If you’re like most people, you probably associate aging with health disorders such as Alzheimer’s disease or arthritis. But researchers who spoke at a congressional briefing in September 2004 warned that some other, lesser-known diseases are poised to strike older adults with a vengeance: chronic obstructive pulmonary disease (COPD), urinary incontinence and age-related macular degeneration (AMD).

With this in mind, we’ve compiled some suggestions about various natural products that, in concert with an overall regimen of proper diet, exercise and smoking cessation, may lower your risk of suffering these diseases.

Many of us are soon going to be afraid of a good belly laugh–for fear of wetting ourselves in public. Over 20 million Americans wouldn’t dare strain to pick up their grandchild or sit on someone’s new couch.

But the condition can produce more than just embarrassment. Bladder infections and skin breakdowns are much more common in people with incontinence. And it can lead to depression and loss of self-esteem. Fractures can even result from mad, unplanned dashes to the washroom.

Science hasn’t pinned down the cause and–short of further research into this rarely studied problem–cannot explain why some people suffer from it and others don’t.

Exercise, relaxation techniques and yoga have been shown to help. People with incontinence should also avoid too many drinks containing alcohol, caffeine or carbonation, and they should limit their liquid intake to two liters of fluid daily. Never go to the toilet “just in case.” Avoid constipation. And try to train your bladder to hold more urine.

As for supplements, calcium and magnesium taken together may improve control of the muscles used in urination. And vitamin C, cranberries and blueberries help by preventing bacterial infections of the urinary tract.

Chronic Obstructive Pulmonary Disease (COPD)

Even as the prevalence rates of many diseases that cause death and disability are declining, rates of COPD are increasing. About 15 million people in the United States have it–with twice as many undiagnosed cases suspected–and it’s the second leading cause of disability.

COPD involves emphysema or chronic bronchitis, depending on its path of destruction in the lungs. Most people with COPD have both. Often a COPD diagnosis is missed because its risk factors are also associated with myriad other disorders. Patients show up with a cough and shortness of breath–and are diagnosed with heart disease. The COPD is left untreated.

The best prevention advice is to avoid cigarette smoke, including the secondhand kind. And limit your exposure to animal dander and dust mites.

Some nutritionists believe that magnesium supplements can help reduce the odds of developing emphysema, although the jury’s still out. But magnesium should be a part of a healthful diet anyway. Dietary sources include legumes, whole grains and green leafy vegetables. Or, you can take magnesium supplements.

Once acquired, COPD-related damage to the lungs will not improve. However, some proponents point to a number of nutrients as potentially beneficial to COPD patients. Dietary and supplemental forms of omega-3 fatty acids–including alpha-linolenic acid (ALA) found in walnuts and flaxseeds–may help lessen COPD symptoms. Bromelain, coenzyme Q10 and L-carnitine may reduce mucus production, say some experts. And increasing the amount of fruit you eat by one or two servings per week or taking vitamin C supplements may help improve lung function. Herbal treatments may include garlic, eucalyptus, licorice, lobelia, marshmallow, red clover and saw palmetto.

Arthritis

Arthritis–a general term for over 100 different inflammatory diseases involving joint pain–affects 70 million Americans, making it one of our most common ailments. And 20 million suffer from the extremely crippling form: rheumatoid arthritis.

Sulfur helps arthritis by rebuilding bone, cartilage and connective tissue. Foods that contain sulfur are asparagus, eggs, garlic and onions.

Boswellia may reduce inflammation, plus it restores blood vessels around inflamed connective tissues. Glucosamine sulfate benefits bones, tendons, ligaments, cartilage and joint fluid. Calcium helps to prevent bone loss. Methylsulfonylmethane (MSM), a sulfur compound, eases pain and inflammation. Cat’s claw may relieve pain. Ginger, an antioxidant, has anti-inflammatory properties. When applied topically, cayenne can lessen pain. And nettle leaf has some anti-inflammatory properties that may also help.

Human transthyretin (TTR) is an amyloidogenic protein. The pathway of TTR amyloid formation has been proposed based on lines of evidence: TTR tetramer first dissociates into native monomers, which is shown to be a rate-limiting step in the formation of fibrils. Subsequently, the monomeric species partially unfold to form the aggregation intermediates. Once such intermediates are formed, the following self-assembly process is a downhill polymerization. Hence, tertiary structural changes within the monomers after the dissociation are essential for the amyloid formation. These tertiary structural changes can be facilitated by partial denaturation. To probe the conformational changes under the partially denaturing conditions, five independent trajectories were collected for the wild-type (WT) and its pathogenic variants at 300 and 350 K, resulting in simulations that totaled 59 ns. Under these conditions, L55P variant is more labile than the wild-type and V30M variant. We have observed that the D strand of WT-TTR is trapped in two local minima: the native conformation and the amyloidogenic fold that resembles the surface loop of residues 54-55 of L55P variant. In the tetrameric state, the F strand is bent with large separations at the F-F’ interface. This strand becomes flatter in the monomeric state, which may facilitate the formation of new F-F’ interface with possible prolonged hydrogen bonds and/or shift in ?-strand register in the fibril state. During the unfolding process, the anticorrelated motion between the strands H and G as well as the strands H and A pulls the H strand out of the inner sheet plane, leading to a more twisted inner sheet. Our simulation has provided important detailed structural information about the partially unfolded state of TTR that may be related to the amyloidogenic intermediates.

