Pulmonary drug delivery: from generating aerosols to overcoming biological barriers—therapeutic possibilities and technological challenges.


Summary

Research in pulmonary drug delivery has focused mainly on new particle or device technologies to improve the aerosol generation and pulmonary deposition of inhaled drugs. Although substantial progress has been made in this respect, no significant advances have been made that would lead pulmonary drug delivery beyond the treatment of some respiratory diseases. One main reason for this stagnation is the still very scarce knowledge about the fate of inhaled drug or carrier particles after deposition in the lungs. Improvement of the aerosol component alone is no longer sufficient for therapeutic success of inhalation drugs; a paradigm shift is needed, with an increased focus on the pulmonary barriers to drug delivery. In this Review, we discuss some pathophysiological disorders that could benefit from better control of the processes after aerosol deposition, and pharmaceutical approaches to achieve improved absorption across the alveolar epithelium, prolonged pulmonary clearance, and targeted delivery to specific cells or tissues.

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Conclusions

Since the introduction of the first metered dose inhalers to the market in 1956,88 pulmonary drug delivery has made substantial progress, even leading to the first introduction of an inhalation form of insulin (Exubera) to the market. However, since the withdrawal of Exubera from the market in 2007, the field of advanced pulmonary drug delivery, other than delivery of anti-asthma and bronchodilating drugs, has stagnated. Until now the main focus of research and development efforts has been on generation of better aerosols by engineering more sophisticated particles or devices. However, optimised aerosol deposition is a necessary, but not sufficient component of pulmonary drug delivery. To overcome the biopharmaceutical challenges associated with absorption across the alveolar epithelium, control of particle clearance and targeting of specific regions or cells within the lungs requires a thorough understanding of the processes occurring at the cellular and non-cellular elements of the air—blood—barrier after aerosol drug deposition.

To achieve these goals, advanced in-vitro models, preferentially based on human cells and tissues, will be important. Furthermore, nanotechnology might contribute to the development of aerosol drug carriers, and might be necessary for the success of pulmonary drug delivery in the future.

Source: Lancet

 

 

 

 

Use of bronchoalveolar lavage to assess the respiratory microbiome: signal in the noise.


In 2007, the US National Institutes of Health added the Human Microbiome Project to the National Institutes of Health Roadmap for Medical Research. The lung—traditionally thought to be a sterile site—was not part of the original programme. However, reports appeared describing a diverse population of non-cultivatable bacteria from other body sites, discovered using 16S rRNA sequencing, challenging notion that the lower respiratory tract was sterile. As a result, in 2009, the Lung HIV Microbiome Project was launched by the National Heart, Lung and Blood Institute to investigate the lung microbiome.

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Microbiome analysis using PCR-amplified 16S rRNA sequencing is highly sensitive1 and thus subject to contamination from the environment and neighbouring microbial communities. Prevention of contamination is especially problematic for the lower respiratory tract, which is directly connected to the densely colonised oral cavity.2 Analysis of the lung microbiome has largely relied on sputum and bronchoscopic samples, which can be contaminated by microorganisms in the upper respiratory tract. In one of the first studies3 to describe the lung microbiome—which used sequential bronchoscopes to take samples along the length of the respiratory tract from the oropharynx to the alveolar compartment—investigators reported that the bacterial composition of the oral cavity and bronchoalveolar lavage were indistinguishable. The researchers concluded that “bacterial populations in the healthy lower respiratory tract largely reflect upper respiratory tract organisms, likely resulting from transient entry rather than independent communities with indistinguishable structure”.3

Unfortunately, many investigators accepted this work as evidence that a lower respiratory tract microbiome does not exist in healthy people. This assumption ignores the fact that if a lung microbiome is present, it is likely to be similar to that of the upper respiratory tract because of chronic asymptomatic aspiration.4 Furthermore, no physiological reason exists to assume that the lung, which is constantly exposed to the air we breathe, is not colonised like any other body cavity that is exposed to the environment. Finally, the lung filters the entire blood supply, and any episodes of bacteraemia could lead to colonisation of the lung. We believe that new data add to these theoretical considerations, providing evidence for a resident lung microbiome.

The first argument for a lung microbiome comes from the discovery of a high incidence of Tropheryma whipplei in bronchoalveolar lavage samples from asymptomatic HIV-infected individuals compared with uninfected people.5 The organism was not detected in paired oral wash. Because T whipplei is primarily found in the gastrointestinal tract, it probably colonises the lung after translocation from the gut. The higher prevalence of T whipplei in people with HIV might be a result of either defects in the function of the gut mucosal barrier or impaired lung clearance in patients with HIV. The presence of organisms found only in bronchoalveolar lavage samples and not in the oral wash significantly counterbalances the argument that a bronchoalveolar lavage sample is merely a dilute oral cavity sample.

Second, the presence of a lung microbiome is supported by studies in which neutral model analysis was used to compare bronchoalveolar lavage and oral wash samples from the same person.67 Neutral model analysis assumes that random dispersal from neighbouring communities, rather than environmental selection, is responsible for the composition of a microbiome. In these studies, although dispersal from the mouth was largely responsible for the composition of the microbial community in the lung, some bacterial groups (ie, Ralstonia spBosea sp, Haemophilus sp, and Enterobacteriaceae sp) could be identified as significantly non-neutral and thus potential members of a healthy lung microbiome. Other investigators have developed similar mathematical approaches to identify unique lung residents in bronchoalveolar lavage samples.8 This modelling requires simultaneous comparison of bronchoalveolar lavage and oral wash samples from the same person and careful assessment of environmental contaminants.

Third, detectable organisms have been isolated from samples obtained under sterile conditions. Two groups have published work describing microbiomes from sterile, whole lung tissue samples. Both groups reported a predominance of Proteobacteria.910 These results complement work showing enrichment of Proteobacteria in bronchoalveolar lavage.611Studies1213 of samples obtained under sterile conditions from mice also identified a respiratory microbiome in whole lung homogenates and bronchoalveolar lavage.

