticulin, a Ca(2+) binding chaperone of the endoplasmic reticulum, is also highly expressed in the embryonic heart, and knockout of the calreticulin gene is lethal during embryogenesis because of impaired cardiac development. The protein is down-regulated after birth, and elevated expression of calreticulin in newborn hearts is associated with severe cardiac pathology and death. Here we show that the transcription factor Nkx2.5 activates expression of the calreticulin gene in the heart. Binding of chicken ovalbumin upstream promoter-transcription factor 1 to the Nkx2.5 binding site suppresses transcription from the calreticulin promoter. Nkx2.5 and chicken ovalbumin upstream promoter-transcription factor 1 play antagonistic roles in regulating the expression of calreticulin during cardiac development. These studies indicate that cardiac-specific transcription factor Nkx2.5 plays a central role in activating calreticulin expression and that there is a cooperation between chicken ovalbumin upstream promoter-transcription factor 1 and Nkx2.5 at the calreticulin promoter.

Animals↗
PubMed2000

Lynch syndrome: genetics, natural history, genetic counseling, and prevention.

Lynch syndrome is the most common hereditary form of colorectal cancer (CRC). Its natural history has been investigated extensively, so that highly targeted surveillance and management strategies, melded to its natural history, have proven effective in cancer control. Most important is the early age of onset of cancer (approximately 44 years), involving CRC and the several extracolonic cancers that are integral to the syndrome. With respect to CRC, approximately 70% of cases occur proximal to the splenic flexure. Synchronous and metachronous CRCs are extremely common. Full colonoscopy should be initiated when the patient is between the ages of 20 and 25, and because of the accelerated carcinogenesis of CRC, it should be performed every 1 to 2 years. The presence of initial CRC requires subtotal colectomy, given the mentioned increased frequency of metachronous cancer. Options available for germ-line mutation carriers, in addition to cancer screening, include prophylactic colectomy as well as prophylactic total abdominal hysterectomy and bilateral salpingo-oophorectomy. The discovery of mismatch repair germ-line mutations (most commonly MSH2 or MLH1) has added significantly to the recognition of this disease as well as to the search for high-risk individuals throughout families who, with genetic counseling, may become candidates for germ-line mutation testing. Clearly, hereditary nonpolyposis colorectal cancer provides an excellent opportunity for learning about the etio-pathogenesis of cancer at the molecular and clinical levels and how this knowledge might ultimately be exploited for cancer control. A search for chemoprevention agents, such as cyclo-oxygenase 2 inhibitors, as well as for putative environmental effects and how they may interact with the genetic component in CRC etiology should abet this entire cancer control process.

Awards and Prizes↗
PubMed2000

The use of artificial intelligence technology to predict lymph node spread in men with clinically localized prostate carcinoma.

BACKGROUND: The current study assesses artificial intelligence methods to identify prostate carcinoma patients at low risk for lymph node spread. If patients can be assigned accurately to a low risk group, unnecessary lymph node dissections can be avoided, thereby reducing morbidity and costs. METHODS: A rule-derivation technology for simple decision-tree analysis was trained and validated using patient data from a large database (4,133 patients) to derive low risk cutoff values for Gleason sum and prostate specific antigen (PSA) level. An empiric analysis was used to derive a low risk cutoff value for clinical TNM stage. These cutoff values then were applied to 2 additional, smaller databases (227 and 330 patients, respectively) from separate institutions. RESULTS: The decision-tree protocol derived cutoff values of < or = 6 for Gleason sum and < or = 10.6 ng/mL for PSA. The empiric analysis yielded a clinical TNM stage low risk cutoff value of < or = T2a. When these cutoff values were applied to the larger database, 44% of patients were classified as being at low risk for lymph node metastases (0.8% false-negative rate). When the same cutoff values were applied to the smaller databases, between 11 and 43% of patients were classified as low risk with a false-negative rate of between 0.0 and 0.7%. CONCLUSIONS: The results of the current study indicate that a population of prostate carcinoma patients at low risk for lymph node metastases can be identified accurately using a simple decision algorithm that considers preoperative PSA, Gleason sum, and clinical TNM stage. The risk of lymph node metastases in these patients is < or = 1%; therefore, pelvic lymph node dissection may be avoided safely. The implications of these findings in surgical and nonsurgical treatment are significant.

Acid Phosphatase↗
PubMed2000

Nitric oxide increases p21(Waf1/Cip1) expression by a cGMP-dependent pathway that includes activation of extracellular signal-regulated kinase and p70(S6k).