Accumulation of amyloid fibrils in tissues or extracellular matrix is the hallmark of amyloid diseases such as Alzheimer’s disease and the systemic amyloidoses (for example, immunoglobulin-light-chain diseases and the familial amyloid polyneuropathies that are associated with transthyretin). Up to date, ~20 human proteins have been found to form amyloid fibrils in vivo (1). These proteins can be divided into two categories based on whether the amyloid fibrils can be converted from a full-length amyloidogenic protein or a fragment of a large precursor protein. For example, Alzheimer’s fibrils are formed from amyloid-? peptide, a fragment of amyloid precursor protein; whereas, human transthyretin (TTR) belongs to the category of fulllength amyloidogenic protein; however, this does not exclude the fact that TTR fibrils also contain fragments of protein (2). It is likely that these two categories follow different pathways of fibril formation.

In this work, we focus on TTR, which is a plasma protein responsible for the transportation of thyroid hormone. It also binds to retinol-binding protein that in turn associates with vitamin A. The structures of the wild-type and various amyloidogenic single-site mutants have been determined by high-resolution x-ray crystallography (3-5). The native state of TTR is a homotetramer with eight ?-strands organized into two sheets, giving rise to a ?-sandwich (3) (Fig. 1 a). The eight ?-strands are named from A to H and arranged into inner (DAGH) sheet and outer (CBEF) sheet. Two monomeric units form a dimer via extensive hydrogen bonds between the two adjacent H (residues Ser-115-Thr-123) strands and F (residues Ala-91-Ala-97) strands from each monomer (Fig. 1 b). There are five main-chain-main-chain hydrogen bonds between the adjacent H strands, whereas the two F strands are separated more widely, as a result, only two hydrogen bonds (between Glu-89 and Val-94) are formed directly through the main-chain interactions. The remaining hydrogen bonding interactions involve water bridges. Two dimers are related by a crystallographic twofold axis to give a tetramer. A central channel wrapped around by the DAGH (inner) sheets runs through the center of the tetramer and accommodates thyroxin molecules.

The pathway of TTR amyloid formation has been proposed based on lines of evidence: TTR tetramer first dissociates into native monomers, which is shown to be a rate-limiting step in the formation of fibrils (6-8). Subsequently, the monomeric species partially unfold to form the aggregation intermediates. Once such intermediates are formed, the following self-assembly process is a downhill polymerization (9). Tetramer dissociation into monomers is necessary but not sufficient to initiate fibril formation because native monomers are nonamyloidogenic unless it is partially denatured (10). Therefore, further tertiary structural changes within the monomers are required. These tertiary structural changes can be facilitated either by partial denaturation (e.g., lowering the pH or the dielectric constant of the medium) (8,11) or by single-point mutation. At pH 7.5 and 370C, both L55P-TTR (Leu-55 [arrow right] Pro) and V30M-TTR (Val-30& rarr; Met) form amyloid protofibrils after two months of incubation, however, V30M-TTR exhibits much smaller amount of protofibrils. By contrast, the wild-type is stable and nonamyloidogenic under the same conditions (12).

A recent official statement of the American Thoracic Society (1) contains statements that are not supported by the literature:

1. “The clinical evaluation…should consider subjective symptoms as well as objective findings…” (p. 695). “The diagnosis of asbestosis is ideally based on an accurate exposure history, obtained whenever possible directly from the patient….” (p. 695).

2. “Plaques are indicators of increased risk for the future development of asbestosis…” (p. 707).

3. “These obstructive findings may be due to asbestos-induced small airway disease. Thus, mixed restrictive and obstructive abnormalities do not rule out asbestosis or necessarily imply that asbestos has not caused an obstructive functional impairment…” (p. 701). “In general, the magnitude of the asbestos effect on airway function is relatively small. This effect, by itself, is unlikely to result in functional impairment or the usual symptoms and signs of chronic obstructive pulmonary disease. However, if superimposed on another disease process, the additional loss of [lung] function due to the asbestos effect might contribute significantly to increased functional impairment, especially in persons with low lung function” (p. 708). “Tobacco smoking is the predominant cause of airway obstruction in asbestos-exposed workers who smoke….” (p. 710).

4. “A chest film…showing characteristic signs of asbestosis in the presence of a compatible history of exposure is adequate for diagnosis of the disease: further imaging procedures are not required” (p. 696). “The positive predictive value of the minimally abnormal chest film alone in making the diagnosis of asbestosis may fall below 30% when exposure to asbestos has been infrequent and exceed 50% when it has been prevalent” (p. 710).

Many of the statements are conflicting or inaccurate. Patient histories and subjective symptoms are unreliable, particularly in legal proceedings (2). Pleural plaques are evidence of exposure and do not indicate a greatly increased risk for asbestos-related disease in those workers with equal exposure and no radiologically visible plaques (3). The implication that asbestos contributes to clinically significant COPD is not supportable (4). The role of the International Labour Organization (ILO) B-reader chest X-ray interpretation has recently come into question (5, 6).

Conflict of Interest Statement: D.D.S. has no financial relationship with any asbestos manufacturer or commercial entity but has been an expert witness for the defense in asbestos litigation.

DORSETT D. SMITH

University of Washington

Seattle, Washington

References

1. American Thoracic Society. Diagnosis and initial management of nonmalignant diseases related to asbestos. Am J Respir Crit Care Med 2004;170: 691-715.

2. Agostoni P, Smith DD, Schoene R, Robertson H, Butler J. Evaluation of breathlessness in asbestos workers: results of exercise testing. Am Rev Respir Dis 1987;135:812-816.