Finally, there is an increasing realisation that colonising organisms might dictate human health and disease. Characteristics of the gut microbiome have been linked to obesity, susceptibility to cancer, and inflammatory bowel disease.14 This relation probably results from bacterial stimulation of immune cells via toll-like receptors and creation of a cytokine environment that regulates the balance between T effector cells and T regulatory cells. One could easily posit a similar dynamic in the lung, thereby defining susceptibility to immunity-mediated diseases such as asthma and sarcoidosis. In support of this idea, several investigators have described substantially different lower respiratory microbiomes between healthy people and patients with chronic obstructive pulmonary disease10 and asthma.15

Thus, many lines of evidence support the existence of a resident lower respiratory microbiome in healthy people. The response to inhaled and aspirated environmental antigenic challenges will depend on the baseline immune and inflammatory state of the lung, which will be related to the resident microbiome. Understanding the interactions between the host, the microbiome, and the environment is crucial to a better understanding of individual susceptibility to lung disease. These studies will need participants from a varied epidemiological, geographical, and exposure background. For practical reasons, specimens from the lower respiratory tract will probably come through bronchoscopic and sputum acquisition. The challenge is to recognise the limitations of these techniques and to develop experimental and mathematical approaches to find the “signal in the noise”. Ultimately, the success of these studies will depend on close collaboration between doctors, epidemiologists, molecular biologists, microbiologists, and mathematicians with expertise in modelling complex interactions between microbial communities.

Source: Lancet

Anti-acid treatment for idiopathic pulmonary fibrosis.


The idea that idiopathic pulmonary fibrosis (IPF) could be mechanistically and pathogenetically attributed to repeated, often silent events of gastric fluid microaspiration (so-called lungburns) was first introduced almost 40 years ago.1 Since then, an increasing body of evidence has provided useful insights about a potential link between diffuse lung fibrosis and gastro-oesophageal reflux. A high prevalence of abnormal acid gastro-oesophageal reflux (identified by 24-h pH monitoring) in patients with IPF—almost 90%—was first reported in two different cohorts.23 However, a much smaller proportion of patients complain of heartburn-related symptoms,4 rendering the diagnosis of abnormal acid gastro-oesophageal reflux clinically occult and thus insidious.

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Several reports have associated anti-reflux treatment with improved survival and substantial functional and radiological benefits in patients with IPF.5 Additionally, increased amounts of microaspiration biomarkers, such as pepsin, in bronchoalveolar lavage fluid of patients with IPF experiencing an acute exacerbation6 directly implicates clinically silent microaspiration of gastric fluid as a triggering factor of fibrogenesis.5

In The Lancet Respiratory Medicine, Joyce Lee and colleagues present results of an analysis of the potential usefulness of anti-acid treatment (proton-pump inhibitors [PPIs] and histamine-receptor-2 [H2] blockers) in patients with IPF.7 Their method was well designed: they used prospectively obtained data from the placebo groups of the three randomised clinical trials from the Idiopathic Pulmonary Fibrosis Clinical Research Network (PANTHER, ACE, and STEP). They assessed the effect of anti-acid treatment on functional deterioration in a 30-week period for 242 patients.

The most important finding of their study was that patients taking anti-acid treatment (n=124) had a significantly smaller decrease in forced vital capacity (—0·06 L, 95% CI −0·11 to −0·01) than did those who were not taking anti-acid treatment (n=118; −0·12 L, −0·17 to −0·08; difference 0·07 L, 0—0·14; p=0·05). Moreover, patients taking anti-acid treatment had significantly fewer acute exacerbations (no events) than did those who were not (nine events; p=0·0017). Although the results suggested improved survival with anti-acid treatment, the difference was not significant (p=0·12).

Nevertheless, several mechanistic issues and safety concerns should be addressed before anti-acid treatment in patients with IPF can be widely implemented. So far, no rigid pathogenetic link between gastro-oesophageal reflux and IPF has been identified, and anti-acid treatment has inconsistent effects on survival, because it does not inhibit reflux.5 Patients included in Lee and colleagues’ analysis,7 and those in previous retrospective analyses,8 were heterogeneous in terms of disease severity and presence of comorbidities, such as sleep apnoea, that can significantly affect survival and cause further deterioration of abnormal gastro-oesophageal reflux. Finally, assessment of abnormal acid gastro-oesophageal reflux and gastro-oesophageal reflux disease was superficially based solely on heartburn symptoms in most patients; endoscopy was used in a small proportion of patients.

But do physicians really need to treat symptoms of gastro-oesophageal reflux? Or should the primary outcome be to prevent further lung injuries by intervening directly in the fibrogenic cascade? A study by Ho and colleagues8 extended the beneficial contribution of PPIs beyond neutralisation of highly acidic gastric juice. The investigators concluded that PPI inhibition of dimethylarginine dimethylaminohydrolase and inducible nitric oxide synthase, which are known to be increased within lung epithelium and fibroblastic foci,910 eliminated aberrant signalling in the TGF-β pathway, ultimately leading to decreased collagen production in an experimental model of lung fibrosis. These findings suggest a novel antifibrotic mechanism for PPIs in patients with IPF.

Another crucial issue is to clarify whether anti-acid treatments will be used as adjunctive or primary therapeutic regimens. Many questions about which patients, the length of treatment, and what doses to use remain unanswered. The idea that all patients with IPF could receive anti-acid treatment as prophylaxis could be risky in view of the potentially harmful side-effects, such as infections, electrolyte disturbances, and, importantly, drug interactions. H2 blockers and PPIs are potent inducers of P450 enzymes, particularly CYP1A2, and therefore might limit the plasma concentrations of several antifibrotic agents, including pirfenidone, which has been approved for IPF treatment.11

Overall, a randomised placebo-controlled trial of patients with IPF, with and without symptoms of gastro-oesophageal reflux, is needed. Assessment of agent-specific and dose-dependent therapeutic outcomes will be necessary to better define individuals who could benefit from such interventions.

Source: Lancet

Has targeted therapy for melanoma made chemotherapy obsolete?