Nitric oxide (NO) regulates the expression of p21(Waf1/Cip1) in several cell types. The present study examined the role of both the extracellular signal-regulated kinase (ERK) and p70 S6 kinase (p70(S6k)) in the NO-induced increase in p21 expression that occurred in adventitial fibroblasts during the cell cycle. Both ERK and p70(S6k) were phosphorylated in response to the NO donor S-nitroso-N-acetylpenicillamine (SNAP) and the activation was rapid, transient, and preceded increased p21 expresion under defined conditions where serum was present. Addition of a selective inhibitor of ERK phosphorylation (PD98059) prevented the subsequent phosphorylation of p70(S6k) and the increase in p21 protein. Both cGMP and cAMP activated both ERK and p70(S6k), whereas only selective inhibitors of protein kinase G prevented the activation of the kinases by SNAP. A complex between ERK and p70(S6k) was documented by immunoprecipitation procedures. Rapamycin blocked p70(S6k) phosphorylation induced by NO and also inhibited p53 phosphorylation and p21 expression whereas PD98059 only prevented the NO-induced increase in p21 protein without influencing either p53 activation or p21 mRNA expression. The studies show a unique relationship between NO, ERK, and p70(S6k) and also provide evidence for a novel role of p70(S6k) in the activation of p53.

Animals↗
PubMed2000

The caudal-related homeodomain protein Cdx1 inhibits proliferation of intestinal epithelial cells by down-regulation of D-type cyclins.

Cdx1 is a homeodomain transcription factor that regulates intestine-specific gene expression. Experimental evidence suggests that Cdx1 may be involved in cell cycle regulation, but its role is ill defined and the mechanisms have not been explored. We used stable transfection of inducible constructs and transient expression with a replication-deficient adenovirus to induce Cdx1 expression in rat IEC6 cells, a non-transformed intestinal epithelial cell line that does not express Cdx1 protein. Expression of Cdx1 markedly reduced proliferation of IEC6 cells with accumulation of cells in the G(0)/G(1) phase of the cell cycle. Cell cycle arrest was accompanied by an increase in the hypophosphorylated forms of the retinoblastoma protein (pRb) and the pRb-related p130 protein. Protein levels of multiple cyclin-dependent kinase inhibitors were either unchanged (p16, p18, p21, p27, and p57) or were not detected (p15 and p19). Most significantly, levels of cyclins D1 and D2 were markedly diminished with Cdx1 expression, but not cyclins D3, E, or the G(1) kinases. Additionally, cyclin-dependent kinase-4 activity was decreased in association with decreased cyclin D protein. We conclude that Cdx1 regulates intestinal epithelial cell proliferation by inhibiting progression through G(0)/G(1), most likely via modulation of cyclin D1 and D2 protein levels.

Adenoviridae↗
PubMed2000

Central nervous system dysfunction as the first manifestation of multiple organ dysfunction syndrome in stem cell transplant patients.

Development of CNS dysfunction in the setting of hematopoietic stem cell transplant (HSCT) has been previously shown to predict for subsequent second organ dysfunction and death. In this paper, we describe the characteristics of this isolated CNS dysfunction, and its relationship to multiple organ dysfunction syndrome (MODS) after HSCT. Twenty-one of 186 patients undergoing HSCT developed CNS dysfunction as their first organ dysfunction a mean of 22.8 +/- 0.9 days after the start of the preparative regimen. Compared with 137 patients who developed no organ dysfunction, patients presenting with CNS dysfunction were more likely to have undergone allogeneic HSCT (P = 0.001) and to have received a total body irradiation-based regimen (P = 0.001), and were less likely to have been transplanted for lymphoma (P = 0.008). Patients who developed CNS dysfunction were more likely to die than those with no organ dysfunction (P < 0. 001). Of the 21 patients who developed CNS dysfunction, 48% resolved their dysfunction by a mean of 4.6 days later without progression to second organ dysfunction, and 90% of these patients survived to day 100. Fifty-two percent of patients with CNS dysfunction progressed to second organ dysfunction (pulmonary or hepatic) a mean of 5.5 days later, and only 36% survived to day 100 (P = 0.02). The patients who progressed to second organ dysfunction and those who did not were not different in terms of type of HSCT (allogeneic vs autologous), stem cell source (blood vs bone marrow), age, diagnosis or preparative regimen. Development of CNS dysfunction in the setting of HSCT, as with other organ dysfunctions (such as hepatic veno-occlusive disease), probably represents an early manifestation of a systemic disorder predisposing for MODS, increasing the risk of transplant-related mortality. Early systemic therapies directed at modulating this systemic disorder are probably indicated. Bone Marrow Transplantation (2000) 25, 79-83.

Adult↗
PubMed2000

Fluconazole vs low-dose amphotericin B for the prevention of fungal infections in patients undergoing bone marrow transplantation: a study of the North American Marrow Transplant Group.

