Age- and gender-associated changes in the concentrations of serum TGF-1ß, DHEA-S and IGF-1 in healthy captive baboons (Papio hamadryas anubis).

Age-related changes in the concentration of factors like TGF-1ß, DHEA-S and IGF-1 may increase the risk of disease and illnesses in advanced life. A better understanding of these changes would aid in the development of more appropriate treatments and/or preventative care for many conditions associated with age. Due to their similar immune system and vulnerability to pathogens, baboons are an ideal model for humans. However, little research has been done examining the general effects of age in baboons. Therefore, we wanted to further examine the effects of aging in baboons by determining the age-dependent changes in serum TGF-1ß, DHEA-S and IGF-1 concentrations. Blood samples were collected during routine health checks in 113-118 captive baboons. In addition, longitudinal samples from 23 to 27 adult individuals were collected an average of 10.7years apart. Both age and gender influenced the concentrations of serum TGF-1ß and IGF-1. When both genders were analyzed together, TGF-1ß increased 16.1% as adults, compared to younger and older animals, but male and female baboons showed a slightly different temporal pattern of change. IGF-1 decreased with increasing age and males had a 30% greater concentration of IGF-1 than did females. While there was no effect of gender among our population, serum DHEA-S was negatively correlated with age, decreasing by 51.6% in the oldest animals. There were no effects of age or gender on serum IGFBP-3. In longitudinal samples collected from the same individuals, the concentrations of TGF-1ß, DHEA-S and IGF-1 were reduced with age. The results presented herein provide additional knowledge of the aging process in baboons and further validate the use of this species as an appropriate model for aging in humans.

Low maternal middle cerebral artery Doppler resistance indices can predict future development of pre-eclampsia.

OBJECTIVE: To determine if decreased resistance (vasodilatation) in the maternal middle cerebral artery (MCA) in the second trimester can predict third-trimester development of pre-eclampsia. METHODS: Four-hundred and five low-risk gravidas had MCA transcranial Doppler (TCD) once in the second trimester. Maternal/neonatal outcomes were evaluated after delivery. Mean blood pressure, MCA velocities, resistance index (RI), pulsatility index (PI) and cerebral perfusion pressure (CPP) were compared between normotensive and pre-eclamptic cohorts. RESULTS: Seven subjects (1.7%) developed pre-eclampsia. An RI of < 0.54 and a PI of < 0.81 were clinically useful in predicting subsequent pre-eclampsia. Areas under the receiver-operating characteristics curves for RI and PI were 0.93 and 0.93, respectively, with optimal sensitivity and specificity of 86% and 93% for both variables. Positive and negative likelihood ratios were 11.8/0.15 (RI) and 12.3/0.15 (PI). CONCLUSION: TCD indices of low maternal MCA resistance in the second trimester are predictive of the subsequent development of pre-eclampsia in a low-risk, ethnically homogeneous population.

Association of fetal cranial shape with shoulder dystocia.

OBJECTIVE: To evaluate whether fetal cranial shape is related to shoulder dystocia. METHODS: We compared shoulder dystocia cases (n = 18) with controls (normal vaginal deliveries, n = 18) in a retrospective matched-pairs observational study. Subjects were matched for known maternal and fetal risk factors and then evaluated for fetal biometric differences, which were measured by ultrasound near delivery. We tested multivariable risk models to predict shoulder dystocia by logistic regression. RESULTS: Cases had a smaller estimated occipitofrontal diameter (OFD) (P = 0.02) and a larger biparietal diameter/estimated OFD ratio (P = 0.003). A multivariable model including estimated fetal weight, estimated OFD, maternal weight and diabetes mellitus had sensitivity and specificity of 86% and 95%, respectively, and positive and negative likelihood ratios of 18.9 and 0.15, respectively. Estimated OFD significantly increased the predictive value of the model. CONCLUSION: A small estimated OFD is a risk factor for shoulder dystocia in the presence of other significant risk factors. A multivariable model including estimated OFD can predict shoulder dystocia in a clinically useful range.

Nasal immunization with subunit proteosome influenza vaccines induces serum HAI, mucosal IgA and protection against influenza challenge.