Targeted therapy for BRAF-mutant melanoma has revolutionised the management of patients with metastatic melanoma12and ignited a quest for even more effective strategies. Situated just downstream of BRAF is MEK, which has become a second molecular target of great interest. The MEK inhibitor trametinib was recently approved by the US Food and Drug Administration (FDA), and other MEK inhibitors are in clinical development.34 Targeted drugs have pushed cytotoxic chemotherapy research into the background, yet chemotherapy regimens are still offered as first-line therapy in countries where access to targeted drugs is limited. Chemotherapy has a deservedly poor reputation in the treatment of advanced melanoma, but it is now valid to ask whether targeted therapy has made chemotherapy obsolete, or alternatively whether combination with a molecularly targeted agent could breathe new life into old drugs.

Caroline Robert and colleagues5 evaluated the combination of dacarbazine with selumetinib, another MEK inhibitor, in a randomised, placebo-controlled phase 2 trial in 91 patients with BRAF-mutant melanoma. The trial’s primary endpoint of improved overall survival was not met. There were, however, signs of clinical benefit for the combination, with a higher confirmed response rate (29% vs 13%) and longer median progression-free survival (5·6 months, 80% CI 4·9—5·9, vs 3·0 months, 2·8—4·6; hazard ratio 0·63, 80% CI 0·47—0·84, one-sided p=0·021) in the selumetinib plus dacarbazine group compared with the placebo plus dacarbazine group. This benefit came at the cost of increased toxicity in the combination group, including rash, oedema, visual disturbances, bleeding, and infection.

The clinical efficacy of the selumetinib-dacarbazine combination was not impressive by the standards now set by BRAF inhibitors. Furthermore, the dacarbazine response rate in the current study (13%)5 was higher than in other recent phase 3 studies,124 which might have inflated results in the combination group as well. Perhaps selumetinib is not the right partner? In other phase 2 trials of selumetinib, the confirmed response rate was 7—11% in patients with BRAF-mutant melanoma.6 Although the combination of selumetinib plus dacarbazine appears to be somewhat better than selumetinib alone, the activity of selumetinib seems less than that reported for trametinib alone (confirmed response rate 22% in the METRIC study).4 Hence, the combination of chemotherapy with a more potent MEK inhibitor could provide superior results.

At the present time selective BRAF inhibitors remain the targeted treatment of choice for metastatic melanoma harbouringBRAF Val600Glu and Lys mutations. The combination of BRAF and MEK inhibitors in patients with BRAF Val600 mutant melanoma is an emerging strategy with early signs of improved clinical benefit.7 Upfront use of concurrent BRAF and MEK inhibition, rather than the addition of a MEK inhibitor after progression on single-agent BRAF inhibitor, seems important.8For patients who do progress after single-agent BRAF inhibitor therapy, the possibility that combination of chemotherapy with a MEK inhibitor might be better than the to-date disappointing results of MEK inhibitors alone deserves further investigation.

Where else might we find a role for MEK inhibitors alone or in combination with chemotherapy as treatment for metastatic melanoma? In patients with this disease whose tumours do not harbour a BRAF Val600 mutation, standard treatment options remain immunotherapy and chemotherapy. There could be a niche for MEK inhibitors with or without chemotherapy in patients not eligible for or refractory to immunotherapy, particularly where their melanomas manifest an upregulated MAP kinase pathway. Indeed, clinical activity of MEK inhibitors has been reported in patients with BRAF Leu597Ser and NRASmutant melanoma, neither of which would be expected to respond to BRAF inhibitor therapy.39 Furthermore, the recently presented results of the phase 2 trial of selumetinib versus temozolomide in uveal melanoma, in which GNAQ or GNA11mutations were identified in 84% of patients, showed superior benefit for patients receiving selumetinib.10 These findings included an objective response rate of 15% in the selumetinib group compared with no responses in the temozolomide group, and more than double the median progression-free survival with selumetinib.

Undoubtedly, MEK inhibitors have a role in the treatment of metastatic melanoma. Although single-agent trametinib is approved by the FDA for front-line use in BRAF Val600 mutant melanoma, MEK inhibitors are likely to become a key element in treatment of melanoma with MAP kinase pathway activation due to oncogenes other than the BRAF Val600 mutation. The combination of a MEK inhibitor with chemotherapy might yet prove to be an effective approach in selected patient populations, such as uveal melanoma, based on the additive benefit of selumetinib and dacarbazine seen in the current study by Robert and colleagues.5 Although treatment paradigms are strongly shifting away from chemotherapy, there might still be an important part for cytotoxic drugs to play in melanoma.

Source: Lancet Oncology

Prevention of acute renal failure post-contrast imaging in cardiology: a randomized study..


Abstract

BACKGROUND:

The contrast-induced nephropathy (CIN) is the third most common cause of acute renal failure (ARF) and the worsening in a pre-existing chronic renal failure (CRF), with a foreseeable increase of morbidity, mortality, length of the stay in hospital and, as a consequence, of the health costs. We studied the effectiveness of N-acetylcysteine (NAC) associated with sodium bicarbonate (Na2HCO3) infusion in order to prevent CIN in patients undergoing coronary angiography with administration of contrast medium.

MATERIALS AND METHODS:

296 patients with indication to perform coronary angiography were included in a randomized, observational study. All patients were randomly assigned to receive pre- and post-contrast hydration with 1500 ml of 0.9% saline solution infusion (Group A) or NAC (1200 mg × 2 days) + Na2HCO3 (Group B). The primary end-point was to examine CIN appearance, defined as a raise in serum values of Cr (Creatinine) ≥ 0.5 mg/dl or ≥ 25% within 24-72 hours after the exposure to the contrast medium.

RESULTS:

It has been observed a frequency of CIN of 9.4% in Gr. A compared to 7.2% in Gr. B. Nevertheless, when we put these results through a more accurate screening according to gender, degree of raise in creatinine levels and the extent of change in GFR (glomerular filtration rate), we observed a very different behaviour. In patients with normal Cr and CrCl (Clearance of Creatinine) the frequency of CIN was similar in both group A and B (approximately 5%). In patients with normal Cr but reduced ClCr the use of NAC was more effective than hydration in preventing CIN (0% vs 18% in prevalence respectively in B and A group). In patients with moderately reduced Cr and CrCl, hydration with saline solution was more effective than NAC + Na2HCO3 (8.6% vs 17.6%) while in patients with severe CRF the combined use of NAC + Na2HCO3 showed off to be very successful in preventing CIN compared to the merely hydration (0% vs 50%).

