Low levels of eicosapentaenoic and docosahexaenoic acids mimic the effects of fish oil upon rat lymphocytes

Fish oil is rich in the long chain n-3 polyunsaturated fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA); typically these fatty acids constitute 20 to 25 g/100 g total fatty acids in fish oil. Feeding rodents diets rich in fish oil has been shown to decrease lymphocyte proliferation and natural killer cell activity. It is not known what level of EPA + DHA is required in the diet to exert these effects. This question was addressed in the current study. Weanling rats were fed on high fat (178 g/kg) diets which contained 4.4 g alpha-linolenic acid (control) or 4.4 g EPA + DHA (4.4 EPA + DHA) or 6.6 g EPA + DHA (6.6 EPA + DHA)/100 g total fatty acids. The n-6 to n-3 polyunsaturated fatty acid ratio was maintained at approximately 7. The fatty acid compositions of the serum and of spleen leukocytes were markedly influenced by that of the diet. Spleen lymphocyte proliferation in response to concanavalin A, spleen natural killer cell activity and PGE2 production by spleen leukocytes were reduced by feeding the EPA + DHA diets compared with feeding the control diet; the 4.4 and 6.6 EPA + DHA diets caused very similar reductions. The 4.4 EPA + DHA diet reduced popliteal lymph node weight following a localised graft versus host response; this response was not investigated in rats fed the 6.6 EPA + DHA diet. The reductions in lymphocyte functions and in the in vivo graft versus host response caused by the EPA + DHA diets were similar to those previously reported following the feeding of diets rich in fish oil. Thus, this study shows that diets containing relatively low levels of EPA + DHA (20 to 25% of the level found in fish oil) exert immunomodulatory effects. Furthermore, this study suggests that the maximal effect of EPA + DHA is exerted when these fatty acids constitute a level of less than or equal to 4.4 g/100 g total dietary fatty acids.     

Inhibition of cyclooxygenase-2 rapidly reverses inflammatory hyperalgesia and prostaglandin E2 production

PGs derived from cyclooxygenase-2 (COX-2), in particular PGE2, play important roles in the initiation of inflammation and pain. In the present study, we evaluated the role of COX-2-derived PGE2 in an animal model of established hyperalgesia. Inflammation and hyperalgesia were first induced by injection of carrageenan into rat footpads. Then we investigated the effects of subsequent therapeutic treatment with a selective COX inhibitor, with a nonsteroidal anti-inflammatory drug and with anti-PGE2 antibody. Test compounds were administered 1 to 3 hr after carrageenan challenge, and inhibition of pain (hyperalgesia, measured by withdrawal from a thermal stimulus), and changes in paw edema and PG levels were evaluated. The i.v. administration of a nonselective COX inhibitor, ketorolac, caused a rapid reduction in hyperalgesia in the inflamed footpad, returning it to near-normal values within 1 hr. Normal (control) paw response times were not affected. Therapeutic administration of ketorolac prevented most further swelling caused by carrageenan but did not reverse edema already present at the time of dosing. Administered p.o., a selective COX-2 inhibitor (SC-58635) was as efficacious as ketorolac in reducing inflammatory hyperalgesia. Footpad PG levels returned to base line or below within 5 min of dosing with ketorolac, which suggests rapid turnover of PG in the inflamed tissue. Therapeutic treatment with a monoclonal anti-PGE2 antibody also fully reversed the hyperalgesia response. These studies suggest that continuous production of PGE2 by the COX-2 enzyme is a critical element in sustaining the hyperalgesic response at sites of tissue inflammation.     

The dual role of 2-acetylaminofluorene in hepatocarcinogenesis: specific targets for initiation and promotion

The main feature separating a living pacemaker from other oscillators is the fact that the former has not only the oscillatory property but also slow and fast changes of the membrane potential corresponding to the sub- and suprathreshold regions. We propose a simple mathematical model called mRIC and show that the model exhibited the essential feature of pacemakers generating spikes at constant time intervals. The behavior of the model driven by periodic pulse trains is analysed using the phase transition curve.     

Functional symmetry of UhpT, the sugar phosphate transporter of Escherichia coli

UhpT, the sugar phosphate transporter of Escherichia coli, acts to exchange internal inorganic phosphate for external hexose 6-phosphate. Because of this operational asymmetry, we studied variants in which right-side-out (RSO) or inside-out (ISO) orientations could be analyzed independently to ask whether the inward- and outward-facing UhpT surfaces have different substrate specificities. To study the RSO orientation, we constructed a histidine-tagged derivative, His10K291C/K294N, in which the sole external tryptic cleavage site (Lys294) had been removed. Functional assay as well as immunoblot analysis showed that trypsin treatment of proteoliposomes containing His10K291C/K294N led to loss of about 50% of the original population, reflecting retention of only the RSO population. To study the ISO orientation, we used a His10V284C derivative, in which a newly inserted external cysteine (Cys284) conferred sensitivity to the thiol-reactive agent, 3-(N-maleimidylpropionyl)biocytin. In this case, 3-(N-maleimidylpropionyl)biocytin treatment of proteoliposomes containing His10V284C gave about a 60% loss of activity, and immunodetection of biotin showed parallel modification of an equivalent fraction of the original population. Together, such findings indicate that the UhpT RSO and ISO orientations are in about equal proportion in proteoliposomes and that a single population can be generated by exposure of these derivatives to the appropriate agent. This allowed us to study proteoliposomes with UhpT functioning in RSO orientation (His10K291C/K294N) or ISO orientation (His10V284C) with respect to the kinetics of glucose 6-phosphate transport by phosphate-loaded proteoliposomes and also the inhibitions found with 2-deoxy-glucose 6-phosphate, mannose 6-phosphate, galactose 6-phosphate, fructose 6-phosphate, and inorganic phosphate. We found no significant differences in the behavior of UhpT in its different orientations, indicating that the transporter possesses an overall functional symmetry.     