The immunogenicity of a mucosally delivered subunit influenza vaccine was assessed in mice. Split influenza virus vaccine (sFlu) was formulated with proteosomes (Pr-sFlu), administered intranasally, and the induced immunity was compared with the responses elicited by sFlu alone given either intramuscularly or intranasally. Intranasal (i.n.) immunization with Pr-sFlu induced specific serum IgG and hemagglutination inhibition (HAI) titers comparable to or better than those induced by intramuscular (i.m.) sFlu, and in contrast to sFlu alone, i.n. Pr-sFlu also induced high levels of influenza-specific IgA in lung and nasal washes. Mice receiving i.n. Pr-sFlu were completely protected against live virus challenge, as were mice immunized by injection with sFlu alone. The i.n. Pr-sFlu elicited cytokine responses polarized towards a type 1 phenotype whereas those elicited by sFlu alone were of a mixed type 1/type 2 phenotype. The data strongly suggest that i.n. proteosome-formulated influenza antigens are highly effective and are excellent candidates for a non-invasive human vaccine.

Preparing for expected bioterrorism attacks.

The threat of bioterrorism in the United States is increasing. Health professionals, especially "front-line" practitioners, must be able to recognize the potential for major impacts from a bioterrorism event. Although an effective attack could produce numbers of casualties equivalent to those resulting from a nuclear weapon, an unannounced attack would be unlikely to be recognized immediately. Health workers may be the first to recognize an attack. However, only limited assistance is available to aid local community medical organizations in planning for bioterrorism. Military medical personnel have had more experience in planning for terrorist activities than many of their civilian colleagues. Their experience may be invaluable to local civilian treatment facilities in developing practical plans to meet the unique aspects of bioterrorism. In addition to considering agent-specific medical problems and requirements, it is particularly important for plans to address command and control, communication, and coordination if the resultant response is to be effective.

Dietary guidelines for chronic disease prevention.

In developed nations, diet is related directly or indirectly to the most prevalent chronic diseases. Research has helped clarify diet-disease relationships and enabled the promulgation of dietary recommendations for chronic disease prevention. We reviewed epidemiologic study results, clinical trial data, and general dietary recommendations from various agencies to develop a set of overall dietary guidelines for the prevention of the most common chronic diseases in the United States, including coronary heart disease, hypertension, cancer, and osteoporosis. Intake of monounsaturated fats, fiber, calcium, vegetables and fruits, and whole grains should be promoted. Consumption of saturated and trans fats, sodium, and refined grains should be minimized. Moderation in alcohol and caloric intake should be encouraged. Although research into associations between diet and disease is constantly in flux, our guidelines are based on replicated findings and provide a starting point for assisting patients in improving their diets.

Bacterial determinants of persistent throat colonization and the associated immune response in a primate model of human group A streptococcal pharyngeal infection.

Group A streptococcal (GAS) pharyngitis and the subsequent bacterial colonization of the human throat elicit an immune response that may precipitate acute rheumatic fever in a susceptible host. To study the bacterial determinants that influence throat colonization and induction of humoral immunity, we characterized the behavior of GAS strains in a baboon model. An M-type 3 clinical isolate of GAS typical of strains that cause pharyngitis and invasive infection was recovered from the pharynx of six out of six baboons for at least 6 weeks after oral inoculation. By contrast, an isogenic mutant deficient in M protein failed to colonize most animals or was rapidly cleared. An isogenic mutant deficient in hyaluronic acid capsule colonized five out of six animals, but only persisted in the pharynx for 14-21 days. Colonized animals developed serum antistreptolysin O (SLO) and anti-M protein immunoglobulin (Ig)G. The kinetics of the antibody responses were similar to those seen after human infection. Peak titres increased with the duration of throat carriage. Colonization with GAS prevented recurrent colonization after challenge with the homologous wild-type strain, but not after challenge with a strain of different M protein type. Early clearance of the M protein-deficient strain was associated with increased susceptibility of this strain to phagocytic killing in non-immune serum, whereas clearance of the acapsular strain was associated with increased susceptibility to phagocytic killing in the presence of specific antibody. These studies support critical and distinct effects of the GAS M protein and capsule on throat colonization and induction of humoral immunity in a model that reproduces important features of pharyngeal colonization and immune response following human infection.

Physician assistants as partners in physician-directed care.

1998 marked the acceptance of Physician Assistants (PAs) as members in the Southern Medical Association. We review the history of the PA profession and, more importantly, the physician/PA relationship. We also provide an overview of PA education and certification requirements. Variations in state law regarding PA utilization, including the delegation of prescribing privileges, are discussed. Current American Medical Association guidelines regarding physician/PA practice are provided.

Diabetes in the managed care setting: a prospective plan.