CONCLUSIONS:

In patients affected by severe CRF who are undergoing investigations with contrast medium administration, such as coronary angiography, the combined use of NAC + Na2HCO3 infusion significantly reduces the risk of developing CIN. In other circumstances the final result is related to the degree of previous GFR or creatinine values alteration or to gender. In such situations the combined use of both substances is more questionable and sometimes ineffective.

Source: Pubmed

 

N-acetylcysteine attenuates the progression of chronic renal failure


Background

 

Lipid peroxidation impairs renal function. Aldosterone contributes to renal injury in the remnant kidney model. This study aimed to determine the effects of the antioxidant N-acetylcysteine (NAC) on renal function and aldosterone levels in chronic renal failure.

Methods

 

Adult male Wistar rats were submitted to 5/6 nephrectomy or laparotomy (sham-operated) and received NAC (600 mg/L in drinking water, initiated on postoperative day 7 or 60), spironolactone (1.5 g/kg of diet initiated on postoperative day 7), the NAC-spironolactone combination or no treatment. Clearance studies were performed on postoperative days 21, 60, and 120.

Results

 

Mean daily NAC and spironolactone ingestion was comparable among the treated groups. Mean weight gain was higher in NAC-treated rats than in untreated rats. A significant decrease in urinary thiobarbituric acid reactive substances (TBARS) concentrations, a lipid peroxidation marker, was observed in NAC-treated rats. By day 120, glomerular filtration rate (GFR), which dropped dramatically in untreated rats, was stable (albeit below normal) in NAC-treated rats, which also presented lower proteinuria, glomerulosclerosis index, and blood pressure, together with attenuated cardiac and adrenal hypertrophy. These beneficial effects, observed even when NAC was initiated on postnephrectomy day 60, were accompanied by a significant reduction in plasma aldosterone and urinary sodium/potassium ratio. The NAC-spironolactone combination lowered blood pressure and improved GFR protection.

Conclusion

 

The NAC-spironolactone combination improves renal function more than does NAC alone. In the remnant kidney model, early or late NAC administration has a protective effect attributable to decreased plasma aldosterone and lower levels of lipid peroxidation.

CONCLUSION

Our data demonstrate that NAC attenuates drops in GFR, as well as lowering proteinuria and blood pressure in nephrectomized rats. This is accompanied by a significant reduction in aldosterone levels. Our results indicate that ROS play an important role in the progression of chronic renal failure. It is evident that NAC has potential utility in preventing glomerulosclerosis and loss of kidney function in patients with chronic renal failure. The findings that NAC attenuated GFR drop and lowered proteinuria, even in end-stage chronic renal failure, and that the combination of NAC and spironolactone improves renal function more than does NAC alone have significant clinical implications.

Source: Nature Kidney

 

How to Prevent and Treat Insect Bites Without Harsh Chemicals.


Story at-a-glance

  • Preventive measures to avoid getting bit by insects such as mosquitoes include: avoiding the outdoors at dawn and dusk—especially when sweaty—draining stagnant water sources, planting marigolds around your yard, installing bat boxes
  • The following can be used to repel bugs: Vick’s Vaporub®; cinnamon leaf oil; clear liquid vanilla extract mixed with olive oil; citronella soap and 100% pure citronella essential oil; catnip oil
  • Most commercial insect repellants contain a chemical known as DEET, which should be used with caution, if at all. Many studies have found DEET to have harmful effects
  • Herbs and other natural agents can help soothe itchy bites, such as: aloe vera, calendula, cinnamon, chamomile, lavender, Neem oil, tea tree oil, basil, peppermint, lemon and lime, and baking soda mixed with witch hazel
  • Using either ice or heat are other options that can help ease the discomfort associated with bug bites. Research has shown that locally administrated heat leads to fast amelioration of symptoms such as swelling, pruritus, and pain.

Summertime calls most of us to spend time outdoors. Alas, bugs can be a real buzz-kill at best, and carriers of disease at worst. Additionally, most commercial insect repellants contain a chemical known as DEET, which should be used with caution, if at all. Many studies have found DEET to have harmful effects.

Fortunately, there are plenty of tricks to keeping biting bugs at bay, and they don’t involve applying toxic chemicals to your skin. There are also many natural remedies that can help take the sting out of your bites, should preventive methods fail.

The Most Common Offenders…

The featured article in Medical News Today1 offers an excellent and extensive overview of a wide variety of bug bites, their signs and symptoms and potential side effects, which can range from mild to severe (allergic reactions):

“When insects bite they release a form of saliva that can cause inflammation, blisters and irritation. Insect bite signs and symptoms vary, depending on the type of insect and the individual’s sensitivity.

While one person may just have a small, itchy lump that clears away in a few days, somebody else can have a more serious reaction, such as papular urticaria — crops of small papules and wheals, which may become infected or lichenified (thickened and leathery) because of rubbing and excoriation.”

WebMD also has a helpful “Bad Bugs Slideshow” to help you identify some 28 different types of bugs and their bites.2 Some of the most common biting insects include:

Mosquitoes Certain flies
Fleas Bedbugs
Gnats Midges
Spiders Ticks

Fortunately, it’s fairly rare to catch diseases from most insect bites if you live in countries far away from the equator, such as northern parts of Europe, United States, and Canada. The closer you are to the equator, the risk of being bit by mosquitoes and other insects carrying diseases such as malaria, sleeping sickness, yellow fever, encephalitis, West Nile virus and dengue fever increases.

Ticks, however, can spread human babesiosis, Rocky Mountain spotted fever, and Lyme disease—one of the most serious and controversial epidemics of our time—regardless of your geographical location. To avoid ticks, make sure to tuck your pants into socks and wear closed shoes and a hat—especially if venturing out into wooded areas.

Simple Preventative Measures to Avoid Mosquito Bites

Mosquitoes are probably the most pervasive when it comes to biting bugs that can ruin an otherwise pleasant outing. There are over 3,000 different species of mosquitoes throughout the world, about 200 of which occur in the US. Naturally, the best way to avoid mosquito bites is to prevent coming into contact with them in the first place.