Systemic fungal infections are a major problem in bone marrow transplant recipients who have prolonged neutropenia or who receive high-dose corticosteroids. Prophylaxis with Fluconazole or low-dose amphotericin B reduces, but does not eliminate these infections. To determine which prophylactic agent is better, we performed a prospective randomized study. Patients undergoing allogeneic (related or unrelated) or autologous marrow or peripheral stem cell transplantation were randomized to receive Fluconazole (400 mg/day p. o. or i.v.) or amphotericin B (0.2 mg/kg/day i.v.) beginning 1 day prior to stem cell transplantation and continuing until recovery of neutrophils to >500/microl. Patients were removed from their study drug for drug-associated toxicity, invasive fungal infection or suspected fungal infection (defined as the presence of fever >38 degrees C without positive culture while on broad-spectrum anti-bacterial antibiotics). Proven or suspected fungal infections were treated with high-dose amphotericin B (0.5-0.7 mg/kg/day). Patients were randomized at each institution and stratified for the type of transplant. The primary end-point of the study was prevention of documented fungal infection; secondary endpoints included fungal colonization, drug toxicity, duration of hospitalization, duration of fever, duration of neutropenia, duration and total dose of high-dose amphotericin B and overall survival to hospital discharge. From July 1992 to October 1994, a total of 355 patients entered into the trial with 159 patients randomized to amphotericin B and 196 to Fluconazole. Patient groups were comparable for diagnosis, age, sex, prior antibiotic or antifungal therapy, use of corticosteroids prior to transplantation and total duration of neutropenia. Amphotericin B was significantly more toxic than Fluconazole especially in related allogeneic transplantation where 19% of patients developed toxicity vs 0% of Fluconazole recipients (p < 0.05). Approximately 44% of all patients were removed from prophylaxis for presumed fungal infection. Proven fungal infections occurred in 4.1% and 7.5% of Fluconazole and amphotericin-treated patients, respectively. Proven fungal infections occurred in 9.1% and 14.3% of related allogeneic marrow recipients receiving Fluconazole or amphotericin B, respectively, and 2.1% and 5.6% of autologous marrow recipients receiving Fluconazole or amphotericin B, respectively (P > 0.05). In this prospective trial, low-dose amphotericin B prophylaxis was as effective as Fluconazole prophylaxis, but Fluconazole was significantly better tolerated.

Adult↗
PubMed2000

Acute psychiatric disturbance in pregnancy and the puerperium.

Psychiatric disturbance occurring during pregnancy or the puerperium can occur as a first presentation or as a recurrence or deterioration of a previously diagnosed psychiatric illness. Whatever the history or aetiology, the occurrence of psychiatric disturbance during this period can have profound, long-term implications not only for the mental health of the mother, but also for her relationship with her child and other family members, as well as for the child's development. The treatment of psychiatric disturbance at this time can present difficult dilemmas and should always involve a careful analysis of the risks and benefits of treatment. Liaison between obstetricians and psychiatrists is to be strongly encouraged in order to ensure the best possible outcome for both mother and baby. The antenatal period offers a unique opportunity to identify individuals at risk and target them in order to promote psychological well-being during pregnancy and the puerperium.

Antidepressive Agents↗
PubMed2000

Body mass index in Australian children: recent changes and relevance of ethnicity.

AIM: To determine changes over time in the body mass index (BMI) profile of Australian primary schoolchildren and to assess the effects of sex and ethnicity. METHODS: Height and weight were measured in 3645 children (1869 girls and 1596 boys), aged 5-12 years from 39 schools in southeastern Sydney during 1994-7. Levels in the four largest ethnic groups of the population were compared with those measured by the 1985 Australian Council on Health, Physical Education, and Recreation (ACHPER) survey. RESULTS: The study population was 59.9% white (north European), 8.5% Mediterranean white, 7.7% Asian, 7.7% other, and 16.2% mixed (mainly Asian-white (36%) and Arab-white (24.7%)). There were sufficient numbers in four groups for analysis and comparison with the ACHPER survey: Mediterranean white, other white, mixed ethnicity, and Asian children. The age and sex adjusted BMI was highest in Mediterranean white, then white, mixed race, and Asian children. There were minimal differences between sexes within each group. However, boys had an age and sex adjusted BMI 1.5-6.5% higher (mean, 3.9%) than in ACHPER in 1985, as did white girls (mean increase, 2.4%). CONCLUSIONS: BMI in southeastern Sydney schoolchildren is related strongly to ethnicity and age; in boys and white girls it is on average 3.9% and 2.4% greater, respectively, than that recorded in the 1985 ACHPER survey. We suggest that this 10 year increase reflects a general trend in developed countries. Because increased BMI in childhood tracks to adulthood and is then associated with adverse effects on health, these findings signal a need for prevention.

Age Factors↗