3. Smith DD. Plaques, cancer and confusion. Chest 1994;105:8-9.

4. Smith DD. Does asbestos exposure cause obstructive airways disease? [letter] Chest 2004;126:1000.

5. Janower ML, Berlin L. “B” Reader’s radiographic interpretations in asbestos litigation: is something rotten in the courtroom? Acad Radiol 2004; 11:841-842.

6. Gitlin JN, Cook LL, Linton OW, Garrett-Mayer E. Comparison of “B” readers’ interpretations of chest radiographs for asbestos related changes. Acad Radiol 2004;11:843-856.

From the Committee:

The Committee appreciates the opportunity to respond to these two additional letters. This is also an opportune time to clarify other issues that may be lost in the detail of the Statement.

Dr. Martin’s letter is entitled “2004 Asbestos disease guidelines ignore mass screening abuse,” as if the Statement condoned abusive practices. In fact, the Statement favorably cites both a 2002 white paper from the National Institute of Occupational Safety and Health and a 2000 resolution by the Association of Occupational and Environmental Clinics regarding characteristics of responsible and ethical screening programs.

Dr. Martin makes two substantive allegations of error by the Committee in his original letter. One involves the interpretation of 1/0 readings, which the Statement describes, correctly, as “presumptively diagnostic but not unequivocal”: this interpretation is inherent in the International Labour Organization (ILO) Classification system. Dr. Martin also requests a reference for the statement that the plain chest film has a sensitivity of no more than 90% and a specificity of about 93% (the source says 90 to 95%): the reference is number 150, cited in the Statement on page 710.

To Dr. Smith, the Committee responds that the passages he describes as contradictory simply make reasonable distinctions. With respect to occupational and medical histories, the Committee has made the unexceptional recommendation that a physician take a history to help guide the diagnosis. With respect to his comment on pleural plaques, the Committee stands by what was written and the evidence cited. With respect to the contribution of asbestos exposure to airway obstruction, the Statement says that asbestos exposure might he clinically significant in the presence of low lung function. Dr. Smith writes: “The role of ILO B-Reader chest X-ray interpretation has recently come into question.” In point of fact, the B-Reader Program belongs to NIOSH. It is not an activity of the ILO.

Four hundred specimens were collected from pediatric patients hospitalized in Singapore; 21 of these specimens tested positive for human metapneumovirus (HMPV), with the A2 genotype predominating. A 5% infection rate was estimated, suggesting that HMPV is a significant cause of population of Singapore.

Human metapneumovirus (HMPV) is a new member of the family Paramyxoviridae. It was first identified in children with respiratory diseases in the Netherlands and is now recognized as a substantial cause of acute respiratory infection in pediatric patients (1). The clinical symptoms in children are similar to those observed during respiratory syncytial virus (RSV) infections and vary from upper respiratory tract infection (URTI) to bronchiolitis and pneumonia. HMPV infections have been detected in young children 5 years of age (2) as well as in adults of all age groups (3). Sequence analysis of HMPV isolates has identified 2 main lineages, A and B; each group is further subdivided into 2 more lineages, A1 and A2, and B1 and B2 (4,5). Both virus genotypes were reported in various countries in the Americas, Europe, and Asia. This study aims to assess the importance of HMPV infection among hospitalized pediatric patients in Singapore.

Kandang Kerbau Women’s and Children’s Hospital is one of the major centers in Singapore for the admission of sick children, including those showing respiratory illness. After obtaining prior approval from the Hospital’s ethics committee (approval number EC/043/2004), we collected nasopharyngeal swabs from 400 pediatric patients between October 2005 and January 2007. When admitted to the hospital, these patients exhibited symptoms of acute lower respiratory tract infections (LRTI) (bronchiolitis, bronchitis, pneumonia, asthma, and wheezing) and URTI (phamygitis). Specimens were sent to the hospital’s microbiologic laboratory for routine testing for influenza A and B viruses, RSV, adenovirus, and parainfluenza virus (serotypes 1-3) by immunofluorescence assay (LIGHTDIAGNOSTICS, Chemicon, Tamacula, CA, USA). The clinical specimens were stored at -80[degrees]C until further analysis for HMPV was performed (not longer than a week after collection). Viral RNA (vRNA) was extracted from each of the thawed nasopharyngeal swabs with the QIAamp viral RNA minikit (QIAGEN Inc., Valencia, CA, USA) according to the manufacturer’s instructions. Of the total RNA extracted from the clinical specimens, 5 [micro]L was subjected to real-time reverse transcription-PCR (RT-PCR) testing by using the N gene specific primer set NL-N (6). This was performed with the OneStep RT-PCR kit (QIAGEN) on a Corbett Research Rotorgene 3000 (Corbett Life Science, Sydney, NSW, Australia). The PCR cycling conditions were 50[degrees]C for 30 min, 95[degrees]C for 15 min, and 45 cycles (95[degrees]C for 20 s and 60[degrees]C for 60 s). Specimens that tested positive by real-time RT-PCR analysis were confirmed by conventional RT-PCR by using the NL-N primer set. The amplified products (163 bp) were detected by using agarose gel electrophoresis, and their identity was confirmed by DNA sequencing.