You can avoid most assaults by staying inside around dawn and dusk, which is when they are most active. If you must be out during those times, wear light-colored, long sleeved shirts and long pants, hats and socks. Mosquitoes are also thicker in shrubby areas and near standing water.

Body temperature and skin chemicals like lactic acid also attract mosquitoes, which explains why you’re more likely to be “eaten alive” when you’re sweaty, such as during or after exercise, so trying to stay as cool and dry as you can may help to some degree. You may also want to forgo bananas during mosquito season. According to Dr. Janet Starr Hull, “there’s something about how your body processes the banana oil that attracts these female sugar-loving insects.”

She also recommends supplementing with one vitamin B1 tablet a day from April through October, and then adding 100 mg of B1 to a B100 Complex daily during the mosquito season to make you less attractive to mosquitoes. Research also suggests that regularly consuming garlic or garlic capsules may help protect against both mosquito and tick bites. The American Mosquito Control Association (AMCA) has a helpful factsheet3 of things you can do to prevent mosquito breeding on your property. The Three D’s of protection from mosquitoes are:

  • Drain—Mosquitoes require water in which to breed, so carefully drain any and all sources of standing water around your house and yard, including pet bowls, gutters, garbage and recycling bins, spare tires, bird baths and so on
  • Dress—Light colored, loose fitting clothing offer the greatest protection
  • Defend—While the AMCA recommends using commercial repellents, I highly recommend avoiding most chemical repellents, especially those containing DEET. Instead, try some of the natural alternatives suggested in this article

Bat houses are becoming increasingly popular since bats are voracious consumers of insects, especially mosquitoes. For more on buying a bat house or constructing one yourself, visit the Organization for Bat Conservation.4 Planting marigolds around your yard also works as a bug repellent because the flowers give off a fragrance that bugs do not like. This is a great way to ward off mosquitoes without using chemical insecticides. A simple house fan could also help keep mosquitoes at bay if you’re having a get-together in your backyard.

Steer Clear of Chemical Repellents, Especially DEET

Currently, DEET (N,N-diethyl-meta-toluamide) is used in more than 230 different products — in concentrations of up to an astounding 100 percent. If a chemical melts plastic or fishing line, it’s not wise to apply it to your skin — and that is exactly what DEET does.

Duke University Medical Center pharmacologist Mohamed Abou-Donia spent 30 years researching the effects of pesticides. He discovered that prolonged exposure to DEET can impair cell function in parts of your brain — demonstrated in the lab by death and behavioral changes in rats with frequent or prolonged DEET use. Children are particularly at risk for subtle brain changes because their skin more readily absorbs chemicals in the environment and chemicals more potently affect their developing nervous systems. Other potential side effects DEET exposure include:

Memory loss Headache Muscle weakness and fatigue
Shortness of breath Muscle and joint pain Tremors

Another potentially harmful chemical found in many bug sprays5 is permethrin. This chemical is a member of the synthetic pyrethroid family, all of which are neurotoxins. The EPA has even deemed this chemical carcinogenic, capable of causing lung tumors, liver tumors, immune system problems, and chromosomal abnormalities. Permethrin is also damaging to the environment, and it is particularly toxic to bees and aquatic life. It should also be noted that permethrin is highly toxic to cats.6

Even a few drops can be lethal to your feline pet. It is used as an ingredient in some topical flea products, so when you see “for dogs only” on the label, it likely contains permethrin. The Environmental Working Group (EWG) recently released an extensive review of the safety (or lack thereof) of virtually all bug repellant ingredients7.

Keeping Insects at Bay the Natural Way

Fortunately, there are highly effective repellents on the market comprised of natural botanical oils and extracts that are every bit as effective as DEET, but with none of the potentially harmful effects. You can also make your own repellent using:

  • Cinnamon leaf oil (one study found it was more effective at killing mosquitoes than DEET)
  • Clear liquid vanilla extract mixed with olive oil
  • Wash with citronella soap, and then put some 100% pure citronella essential oil on your skin. Java Citronella is considered the highest quality citronella on the market
  • Catnip oil (according to one study, this oil is 10 times more effective than DEET)8

Another option is to use the safe solution I have formulated to repel mosquitoes, fleas, chiggers, ticks, and other biting insects. It’s a natural insect spray with a combination of citronella, lemongrass oil, peppermint oil, and vanillin, which is a dynamite blend of natural plant extracts. In fact, an independent study showed my bug spray to be more effective than a product containing 100 percent DEET. And it’s safe for you, your children, and your pets.

Treating Bites and Stings with Herbs and Other Natural Agents

Once you’ve been bitten, the objective changes from repelling to treating the itch and inflammation caused by the bite. Fortunately, many herbs and other natural agents are soothing to the skin, and many have anti-inflammatory properties. So for your occasional mosquito bites, try one of the following:

Aloe vera: It contains over 130 active compounds and 34 amino acids that are beneficial to your skin. Calendula: An herb with soothing, moisturizing and rejuvenating properties. Chamomile: The most soothing herb of all, whether used in a tea or applied to the skin. It is rich in the bioflavonoids apigenin, luteolin and quercetin.
Cinnamon: In addition to possibly repelling mosquitoes, cinnamon has antibacterial and antifungal properties. Cucumbers are helpful for reducing swelling. Raw organic honey: An especially powerful variety is Manuka honey from New Zealand, made from bees that feed on flowers of the Manuka bush, also known as the “Tea Tree.”
Lavender: One of the most popular essential oils for its calming scent, lavender is as antimicrobial as it is soothing. Neem oil: Effective against fungal conditions, boils, eczema, and ringworm, and it would undoubtedly help an insect bite as well. Tea Tree oil: Helpful for healing cuts, burns, infections and a multitude of other skin afflictions. It is also a good antimicrobial, including fungal infections.
Basil contains camphor and thymol, two compounds that can relieve itching. Either crush up some fresh herb and apply directly to the bite, or buy the essential oil. Lemon and lime both have anti-itch, antibacterial and antimicrobial actions. Avoid applying citrus juices to your skin when outdoors however, as blistering can occur when exposed to sunlight. Peppermint—the cooling sensation can block other sensations, such as itching, providing temporary relief. Either the essential oil or crushed fresh leaves will do.