BACKGROUND: As managed care organizations (MCOs) continue to expand into the care of the chronically ill, the concept of providing cost-effective care with a preventive approach is vital for primary care providers (PCPs) to embrace. Diabetes is an ideal disease to incorporate this concept. METHODS: We reviewed the literature using MEDLINE. We used the American Diabetes Association (ADA) Provider Recognition Program guidelines as the foundation for MCOs to establish a diabetes disease management program. RESULTS: The implementation of disease management protocols, the use of computerized management systems, and the team approach can provide cost-effective diabetic care. CONCLUSIONS: To compete in the managed care market, it is vital for providers to link with their Independent Practice Associations (IPA), the ADA, and MCOs to implement standard protocols and negotiate for adequate reimbursement.

Analysis of nonhuman primate peripheral blood mononuclear cells for susceptibility to HIV-1 infection and HIV coreceptor expression.

HIV-1 infection of nonhuman primates does not lead to the acquired immunodeficiency syndrome seen in humans. The basis for this lack of disease progression in these animals is still unknown. In this study, primary nonhuman primate peripheral blood mononuclear cells (PBMC) were tested for their susceptibility to in vitro infection by several different primary HIV-1 isolates representing distinct subtypes or clades. None of the five HIV-1 subtypes tested were able to readily establish an infection in chimpanzee or baboon PBMC, as determined by p24 antigen capture assays. To address the mechanism of in vitro resistance to HIV-1 infection, PBMC were analyzed for HIV coreceptor mRNA expression and cell surface expression. Flow cytometry analysis of the nonhuman primate PBMC demonstrated that they do express CD4, CCR3, CCR5, and CXCR4 on their cell surface. Therefore, the level of restriction in the virus replication cycle does not appear to lie at the point of entry in these cells.

Impaired synaptic plasticity and learning in aged amyloid precursor protein transgenic mice.

We investigated synaptic communication and plasticity in hippocampal slices from mice overexpressing mutated 695-amino-acid human amyloid precursor protein (APP695SWE), which show behavioral and histopathological abnormalities simulating Alzheimer's disease. Although aged APP transgenic mice exhibit normal fast synaptic transmission and short term plasticity, they are severely impaired in in-vitro and in-vivo long-term potentiation (LTP) in both the CA1 and dentate gyrus regions of the hippocampus. The LTP deficit was correlated with impaired performance in a spatial working memory task in aged transgenics. These deficits are accompanied by minimal or no loss of presynaptic or postsynaptic elementary structural elements in the hippocampus, suggesting that impairments in functional synaptic plasticity may underlie some of the cognitive deficits in these mice and, possibly, in Alzheimer's patients.

Cellular and molecular effects of a pulse butyrate regimen and new inducers of globin gene expression and hematopoiesis.

Cooley's anemia is characterized by a deficiency of beta-globin chains, a relative excess of alpha-globin chains, and consequent accelerated programmed death of developing erythroid cells in the bone marrow. Increasing expression of the gamma-globin genes to adequately balance excess alpha-globin chains can ameliorate this disorder. Butyrates induce gamma-globin experimentally, but can also cause cell growth arrest with prolonged exposure or high concentrations, which in turn can accelerate apoptosis. To determine if these potentially opposing effects can be balanced to enhance therapeutic efficacy, an intermittent "pulsed" regimen of butyrate was evaluated. Following induction of gamma-globin mRNA and protein synthesis, total hemoglobin increased in beta-thalassemia patients by more than 2 g/dl above baseline, and Hb F increased above 20% in 5/8 sickle cell patients from baseline levels of 2% Hb F. Specific regulatory regions were identified in the gamma- and beta-globin gene promoters to which new binding of transcription factors, including alpha CP2 (an activator of gamma globin) occur during therapy solely in the butyrate-responsive patients. Other compounds which induce gamma globin, derivatives of acetic, phenoxyacetic, propionic, and cinnamic acids, and dimethylbutyrate, are under investigation. Some of these newer gamma-globin inducers (designed hemokines) provide better potential as therapeutics by also acting to increase hematopoietic cell viability and proliferation. Pharmacologic induction of expression of the endogenous gamma-globin genes is a realistic approach to therapy of the beta-globin disorders for many patients, with some effective agents available now and new therapeutics, with enhanced activities, under development.

Attenuation of tissue thrombosis and hemorrhage by ala-TFPI does not account for its protection against E. coli--a comparative study of treated and untreated non-surviving baboons challenged with LD100 E. coli.