Of the 400 samples collected, 21 tested positive for HMPV infection, which suggests an incidence rate of [approximately equal to] 5.3%, compared with an 11.5% incidence rate for RSV (Table 1). Previous reports have suggested that in some cases severe symptoms exhibited by RSV-infected patients are associated with dual infections involving HMPV (7). Although we detected the presence of HMPV and RSV in the patients screened, no evidence for co-infections was observed, which suggests a low occurrence for these viruses in Singapore. In a recent study in Australia, only 8 of 10,000 screened hospitalized patients showed evidence of co-infection with HMPV and RSV (8). In contrast, several recent studies suggest that co-infections may account for a substantial number of instances in which HMPV has been detected. For example, a recent study in Brazil, which used a lower sample size than in our study, reported an 8% incidence rate for pediatric patients who had RSV and HMPV co-infections (9). Therefore, environmental factors may be a key feature in the development of co-infections.

The entire P gene sequences were amplified directly from the specimens by RT-PCR using the primers hmptPF 5′-ATGTCGTTCCCTGAAGGAAAAGATATTC-3′ and hmptPR 5′-TTAAACTACATAATTAAGTGGTAAAT-3′. Amplicons 884 bp in size were generated and corresponded to 1209 nt-2093 nt of the HMPV genome (strain JPS03-240, AY530095). PCR cycling was performed on a conventional thermal cycler by using a “touch-down” procedure; conditions were 94[degrees]C for 5 min followed by 30 cycles of 94[degrees]C for 15 s, 62[degrees]C (reducing by 0.5[degrees]C/cycle) for 30 s, 72[degrees]C for 1 min, and a final extension step of 72[degrees]C for 7 min. The sizes of the respective PCR-amplified products were examined by using agarose gel electrophoresis, gel-purified, and confirmed by DNA sequencing. The sequences were submitted to GenBank under accession nos. EF409351-EF409371. The genetic relationship between the Singapore HMPV isolates and those HMPV isolates described previously was analyzed by comparing the P gene sequences (10). Alignments of nucleic acid sequences were created by using ClustalX version 1.83 (bips.u-strasbg.fr/fr/ documentation/clustalx).Phylogenetic treeswereconstructed by using the neighbor-j oining method (1,000 bootstrap replicates) and edited with MEGA 3.1 (11). Comparisons were made with representatives of the 4 genetic lineages (Figure). This analysis shows that although isolates representing both A and B genotypes were detected, the Singapore isolates clustered more predominantly with representative HMPV strains in lineage A, in particular the sublineage A2. In this study HMPV was detected throughout the year, which suggests that in Singapore, HPMV is present in the pediatric community throughout the year. We also noted a slight increase in the incidence of B genotypes (B1 and B2) during the last quarter of 2006, but the implications of this finding are unclear.

To the Editor: Chlamydia trachomatis (CT) is the most prevalent bacterial sexually transmitted infection worldwide. Recently, a new variant of CT (swCT) has been reported in Halland County, Sweden. A total of 12 swCT specimens were sequenced and found to have the same deletion, a 377-bp deletion in the cryptic plasmid (1). Because the deletion was found in the target area of 2 commercial CT nucleic acid amplification tests (Roche, Basel, Switzerland, and Abbott Laboratories, Abbott Park, IL, USA), screening tests have produced false-negative results for patients infected with this new Swedish variant (1). In specific regions of Sweden, the proportion of all detected CT cases attributable to swCT ranges from 13% to 39%; a considerable number of chlamydia infections have escaped detection by commonly used test systems (1).

Although the first 2 studies to monitor potential spread of the swCT variant outside Sweden (Ireland and the Netherlands) did not detect swCT, a third study (Norway) did identify this variant (2-4). Subsequently, the European Surveillance of Sexually Transmitted Infections network and the European Center for Disease Prevention and Control launched an initiative, consisting of a short questionnaire, to learn more about this swCT variant problem outside Sweden (5).
Advertisement

However, quick monitoring of the spread of the swCT variant has been hampered by lack of a direct test to detect this swCT variant and by lack of a readily available positive control. We therefore constructed a positive control by using a clinical specimen of the swCT variant in which the deletion was present (forward swCT 5′-TCC GGA TAG TGA ATT ATA GAG ACT ATT TAA TC-3′ reverse swCT 5′GGT GTT TGT ACT AGA GGA CTT ACC TCT TC-3′) (2). The specimen was obtained in Sweden (by B.H.) and confirmed as swCT by the method described by Ripa and Nilsson (6). The obtained 98-bp amplicon was subsequently cloned in a pGEM-T Easy Vector (Promega Benelux b.v., Leiden, the Netherlands) and transformed in Escherichia coli DH5 [alpha]. After extraction the plasmid was verified for the correct insert by sequencing and quantified as described (7). This positive control is available for researchers and clinicians free of charge.

Subsequently, we developed a real-time PCR (TaqMan assay) that specifically detects the swCt variant by using a probe that spans the 377bp left and right gap border sequences: probe- [swCT 5′-.sup.FAM] GGA TCC GTT TGT TCT GG [sup.MGB] -3′. One copy of cloned positive swCT control could be detected in our swCT assay. We selected 10 copies per PCR as positive swCT control for each run. A total of 239 recent samples known to be CT positive and identified with techniques detecting the swCT variant were retrospectively analyzed with our new swCT real-time PCR for 3 cohorts: 1) 30 real-time PCR CT-positive clinical samples (CT prevalence in the population, 1.8%) from the Department of Medical Microbiology and Infection Prevention, VU University Medical Center, Amsterdam, the Netherlands; 2) 57 Becton Dickinson (Franklin Lakes, NJ, USA) CT-positive samples (CT prevalence in the sexually transmitted disease population, 7.3%) from the Department of Infectious Diseases, South Limburg Public Health Service, Heerlen, the Netherlands; and 3) 152 CT-positive culture samples (CT prevalence in the population, average 15% [8]) from the Faculty of Medicine, St. Petersburg State University, St. Petersburg, Russia, and from the Laboratory of Microbiology, D.O. Ott Research Institute of Obstetrics and Gynaecology, St. Petersburg, Russia.