Swiping a cooled tea bag over your bites can also help, as the tannins in the tea acts as an astringent, reducing swelling. For bites all over your body, try soaking in a bathtub of warm water with two to three cups of apple cider vinegar added to it. The acidity of the vinegar can help stop the maddening itch. Alternatively, dissolve some baking soda in your bath and soak for about 30 minutes. You can also mix some baking soda with a small amount of water or witch hazel to create a paste, and apply directly to the bite. The witch hazel works synergistically with the baking soda, making for a more potent mix to reduce swelling.

Hot or Cold Therapies Can Take the Sting Out of a Bug Bite

Using either ice or heat are other options that can help ease the discomfort associated with bug bites. For example, an article inScientific American9 recommends using a simple ice pack to treat painful insect bites in lieu of analgesics. The article also explains why common topical steroids like hydrocortisone aren’t always the answer—one reason being that you’re not supposed to put them on broken skin.

According to an article published in the Drug and Therapeutics Bulletin10 just last year, there is also little direct evidence supporting the efficacy of commercial preparations for insect bites, including antihistamines and topical corticosteroids. The authors concluded that the best course of action for mild local reactions is to simply clean the area and apply a cold compress.

Alternatively, applying heat directly to the bite also appears to relieve itchiness. One simple way is to apply a heated spoon directly to the area, as demonstrated by Lifehacker.com.11 Just hold the spoon under hot tap water for about a minute to heat the metal, then press it against the bite for a couple of minutes. Naturally, make sure the spoon is not too hot.

It shouldn’t be scalding enough to actually hurt, so please use some common sense, and make sure to test it on your own skin before applying the heated utensil to a child. The receptors that respond to heat are the same ones that respond to cold, so you will likely achieve the same benefits with a metal spoon taken from your freezer, or simply rubbing ice cubes on it. I have also found that covering the bite with tape works really well to suppress the itch.

A more high-tech version of a heated spoon is the Therapik—a handheld wand that provides targeted heat for the treatment of itchy bites from a range of insects, including mosquitoes, bees, wasps, hornets, black flies, ants, fleas, ticks, chiggers, as well as jellyfish and stinging nettles. Gizmodo12 tested it, and determined that it works as advertised, giving it four out of five stars:

“You put the tip of the Therapik onto your bug bite, then you press and hold down the button. The tip uses light to heat the bite up. You hold it there for as long as you can take it, up to a minute. The burning sensation gets pretty intense after 30 seconds or so… It actually works! Mosquito bites (the only thing we tested it with) stopped itching within a few seconds of taking it off, and in most cases they never itched again. We are officially stunned. … It works on the principle that most insect venom is thermolabile (sensitive to heat). Therapik claims to deliver “heat in the precise temperature range necessary to deactivate the venom from over 20,000 different species of insects and sea creatures.”

A German study13 published in 2011 confirms the hypothesis of such claims. Testing another medical device called Bite Away, they concluded that:

“Locally administrated concentrated heat leads to fast amelioration of symptoms [swelling, pruritus and pain]. Usually an absence of symptoms is noticeable 10 minutes after administration. Pain reduction is the dominant effect.”

To Enjoy the Outdoors, a Little Preparation and Planning Can Go a Long Way

With a little planning and preparation, you should be able to enjoy the outdoors without getting eaten alive. Remember the Three D’s of protection from mosquitoes: drain, dress, and defend. Eliminating the breeding grounds for mosquitoes is the first step to limiting their numbers. Planting marigolds around your yard and maybe installing a bat box or two can also go a long way toward preventing them in the first place.

When it comes to defense, I recommend avoiding harsh chemical concoctions and experimenting with some natural alternatives instead. Some may work better than others for each individual, as mosquitoes in particular are attracted to certain biochemical components in your skin.

Should your preventive measures fail, there are well over a dozen different home remedies that can help, from herbs to baking soda to ice packs or heat, whether in the form of a heated or cold spoon, compress, or electronic gadget, or maybe even just a piece of tape.

Source: mercola.com

The Art of Hand Washing Has Yet to Be Mastered.


Story at-a-glance

  • Only 5 percent of people washed their hands properly, in a way that would kill infection and illness-causing germs, according to new research
  • Simply rinsing your hands with water, or giving a quick scrub with soap, is not enough to remove germs; you need to scrub all areas of your hands with plain soap for 15-20 seconds, then rinse under running water, to be effective
  • Over-washing your hands can lead to cracks in your skin that provide an easy entrance for disease-causing germs; it’s particularly important to avoid over-washing your hands in arid environments or winter
  • Actively building up and nurturing your immune system, and the makeup of beneficial microorganisms in your gut, works in tandem with hand washing to help you avoid getting sick.
  • hand-wash

Hand washing is an incredibly simple way to reduce your exposure to potentially disease-causing germs and reduce your chances of getting sick.

It’s not the only factor, however, as the state of your immune system is actually what ultimately determines whether you stay healthy or get sick when you’re exposed to germs.

Regular hand washing is important, though, because it can drastically reduce the germs that get access to your body, especially when you do it at key times, such as before eating or touching your mouth, eyes and nose, and after using the restroom or visiting public areas.

The trick is, hand washing is only effective if it’s done correctly. This might sound obvious, but a new study found that most people are not really killing germs when they wash their hands.

95 Percent of People Are Not Washing Their Hands Correctly

In a study of more than 3,700 bathroom-goers in a college town, only 5 percent washed their hands properly, in a way that would kill infection and illness-causing germs.1

Among the rest, 33 percent didn’t even use soap and 10 percent neglected to wash their hands at all after using the restroom. Others did not wash their hands long enough to be effective at removing germs.

There were some trends noted, too. Older generations typically washed their hands more frequently, and for longer, than younger generations, and women tended to wash their hands more often, and more effectively, than men.