This study was designed to determine the effect of a delayed infusion (T+120 min) of alanyl tissue factor pathway inhibitor (ala-TFPI) on the response to LD100 E. coli. We hypothesized that baboons treated with a low dose of TFPI (5 mg/kg) which did not survive would exhibit thrombosis, infarction and hemorrhage of target tissues such as that seen in untreated animals infused with LD100 E. coli. Eight baboons were infused with 5 mg/kg of ala-TFPI over a 10 h period beginning immediately after a 2 h infusion of LD100 E. coli (experimental group). Four baboons were infused with E. coli followed by a 10 h infusion of saline (control group). Of the 12 baboons, the 11 non-survivors (TFPI = 7 out of 8; controls = 4 out of 4) were evaluated for the extent of thrombosis, necrosis, hemorrhage, and congestion of target tissues and for changes in clinical chemical parameters. We expected that failure to protect would correlate with failure to inhibit thrombosis of target tissue (8). Surprisingly ala-TFPI significantly inhibited thrombosis, hemorrhage and necrosis of adrenal and renal tissues and attenuated the rise in creatinine in the 7 treated non-survivors. The lungs of these non-survivors, however, exhibited intra-alveolar fibrin and a mild degree of hemorrhage and edema. We concluded that low doses of ala-TFPI begun as late as T+120 in minutes failed to protect against the lethal effects of LD100 E. coli in spite of completely preventing thrombosis and hemorrhage in target organs, and that thrombosis, infarction and hemorrhage of adrenal and renal tissue are not part of the lethal chain of events in this IV model of E. coli sepsis.

A generic drug primer: regulatory aspects and scientific concepts.

The regulatory aspects of generic drug substitution and the scientific concepts that serve as the basis for generic drug approval are discussed, with emphasis on the source of therapeutic equivalence information compiled by the Food and Drug Administration in Approved Drug Products with Therapeutic Equivalence Evaluations. The Food and Drug Administration's determination of bioequivalence for immediate-release and extended-release dosage forms is summarized, with a discussion of the underlying assumptions and current issues regarding bioequivalence testing. Medical practitioners must comply with the regulations stated in each state's Pharmacy Practice Act when allowing generic substitution and should ensure that the substituted product is therapeutically equivalent to the prescribed product.

Shedding and transmission of baboon Herpesvirus papio 2 (HVP2) in a breeding colony.

Baboons in a captive breeding colony were monitored twice a year, and new additions were screened on arrival for shedding of Herpesvirus papio 2 (HVP2) and serologic reactivity to the agent. For 128 individual animals tested over a period of 1.5 years, shedding of infective virus was detected in 13 of 342 swab specimens (3.8%), each of these incidents representing shedding by a different animal. Among long-term colony animals, infective virus was recovered on only two occasions (5 of 236 swab specimens from five individuals). In all but one instance, animals shedding virus were infants, not adults, and all animals were shedding virus in the oral cavity. One of these five instances was an isolated case, but four (three infants and one adult) were clustered within a single breeding group. Molecular analyses of the HVP2 isolates from this cluster indicated that they likely arose from a single common source, probably the mother of one of the infants. None of 31 wild-caught baboons added to the colony during this period were found to be shedding infective virus, despite 93.5% of them being seropositive for HVP2. In contrast, 6 of 18 adult baboons (all seropositive) transferred into the colony from another breeding colony were found to be shedding HVP2 either orally (3 of 6) or genitally (3 of 6). In addition, 2 of 8 juvenile baboons in this shipment were found to be shedding virus in the oropharynx. Overall, 10 of 13 instances of HVP2 isolation were from the oropharynx rather than the genital tract, and 6 of 13 baboons shedding virus were infants or juveniles rather than adults. These results suggest that, although venereal transmission of HVP2 occurs among adult animals, oral infection of young, sexually immature baboons is not uncommon.

Prostate cancer: clinical perspectives.

1. When obtaining a screening history for prostate cancer, important risk factors include age, family history, and ethnicity. The digital rectal examination remains the "gold standard" physical examination screening technique. 2. If prostate cancer is detected at an early stage, it is potentially curable. It is incumbent upon occupational health care providers to afford those constituents who fall into a high risk category, or who are > or = 40 years of age, every opportunity for prostate cancer screening. 3. Education is the "sine-qua-non" of complete health care provision for prostate cancer clients. The occupational health care provider can play a pivotal role in allaying a client's fear and misconception of this disease. 4. Providing appropriate assessment and advocacy for clients returning to the workplace following diagnosis and treatment of prostate cancer is crucial.