Cohort 1 consisted of cervical swabs in 2-sucrose-phosphate (2SP) transport medium, stored at -80[degrees]C. Cohort 2 consisted of frozen dry swabs that had been shaken for 10 s in 1 mL 2SP transport medium before sample preparation. Cohort 3 consisted of positive cultured samples. DNA extraction used 200 [micro]L 2SP and was performed with the NucliSens easyMAG (bioMerieux, Boxtel, the Netherlands); the DNA was eluted in 110 [micro]L 2SP (7). Presence of CT DNA was reconfirmed for all samples with our in-house PCR. Sensitivity of this assay was determined by using a previously described serial dilution of lymphogranuloma venereum (LGV) strain L2 and was assessed at 0.01 inclusion-forming units (9). Amplification and detection were performed with an ABI Prism 7000 sequence detection system (Applied Biosystems, Foster City, CA, USA) by standard PCR conditions of the manufacturer, with 45 cycles. The Swedish variant was found in none of the 3 cohorts tested. Sensitivity and specificity were confirmed by using 12 swCT variant samples from Sweden, which were all positive according to our swCT TaqMan assay.

Our new swCT TaqMan assay, combined with the positive control (which can be obtained by contacting S.M.), will be a helpful tool for determining whether this Swedish CT variant is present outside Sweden, other than in the 2 case-patients identified in Norway. We did not find any evidence of the swCT variant in the Netherlands or St. Petersburg, Russia, each of which is near Scandinavia (Table). Recently, the C. trachomatis LGV strain was discovered in the Netherlands in a population of men who have sex with men. In this instance, the real-time TaqMan assay also proved helpful in determining spread (10).

Protection from employment discrimination just got a little shakier for people with HIV and other chronic diseases. The Supreme Court on June 10 ruled that the Americans With Disabilities Act does not prevent companies from being able to deny employment to workers with chronic health conditions if the firm deems the job threatening to the employee’s health. The case revolved around refinery worker Mario Echazabal, who was denied a job at a Chevron plant in El Segundo, Calif., because he has hepatitis C. Chevron officials said that the solvents and other chemicals used in the workplace could endanger Echazabal’s health and accelerate his hepatitis.

AIDS activists worry that the decision could be used by companies to deny employment to qualified HIV-positive workers or to decline to provide workplace accommodations.

“It’s a very, very thin line that separates a genuine paternalistic concern for the workers and outright discrimination,” said Catherine Hanssens, director of Lambda Legal Defense and Education Fund’s AIDS Project.

* Cardiovascular health offers opportunities

* Antioxidant and anti-inflammatory key health properties

* Food-based nutraceutical components are one trend to watch

Autopian goal for most societies is that their citizens live long in health and peace, and that their children enjoy the same prospects. The achievement of such an idyllic existence depends on many factors, not the least of which is a well-crafted food supply.

Demographic data and other studies point to the importance of whole foods–grains, fruits, vegetables and judicious protein choices–to help avoid the ravages of cardiovascular disease, cancer and a multitude of other illnesses that plague mankind. However, convenience, taste and even economics lead consumers to choose diets of prepared foods, enhanced with supplements, to meet their dietary and medicinal needs. In response, researchers strive to identify individual healthful compounds that can be added to diets, and companies work to identify compounds–backed by sound science–that will attract customers.

Catering to Cardiovascular

According to a 2003 survey by HealthFocus International (St. Petersburg, Fla.), cardiovascular disease is one of consumers’ top three health concerns–not only in the U.S.–but also in regions from India and China to France and the U.K. to Latin America.

Food and dietary supplement companies recognize this. In the 2004 Prepared Foods R&D Trends: Functional Foods and Beverages Survey, marketers and those in R&D ranked cardiovascular health at the top of a list of ingredients and health conditions offering a business opportunity.

In 2004, Mintel International’s Global New Products Database (GNPD, Chicago) logged 334 new product records from around the world that referenced cardiovascular and/or heart health. (See chart “Helping Heart Health.”) While dietary supplement products frequently use the term “cardiovascular” to describe their health benefits, foods rarely do so, instead preferring the more simple term “heart health.”

Most functional foods offering heart health benefits do so based on being reduced in or free from deleterious components (such as fat), being a healthier alternative (olive oil rather than a hydrogenated margarine) and/or being composed of healthful components (e.g., with fruits, nuts and whole grains). However, some also are formulated with specific extracts or other beneficial compounds.

In the U.S., FDA-allowed health claims heavily guide food manufacturers. As a result, whole grains, dietary fiber, fruit ingredients and soy protein often are the basis on which foods make heart health references. Some supplements base their benefits–in part–on these components as well, such as PhytoCeutical Formulations’ (New Orleans) OptiPro S with a “specially formulated blend of soy proteins,” and Nature Made Nutritional Products’ (Mission Hills, Calif.) B Heart Health supplements. The latter contains a blend of phytonutrients from a variety of fruit (berry) extracts as well as green tea leaf and grape seed. Vitamins B-6, B-12 and folate round out this product’s ingredient list.