Still, the study suggests that a lot of people – the majority – are receiving a false sense of security when they wash their hands, believing them to be ‘clean’ when in fact they’ve done little to actually remove the germs…

How to Wash Your Hands Effectively in 5 Simple Steps

If you’re taking the time to wash your hands, you’ll want to be sure they are, in fact, clean when you’re done. Simply rinsing your hands with water, or giving a quick scrub with soap, is probably not enough.

To make sure you’re actually removing the germs when you wash your hands, follow these guidelines:

  1. Use warm, running water and a mild soap (avoid antibacterial soap)
  2. Work up a good lather, all the way up to your wrists, scrubbing for at least 15 or 20 seconds (most people only wash for about 6 seconds)
  3. Make sure you cover all surfaces, including the backs of your hands, wrists, between your fingers, and around and below your fingernails
  4. Rinse thoroughly under running water
  5. In public places, use a paper towel to open the door as a protection from germs that the handles may harbor

Too Much Hand Washing Can be Harmful… Proper Balance Is Key

You’re exposed to germs just about every moment of your life. And this isn’t necessarily a bad thing. A child raised in an environment devoid of dirt and germs, and who is given antibiotics that kill off all of the bacteria in his gut, is not able to build up natural resistance to disease, and becomes vulnerable to illnesses later in life.

This theory, known as the hygiene hypothesis, is likely one reason why many allergies and immune system diseases have doubled, tripled or even quadrupled in the last few decades. Your immune system needs regular exposure to “dirt” and germs to stay healthy.

If you’re healthy, exposure to bacteria and viruses may serve as “natural vaccines” that strengthen your immune system and provide long-lasting immunity against disease. If you don’t get this healthy exposure to germs in your environment, it may end up making you sick.

So the solution to staying healthy is not to turn into a modern-day Howard Hughes where you avoid all public interactions at any cost or disinfect your environment obsessively. What you want, ideally, is a healthy balance.

You certainly don’t want to expose yourself to disease-causing germs unnecessarily, and this is why it makes sense to wash your hands. But you needn’tfear all germs, as some germ exposure is inevitable, and likely even good for you in the long run.

You can count on your immune system to protect you, but don’t unnecessarily jeopardize yourself.   Without proper hygiene, one cannot achieve optimal health.  Overwashing and excessive exposure to disinfectants can likewise be a detriment.   It seems moderation is again the key.

Beware of Washing Your Hands Too Often in Arid Environments or Winter

Your skin is one of your primary defenses against bacteria, so resist the urge to become obsessive about washing your hands. If you wash them too harshly, too frequently, you can extract many of the protective oils in your skin, which can cause your skin to crack and potentially even bleed. This is completely counterproductive and only invites trouble…

While it’s rare for infectious agents on your skin to cause a problem (it is typically only an issue when you transfer that to your nose, mouth or an open wound like cracked skin), obsessive-compulsive washing can increase your risk of getting sick by providing an entryway for potentially dangerous pathogens through the cracked skin. This is especially true in the winter or in dry environments where humidity levels frequently drop below 10 percent. In the summer or in humid environments, this is less of an issue, but no matter where you live, be sure that your hand washing is not irritating your skin, leading to dry, cracked areas that are a perfect entryway for germs.

Why Antibacterial Soap Is Not Necessary

Another major misconception about hand washing is that you need to use antibacterial soap. These types of disinfectants are extremely useful in a hospital setting, but they can do far more harm than good when used on a daily basis in your home.

Studies have repeatedly shown that regular soap is just as effective (sometimes even more effective) than antimicrobial soap for the prevention of infectious diseases. Furthermore, antimicrobials like triclosan, commonly used in antibacterial soap, are linked to hormone disruption, heart disease and heart failure. Using triclosan-containing products may actually increase your chances of contracting an infection if you already have a chronic disease, promotes the emergence of antibiotic-resistant superbugs, and contaminates waterways and harms wildlife.

There’s no reason to expose yourself to antimicrobials like triclosan, as plain soap and water works just as well. In one study, published in the journal Annals of Internal Medicine,2 people who used antibacterial soaps and cleansers developed a cough, runny nose, sore throat, fever, vomiting, diarrhea and other symptoms just as often as people who used products that did not contain antibacterial ingredients.

The researchers pointed out that most of the symptoms experienced by the study participants are typically caused by viruses, which the antibacterial soaps won’t protect against anyway. And for the symptoms like vomiting and diarrhea, which may be caused by bacteria, the people who used regular soaps had no greater risk than those who used antibacterial products. So when washing your hands, stick with good old-fashioned non-antibacterial soap and water.

A Healthy Immune System Is Your ‘Secret Weapon’ to Avoid Getting Sick

There’s a common misconception that if you’re exposed to a germ, such as a flu virus, and it enters your body, you’re going to get sick. But simply being exposed to a virus or bacteria does not dictate whether or not you’ll get sick – the state of your immune system determines that. In one study, when 17 people were infected with a flu virus, only half of them got sick.3 The researchers found changes in blood took place 36 hours before flu symptoms showed up, and everyone had an immune response, regardless of whether or not they felt sick. But the immune responses were quite different…

In symptomatic participants, the immune response included antiviral and inflammatory responses that may be related to virus-induced oxidative stress. But in the non-symptomatic participants, these responses were tightly regulated. The asymptomatic group also had elevated expression of genes that function in antioxidant responses and cell-mediated responses.

The bottom line is, in half of the group their immune systems were able to effectively fight off the virus so they did not experience flu symptoms. So while hand washing is important, you’ll also want to be sure you are actively building up and nurturing your immune system to ‘catch’ any germs that do invade your body. How do you do this?

Top Lifestyle Tips for Staying Healthy

Healthy eating, regular stress reliefexercise, and proper sleep are the foundations of a healthy immune system. In particular, increasing your intake of fermented foods will nourish the healthful microorganisms in your gut (where about 80 percent of your immune system resides), allowing it to effectively fight off pathogenic microbes that find their way into your body.

The culturing process produces beneficial microbes that are extremely important for your health as they help balance your intestinal flora and produce a wide range of metabolic byproducts that benefit your health, e.g. lipoic acid, beta-glucans, infection-killing bacteriocins, etc. If you do not regularly consume traditionally fermented foods, a high-quality probiotic supplement will provide similar benefits. Along with eating naturally fermented foods and/or taking a high-quality supplement, it’s essential that you avoid sugar, including fructose.