Fungal infections of the hand

Fungal infections of the upper extremity are of four main types--cutaneous, subcutaneous, deep, and systemic. Cutaneous infections are caused by organisms capable of metabolizing keratin. They involve the skin and nails but do not penetrate deeper. Most cutaneous infections respond to topical or local therapy. Subcutaneous infections (at least in North America) are most commonly caused by Sporothrix schenckii. Diagnosis is often delayed because associated secondary bacterial colonization may be mistaken for the primary infectious agent. Treatment with systemic antifungal agents is usually successful. Deep infections are usually caused by direct inoculation or, rarely, hematogenous spread of fungi. Systemic fungal infections are of two types--those that occur in normal hosts and those that occur primarily in immunocompromised patients. For both deep and systemic fungal infections, permanent impairment is likely. Diagnosis of deep and systemic fungal infections is often delayed. Treatment of such infections usually requires a combination of surgical excision and systemic antifungal therapy.     

Clinical predictability of the waist-to-hip ratio in assessment of cardiovascular disease risk factors in overweight, premenopausal women

The waist-to-hip ratio (WHR) is one of the most commonly used anthropometric measures to indicate a central obesity pattern and an increased risk of cardiovascular disease in normal-weight women. Although the American Heart Association has reported that a WHR >0.80 be used to indicate increased risk of cardiovascular disease in women, the present study assessed the WHR above which is seen elevations in cardiovascular disease risk factors in a sample of overweight women. Using data from 240 women aged 27.5-47.5 y enrolled in a university weight-loss program, we determined WHR quartiles: <0.80, 0.80 to <0.84, 0.84 to <0.90, and > or =0.90. Subjects were placed into high-risk categories for cardiovascular disease on the basis of age- and population-defined norms. Women had an increased likelihood of elevated VLDL cholesterol, triacylglycerol, diastolic blood pressure, and composite risk (ie, having > or =4 cardiovascular disease risk factors) and an increased risk of having low concentrations of HDL at a WHR > or =0.90. All aforementioned variables had a significant odds ratio at a WHR > or =20.90 after adjustment for smoking, whereas elevated VLDL, triacylglycerol, and diastolic blood pressure were observed at this WHR after adjustment for a body mass index (in kg/m2) < or > or =35. Only 2 variables, VLDL and triacylglycerol, had a significant odds ratio at a WHR <0.90 before and after adjustment for BMI and smoking. These data suggest an upward shift in the critical threshold for WHR to > or =0.90, at which point there was an elevation in cardiovascular disease risk factors in already overweight women. This trend persisted regardless of whether the women smoked or whether their body mass index was < or > or =35.     

Outcomes research: a review

PURPOSE: The purpose of this article is to review the history of the medical outcomes movement as well as the methodologies used in outcomes research. CONCEPT: Outcomes research refers to a genre of clinical investigation that emphasizes the measurement of patient health outcomes, including the patient's symptoms, functional status, quality of life, satisfaction with treatment, and health care costs. RATIONALE: Outcomes research evolved from studies that demonstrated the presence of wide geographic variations in the practice of medicine and surgery. Such differences in utilization were unaccompanied by any discernible difference in patient outcomes. With escalating health care costs, there has been a growing interest in measuring the outcomes of medical intervention to determine the quality and appropriateness of medical care. DISCUSSION: Outcomes may be measured both directly and indirectly, over differing periods of time, and with varying degrees of objectivity, reliability, and validity. Current research has focused on quality of life issues, which include the extent to which a patient's usual or expected physical, emotional, and social well-being have been affected by a medical condition or treatment. The true value of health care can be determined only by a systematic examination of patient outcomes. To accomplish this goal, methods are required that are relatively unfamiliar to many clinical researchers. Future clinical research should include patient-oriented outcome measures that would otherwise focus solely on physiological or anatomic outcomes. Such information will be essential in determining which medical and surgical treatment strategies should be abandoned and which will gain acceptance in the future.     

Follow-up immunogenicity of an inactivated hepatitis A virus vaccine in healthy children: results after 5 years

Long-term persistence of hepatitis A virus (HAV) serum antibody in vaccinated children has not been demonstrated in previous studies. To study the long-term immunogenicity to HAV vaccine, three doses of strain HM 175 HAV vaccine with 360 enzyme-linked immunosorbent assay units were administered to 107 children, aged from 1.0 to 6.8 years, at 0, 1, and 6 months. The administration of one vaccine dose induced seropositivity (anti-HAV titer > or = 20 mIU ml-1) in 95% of all vaccinees at month 1. All subjects remained seropositive until month 6. The titers of HAV antibody remained above 20 mIU ml-1 in all subjects followed up to 60 months. The geometric mean titer (GMT) reached its peak (3802 mIU ml-1) at month 7, i.e. 1 month after the booster dose, and then declined until the end of follow-up at month 60 (661 mIU ml-1). A trend of higher GMT in female subjects persisted up to month 60. The changes of the GMT over time were best described by the regression equation: log (GMT) = 3.26-0.08 x (age in years) (r = -0.95, P = 0.014). According to this equation, the geometric mean concentration would reach 20 mIU ml-1 at around 24.5 years after the beginning of vaccination. In conclusion, those who completed the recommended three-dose inactivated HAV vaccination series remained seroprotective for at least 5 years. Theoretically, such a vaccination program can provide a protective period of over 20 years in children. This paper may be the first to describe at least 5-year immunogenicity of inactivated HAV vaccination in healthy children.