The use of folic acid (which lowers levels of undesirable homocysteine) in other dietary supplements such as Royal Numico N.V.’s General Nutrition Centers (Pittsburgh) GNC B-12 tablets and Atkins Nutritionals’ (Hauppauge, N.Y.) Cardio-Folin with CoQ10 (which also contains folic acid and B vitamins) serve as a testament of how the supplement industry often is one step ahead of a more conservative food industry in regards to tracking and acting on clinical research that supports specific ingredients. The GNPD does not yet list a North American-introduced food claiming heart health benefits based on homocysteine reduction.

Other popular heart-helpful ingredients include coenzyme Q10, which is found in products such as Rexall Sundown’s (Boca Raton, Fla.) CoQ-10 Plus L-Carnitine Dietary Supplement and Twinlabs’ (Hauppauge, N.Y.) Twinsorb CoQ10, as well as omega fatty acids and vitamin E. Omega fatty acids and vitamin E also are promoted in a large number of heart-healthy foods. However, while research (and at least one FDA claim) gives a thumbs-up to a bright future for omega-3s, the meta-analysis study on vitamin E by a John Hopkins University (Baltimore) researcher will cause some marketers to pull this component from supplements positioned for cardiovascular health.

Conquering Cancer

The HealthFocus International study shows cancer concerns are nearly as widespread among consumers as cardiovascular health. However, foods and supplements positioning themselves as reducing the risk of cancer are very rare.

Using the term “cancer” to search the GNPD for U.S. consumable products introduced in 2004 that link an ingredient’s benefits to cancer risk-reduction, only four products appear. Reasons why so few make the disease connection–compared to heart disease–are that the FDA allows few claims in regards to cancer risk reduction, and the term itself is far from consumer-friendly. Two companies making the association include Maximum International’s (Deerfield Beach, Fla.) Aspen Naturally Lycopene Dietary Supplement that notes, “Lycopene is an antioxidant that protects the body against free radical damage. It also supports prostate health and protects against some forms of cancer.” Laguna Tuna’s (San Francisco) Fresh Seafood Pasta Sauces claim: “Each jar is said to have plenty of heart-healthy lycopene and cancer-fighting omega-3s because of its seafood ingredient properties.” If the GNPD search is extended back to 1999 to include all global products, over 100 products making cancer-fighting type claims can be found. Beneficial components frequently mentioned include polyphenols (often contained in wine, grape seed, juice and cocoa); other antioxidants including those in green and white tea and blueberries; soybean-derived ingredients (isoflavones, soy protein); various dietary fibers including chitosan; certain mushrooms; beta-carotene, lycopene as well as carotenoids in general (including those in pink grapefruit); and, finally, Korean ginseng.

Induced sputum 8-iso-prostaglandin F^sub 2?^ (PGF^sub 2?^) concentrations may be a useful marker of oxidative stress in airways disease. This study examines oxidative stress (measured by 8-iso-PGF^sub 2?^) in airway disease according to disease type (asthma and bronchiectasis), disease activity (stable and acute asthma), and disease pattern (intermittent, mild, moderate, and severe persistent asthma). We compared subjects with stable asthma (n = 71) and bronchiectasis (n = 23) with healthy control subjects (n = 29). Another group of patients with asthma (n = 39) were assessed during and after acute exacerbation. Induced sputum 8-iso-PGF^sub 2?^ concentrations were validated and found to be elevated in subjects with stable asthma and bronchiectasis versus control subjects (median [interquartile range] 216 [103-389] and 698 [264-1,613] ng/L vs. 123 [41-290] ng/L, p

Oxidative stress is believed to play an important role in the pathophysiology of respiratory disease (1-6). The most commonly recognized mechanism leading to oxidative stress in respiratory disease is chronic inflammation, which involves recruitment and activation of inflammatory cells. During the respiratory burst, inflammatory cells produce excessive quantities of free radicals, which overwhelm host antioxidant defenses, leading to oxidative stress (7). Oxidative stress can have many detrimental effects on airway function, including airway smooth muscle contraction (8), induction of airway hyperresponsiveness, mucus hypersecretion, epithelial shedding, and vascular exudation (reviewed in Reference 7). Furthermore, reactive oxygen species can induce cytokine and chemokine production through activation of intracellular signaling cascades. For example, the transcription factor NF-?B has been shown to be activated by oxidative stress in bronchial epithelial cells (9).

Oxidative damage to lipids (lipid peroxidation) leads to the production of isoprostanes. Isoprostanes, of which 8-iso-prostaglandin F^sub 2?^ (PGF^sub 2?^) is the best-characterized isomer, are produced independently of the cyclooxygenase enzyme by the peroxidation of arachidonic acid, catalyzed by free radicals. They are considered to be a reliable index of in vivo oxidative stress because they are structurally stable and are produced in vivo (10, 11). In recent years, many studies have demonstrated that increased concentrations of 8-iso-PGF^sub 2?^ are a common feature of respiratory disease (11). Elevated 8-iso-PGF^sub 2?^ concentrations have been reported in patients with asthma (12-14), chronic obstructive pulmonary disease (15, 16), cystic fibrosis (17-19), interstitial lung disease (20), pulmonary hypertension (21), and acute respiratory distress syndrome (22), and in infants with respiratory failure (23). These reports highlight the involvement of lipid peroxidation in respiratory diseases.