Sugar feeds the growth of pathogenic bacteria, yeast, and fungi in your gut, which may actually harm you more than its adverse impact on insulin resistance. One of the major results of eating a healthy diet like the one described in my nutrition plan is that you cause your beneficial gut bacteria to flourish, and they secondarily perform the real “magic” of restoring your health and protecting you from the pathogenic germs that you will inevitably come across in your day-to-day life.

Source: mercola.com

NSA locates cell phones even when switched off .


Never mind the non-stop collection of metadata and other sneaky surveillance tools being implemented by the US: a new report has revealed the National Security Agency’s spy powers allow the government to grab location data on just about anyone.

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The technology was allegedly developed by the NSA in 2004 as part of the agency’s cooperation with the military, the CIA and the clandestine Joint Special Operations Command (JSOC). By the time NSA analysts and data collectors have been helping them for three years to track down and kill “high value targets” among terrorist and militant groups in Afghanistan and later Iraq, according to a Washington Post report.

The newspaper provides few further details on the technology, only saying that JSOC troops called it “The Find” and that it gave them thousands of new targets to track and attack. The article further describes how post-September 2001 the NSA made “a gigantic leap from using the nation’s most sophisticated spy technology to record the words of presidents, kings and dictators to using it to kill a single man in a terrorist group.”

The fact that a mobile phone doubles as a tracking device, which identifies the owner’s location in real time through a mobile network’s communication with the device, through spy software operating on the phone, or by some other means, is hardly secret. But it is widely considered that a phone that is turned off cannot emit signals and is thus untraceable.

Some privacy-cautious people suggest removing a battery as an extra precaution. More hardline privacy activists, like software freedom activist and founder of the Free Software Foundation Richard Stallman, don’t use cellphones at all, saying that they can be not only used for tracking, but also converted remotely into listening devices with specific spyware.

The NSA is currently the focus of much criticism after former contractor Edward Snowden leaked secret documents revealing that the agency is involved in massive worldwide collection of personal data. The agency is accused of trawling phone communications, emails, financial transactions and other records concerning hundreds of millions of people who are not suspected of any crimes or considered a threat to any country’s national security. Critics call it a gross violation of privacy.

The targeted killings of militants by US military and the CIA is another controversial practice of the Bush and the Obama administrations. It expanded greatly with the wide introduction of drone aircraft, which made such killings more affordable. Critics question it on many accounts, from dubious legal grounds to murky process for selection of targets to civilian casualties and public outcries that such killings prompt.

Source: http://rt.com

Stem cells reprogrammed using chemicals alone.


Patient-specific cells could be made without genetic manipulation.

Scientists have demonstrated a new way to reprogram adult tissue to become cells as versatile as embryonic stem cells — without the addition of extra genes that could increase the risk of dangerous mutations or cancer.

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Researchers have been striving to achieve this since 2006, when the creation of so-called induced pluripotent (iPS) cells was first reported. Previously, they had managed to reduce the number of genes needed using small-molecule chemical compounds, but those attempts always required at least one gene, Oct423.

Now, writing in Science, researchers report success in creating iPS cells using chemical compounds only — what they call CiPS cells1.

Hongkui Deng, a stem-cell biologist at Peking University in Beijing, and his team screened 10,000 small molecules to find chemical substitutes for the gene. Whereas other groups looked for compounds that would directly stand in for Oct4, Deng’s team took an indirect approach: searching for small-molecule compounds that could reprogram the cells in the presence of all the usual genes except Oct4.

Then came the most difficult part. When the group teamed theOct4 replacements with replacements for the other three genes, the adult cells did not become pluripotent, or able to turn into any cell type, says Deng.

Fine-tuning

The researchers tinkered with the combinations of chemicals for more than a year, until they finally found one that produced some cells that were in an early stage of reprogramming. But the cells still lacked the hallmark genes indicating pluripotency. By adding DZNep, a compound known to catalyse late reprogramming stages, they finally got fully reprogrammed cells, but in only very small numbers. One further chemical increased efficiency by 40 times. Finally, using a cocktail of seven compounds, the group was able to get 0.2% of cells to convert — results comparable to those from standard iPS production techniques.

The team proved that the cells were pluripotent by introducing them into developing mouse embryos. In the resulting animals, the CiPS cells had contributed to all major cell types, including liver, heart, brain, skin and muscle.

“People have always wondered whether all factors can be replaced by small molecules. The paper shows they can,” says Rudolf Jaenisch, a cell biologist at the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts, who was among the first researchers to produce iPS cells. Studies of CiPS cells could give insight into the mechanisms of reprogramming, says Jaenisch.

The frog’s secret

The achievement could even help regenerative biologists to work out how amphibians grow new limbs. Deng’s group found that one gene indicative of pluripotency, Sall4, was expressed much earlier in the CiPS-cell reprogramming process than in iPS-cell reprogramming. The same Sall4involvement is seen in frogs that regenerate a lost a limb4: before the regeneration, cells in the limb de-differentiate, a process akin to reprogramming, and Sall4 is active early in that process.

The discovery “provides an important framework to decipher the signalling pathways leading to Sall4expression” in regulating limb regeneration, says Anton Neff, who studies organ regeneration at Indiana University in Bloomington.

Sheng Ding, a reprogramming researcher at the Gladstone Institutes in San Francisco, California, says that the study marks “significant progress” in the field, but notes that chemical reprogramming is unlikely to be used widely until the team can show that it can work for human cells, not just mouse ones. Other strategies, including one that uses RNA, can complete reprogramming with less risk of disturbing the genes than the original iPS-generation method, and are already in use in humans. Indeed, clinical trials with iPS cells derived through such means are already being planned.

Deng has made some progress towards using his method in human cells, but it will require tweaks. ”Maybe some additional small molecules are needed,” he says.

If it the technique is found to be safe and effective in humans, it could be useful for the clinic. It does not risk causing mutations, and the compounds themselves seem to be safe — four of them are in fact already in clinical use. The small molecules can easily pass through cell membranes, so they can be washed away after they have initiated the reprogramming.

Source: Nature