Induced sputum is collected from the intrapulmonary airways, at the site directly adjacent to asthma pathology, and thus may accurately reflect conditions at the site of oxidative damage (24). Other methods used for sampling the airways are limited: the collection of bronchoalveolar fluid is extremely invasive and expired air collection has questionable reproducibility (25). Induced sputum samples contain a range of biomarkers useful for studying the lower respiratory tract (26), and sample collection is noninvasive. Thus, induced sputum may be a useful medium for examining oxidative stress in the airways. However, to date there are no reports of 8-iso-PGF^sub 2?^ in induced sputum. This study investigates oxidative stress in inflammatory airway diseases according to disease type, pattern, and activity using induced sputum 8-iso-PGF^sub 2?^ as a biomarker. We tested the hypothesis that induced sputum 8-iso-PGF^sub 2?^ would be elevated in inflammatory airway diseases (asthma and bronchiectasis) and would increase in asthma as disease pattern and activity worsened. Some of these results have previously been presented in the form of a conference abstract (27).

METHODS

Adults with stable asthma (n = 71), acute asthma exacerbation (n = 39), bronchiectasis (n = 23), and healthy control subjects (n = 29) were recruited. Subjects with stable asthma were recruited from the John Hunter Hospital Asthma Clinic. Asthma was diagnosed on the basis of current episodic respiratory symptoms, doctor’s diagnosis of asthma, and airway hyperresponsiveness to hypertonic saline. The clinical asthma pattern was categorized according to Global Initiative for Asthma guidelines (28). Subjects with acute asthma were recruited and studied on hospital admission and again 4 to 6 weeks after exacerbation, as previously reported (29). Subjects with bronchiectasis confirmed by chest computed tomography (17 previously described with allergic bronchopulmonary aspergillosis, a hypersensitivity reaction to the fungus Aspergillus fumigatus, which causes severe asthma [30]) were recruited from the John Hunter Hospital Respiratory Clinic. Healthy control subjects without asthma were recruited by advertisement. The study was approved by the Hunter area and University of Newcastle human research ethics committees.

If you’re like most people, you probably associate aging with health disorders such as Alzheimer’s disease or arthritis. But researchers who spoke at a congressional briefing in September 2004 warned that some other, lesser-known diseases are poised to strike older adults with a vengeance: chronic obstructive pulmonary disease (COPD), urinary incontinence and age-related macular degeneration (AMD).

With this in mind, we’ve compiled some suggestions about various natural products that, in concert with an overall regimen of proper diet, exercise and smoking cessation, may lower your risk of suffering these diseases.

Many of us are soon going to be afraid of a good belly laugh–for fear of wetting ourselves in public. Over 20 million Americans wouldn’t dare strain to pick up their grandchild or sit on someone’s new couch.

But the condition can produce more than just embarrassment. Bladder infections and skin breakdowns are much more common in people with incontinence. And it can lead to depression and loss of self-esteem. Fractures can even result from mad, unplanned dashes to the washroom.

Science hasn’t pinned down the cause and–short of further research into this rarely studied problem–cannot explain why some people suffer from it and others don’t.

Exercise, relaxation techniques and yoga have been shown to help. People with incontinence should also avoid too many drinks containing alcohol, caffeine or carbonation, and they should limit their liquid intake to two liters of fluid daily. Never go to the toilet “just in case.” Avoid constipation. And try to train your bladder to hold more urine.

As for supplements, calcium and magnesium taken together may improve control of the muscles used in urination. And vitamin C, cranberries and blueberries help by preventing bacterial infections of the urinary tract.

Chronic Obstructive Pulmonary Disease (COPD)

Even as the prevalence rates of many diseases that cause death and disability are declining, rates of COPD are increasing. About 15 million people in the United States have it–with twice as many undiagnosed cases suspected–and it’s the second leading cause of disability.

COPD involves emphysema or chronic bronchitis, depending on its path of destruction in the lungs. Most people with COPD have both. Often a COPD diagnosis is missed because its risk factors are also associated with myriad other disorders. Patients show up with a cough and shortness of breath–and are diagnosed with heart disease. The COPD is left untreated.

The best prevention advice is to avoid cigarette smoke, including the secondhand kind. And limit your exposure to animal dander and dust mites.

Some nutritionists believe that magnesium supplements can help reduce the odds of developing emphysema, although the jury’s still out. But magnesium should be a part of a healthful diet anyway. Dietary sources include legumes, whole grains and green leafy vegetables. Or, you can take magnesium supplements.

Once acquired, COPD-related damage to the lungs will not improve. However, some proponents point to a number of nutrients as potentially beneficial to COPD patients. Dietary and supplemental forms of omega-3 fatty acids–including alpha-linolenic acid (ALA) found in walnuts and flaxseeds–may help lessen COPD symptoms. Bromelain, coenzyme Q10 and L-carnitine may reduce mucus production, say some experts. And increasing the amount of fruit you eat by one or two servings per week or taking vitamin C supplements may help improve lung function. Herbal treatments may include garlic, eucalyptus, licorice, lobelia, marshmallow, red clover and saw palmetto.

Arthritis

Arthritis–a general term for over 100 different inflammatory diseases involving joint pain–affects 70 million Americans, making it one of our most common ailments. And 20 million suffer from the extremely crippling form: rheumatoid arthritis.

Sulfur helps arthritis by rebuilding bone, cartilage and connective tissue. Foods that contain sulfur are asparagus, eggs, garlic and onions.

Boswellia may reduce inflammation, plus it restores blood vessels around inflamed connective tissues. Glucosamine sulfate benefits bones, tendons, ligaments, cartilage and joint fluid. Calcium helps to prevent bone loss. Methylsulfonylmethane (MSM), a sulfur compound, eases pain and inflammation. Cat’s claw may relieve pain. Ginger, an antioxidant, has anti-inflammatory properties. When applied topically, cayenne can lessen pain. And nettle leaf has some anti-inflammatory properties that may also help.

Alzheimer’s Disease

Alzheimer’s disease (AD) afflicts about 4 million Americans–and this number is expected to hit 16 million by the year 2050. One in 20 seniors suffers from vitamin [B.sub.12] deficiency, a condition associated with neurological disorders–such as AD–and other major health problems. Good sources of [B.sub.12] are red and organ meats and the range of vitamin B supplements.

Eating nuts, leafy green vegetables and other foods rich in antioxidants such as vitamin E may reduce the risk of AD, two studies suggest.

Human transthyretin (TTR) is an amyloidogenic protein. The pathway of TTR amyloid formation has been proposed based on lines of evidence: TTR tetramer first dissociates into native monomers, which is shown to be a rate-limiting step in the formation of fibrils. Subsequently, the monomeric species partially unfold to form the aggregation intermediates. Once such intermediates are formed, the following self-assembly process is a downhill polymerization. Hence, tertiary structural changes within the monomers after the dissociation are essential for the amyloid formation. These tertiary structural changes can be facilitated by partial denaturation. To probe the conformational changes under the partially denaturing conditions, five independent trajectories were collected for the wild-type (WT) and its pathogenic variants at 300 and 350 K, resulting in simulations that totaled 59 ns. Under these conditions, L55P variant is more labile than the wild-type and V30M variant. We have observed that the D strand of WT-TTR is trapped in two local minima: the native conformation and the amyloidogenic fold that resembles the surface loop of residues 54-55 of L55P variant. In the tetrameric state, the F strand is bent with large separations at the F-F’ interface. This strand becomes flatter in the monomeric state, which may facilitate the formation of new F-F’ interface with possible prolonged hydrogen bonds and/or shift in ?-strand register in the fibril state. During the unfolding process, the anticorrelated motion between the strands H and G as well as the strands H and A pulls the H strand out of the inner sheet plane, leading to a more twisted inner sheet. Our simulation has provided important detailed structural information about the partially unfolded state of TTR that may be related to the amyloidogenic intermediates.

Accumulation of amyloid fibrils in tissues or extracellular matrix is the hallmark of amyloid diseases such as Alzheimer’s disease and the systemic amyloidoses (for example, immunoglobulin-light-chain diseases and the familial amyloid polyneuropathies that are associated with transthyretin). Up to date, ~20 human proteins have been found to form amyloid fibrils in vivo (1). These proteins can be divided into two categories based on whether the amyloid fibrils can be converted from a full-length amyloidogenic protein or a fragment of a large precursor protein. For example, Alzheimer’s fibrils are formed from amyloid-? peptide, a fragment of amyloid precursor protein; whereas, human transthyretin (TTR) belongs to the category of fulllength amyloidogenic protein; however, this does not exclude the fact that TTR fibrils also contain fragments of protein (2). It is likely that these two categories follow different pathways of fibril formation.

In this work, we focus on TTR, which is a plasma protein responsible for the transportation of thyroid hormone. It also binds to retinol-binding protein that in turn associates with vitamin A. The structures of the wild-type and various amyloidogenic single-site mutants have been determined by high-resolution x-ray crystallography (3-5). The native state of TTR is a homotetramer with eight ?-strands organized into two sheets, giving rise to a ?-sandwich (3) (Fig. 1 a). The eight ?-strands are named from A to H and arranged into inner (DAGH) sheet and outer (CBEF) sheet. Two monomeric units form a dimer via extensive hydrogen bonds between the two adjacent H (residues Ser-115-Thr-123) strands and F (residues Ala-91-Ala-97) strands from each monomer (Fig. 1 b). There are five main-chain-main-chain hydrogen bonds between the adjacent H strands, whereas the two F strands are separated more widely, as a result, only two hydrogen bonds (between Glu-89 and Val-94) are formed directly through the main-chain interactions. The remaining hydrogen bonding interactions involve water bridges. Two dimers are related by a crystallographic twofold axis to give a tetramer. A central channel wrapped around by the DAGH (inner) sheets runs through the center of the tetramer and accommodates thyroxin molecules.

The pathway of TTR amyloid formation has been proposed based on lines of evidence: TTR tetramer first dissociates into native monomers, which is shown to be a rate-limiting step in the formation of fibrils (6-8). Subsequently, the monomeric species partially unfold to form the aggregation intermediates. Once such intermediates are formed, the following self-assembly process is a downhill polymerization (9). Tetramer dissociation into monomers is necessary but not sufficient to initiate fibril formation because native monomers are nonamyloidogenic unless it is partially denatured (10). Therefore, further tertiary structural changes within the monomers are required. These tertiary structural changes can be facilitated either by partial denaturation (e.g., lowering the pH or the dielectric constant of the medium) (8,11) or by single-point mutation. At pH 7.5 and 370C, both L55P-TTR (Leu-55 [arrow right] Pro) and V30M-TTR (Val-30& rarr; Met) form amyloid protofibrils after two months of incubation, however, V30M-TTR exhibits much smaller amount of protofibrils. By contrast, the wild-type is stable and nonamyloidogenic under the same conditions (12).