The mere mention of the plague brings to mind the devastating “Black Death” pandemic that spread across Europe in the 1300s. Mass graves were piled high with the corpses of its millions of victims, while the disease rampaged across Europe for many decades. Yersinia pestis, the bacterium responsible for that plague pandemic, still persists in the environment among rodent and flea populations today, and human outbreaks regularly occur around the world. Most recently, an outbreak of plague was confirmed late last year in Madagascar as well as within a prairie dog colony in Colorado just this June.

Y. pestis can cause three different forms of plague: bubonic, pneumonic and septicemic. Pneumonic plague infects the lungs, causing severe pneumonia. It’s the most serious form of the disease, with fatality rates approaching 100% if untreated, although recovery is possible with antibiotics if caught in time. While increased basic hygiene and developments in modern medicine have greatly reduced the severity of plague outbreaks, the symptoms of pneumonic plague are so similar to that of the flu that misdiagnosis or delays in treatment can have fatal consequences.

Y. pestis is known to have evolved from the relatively mild gut pathogen Yersinia pseudotuberculosis sometime within the last 5,000 to 10,000 years – very recently on an evolutionary timescale. Sometime during this evolution Y. pestis developed new modes of transmission and disease manifestations, which allowed it to adapt to new animals and environments. Rather than simply causing an upset stomach, the bacterium became the killer we know from the Middle Ages.

One of our lab’s major research goals is to figure out how Y. pestis developed its ability to specifically cause pneumonic plague. Our research, recently published in Nature Communications, offers new insights into how small genetic changes fundamentally affected the emergence of Y. pestis as a severe respiratory pathogen.

Prior to our study, the consensus in the field has been that pneumonic plague was a secondary byproduct of the invasive disease associated with bubonic plague. As pneumonic plague represents only 5%–10% of current plague infections in humans, the field has presumed that pneumonic plague occurs only once Y. pestis reaches the lungs following systemic infection, as might occur during bubonic plague. While this may be the case now, it may not necessarily represent what occurred in the past, especially as Y. pestis was just emerging from its ancestor Y. pseudotuberculosis.

First, target the lungs

Therefore, we began our study by asking a relatively simple question: “When did Y. pestis develop the ability to infect the lung and cause pneumonic plague?” Remember, it was only recently, evolutionarily speaking, that it started targeting the lungs rather than the gut. Y. pestis is believed to have emerged as a species 5,000–10,000 years ago, but the first known pandemic of plague in humans didn’t occur until the Justinian Plague that afflicted the Byzantine empire about 1,500 years ago.

A recent discovery helped us investigate. Scientists successfully recovered DNA from Y. pestis from human skeletons in a Black Death mass grave in London, England. The genetic material from the historic site is very similar to DNA isolated from recent modern plague outbreaks. The fact that the DNA from then is similar to the DNA from now indicates that today’s Y. pestis has maintained its devastating disease-causing capability.

To answer the question of how Y. pestis made that crucial leap to targeting the lung and therefore being able to cause pneumonic plague, we used strains of both ancestral and modern Y. pestis in our study. These ancestral strains of Y. pestis, isolated from voles in the Transcauscaian highland, carry characteristics of both modern, pandemic Y. pestis and the relatively benign predecessor species Y. pseudotuberculosis that still exists today.

Thus, these ancestral versions can be considered “intermediate” strains, trapped somewhere between the gut Yersiniae and modern, virulent Y. pestis. Indeed, these “intermediate” lineage ancestral strains are as closely related to Y. pseudotuberculosis as we can get while still technically representing species of Y. pestis. Because of their unique genetic characteristics, these ancestral strains can provide crucial insights into how this bacterium may have adapted to new host environments as it evolved from Y. pseudotuberculosis.

Surprisingly, we found that these ancestral strains were able to cause pneumonic plague in a manner indistinguishable from that of modern Y. pestis in mice – but only if the bacteria carried the gene for a single protein called Pla. Pla is unique to Y. pestis and was acquired very early in the evolution of the species.

Almost all ancestral strains of Y. pestis carry the gene for Pla, but there still exist a few that represent ancestral Y. pestis just prior to acquisition of Pla. We were able to test if these pre-Pla strains were able to cause pneumonic plague – and they did not. But as soon as Y. pestis picked up this gene, the bacteria could cause epidemics of pneumonic plague. No further changes were necessary, even though there are dozens of additional differences between these ancestral strains and modern Y. pestis. So Y. pestis was able to cause pneumonic plague much earlier in its history than had previously been thought – as soon as it acquired this single gene for Pla.

Second, increase infectiousness

But that’s not where the story ends. It turns out that all modern pandemic strains of Y. pestis contain a single amino acid mutation in Pla compared to ancestral Y. pestis. This change slightly alters the function of the Pla protein. The mutation, however, plays no role in the ability of any Y. pestis isolates to cause pneumonic plague – ancestral or modern.

Quite surprisingly, this modification allowed the Y. pestis to spread deeper into host tissue following a bite from an infected flea or rodent, leading to the development of bubonic plague with its trademark swollen lymph nodes. This suggests that Y. pestis was first a respiratory pathogen before it was able to efficiently cause invasive infections.

This discovery challenges our traditional notion of how plague evolved. Rather than pneumonic plague being a late addition to Y. pestis’s arsenal as commonly believed, its ability to target the lung came before the change that makes it such an infectious pathogen. Our research suggests that the acquisition of Pla and its ability to cause pneumonic plague occurred well before 1,500–5,000 years ago. But the amino acid modification didn’t occur until just prior to 1,500 years ago, allowing Y. pestis to become much more deadly. All strains of Y. pestis from the time of the Justinian Plague and after have the deadly modification of Pla, while strains prior do not.

Our results may explain how, through one small amino acid change, Y. pestis quickly transitioned from causing only localized outbreaks of disease to the pandemic spread of Y. pestis as seen during the Justinian Plague and the Black Death.

And it raises the ominous possibility that other respiratory pathogens could emerge from similar small genetic changes.

Daniel Zimbler is Postdoctoral Fellow in Bacteriology at Northwestern University.
Wyndham Lathem is Assistant Professor of Microbiology-Immunology at Northwestern University.

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This article is part of a series The Conversation Africa is running on issues related to LGBTI in Africa. You can read the rest of the series here.

People who are attracted to others of the same sex develop their orientation before they are born. This is not a choice. And scientific evidence shows their parents cannot be blamed.

Research proving that there is biological evidence for sexual orientation has been available since the 1980s. The links have been emphasised by new scientific research.

In 2014, researchers confirmed the association between same-sex orientation in men and a specific chromosomal region. This is similar to findings originally published in the 1990s, which, at that time, gave rise to the idea that a “gay gene” must exist. But this argument has never been substantiated, despite the fact that studies have shown that homosexuality is a heritable trait.

Evidence points towards the existence of a complex interaction between genes and environment, which are responsible for the heritable nature of sexual orientation.

These findings are part of a report released by the Academy of Science South Africa. The report is the outcome of work conducted by a panel put together in 2014 to evaluate all research on the subject of sexual orientation done over the last 50 years.

It did this against the backdrop of a growing number of new laws in Africa which discriminate against people attracted to others of the same sex. The work was conducted in conjunction with the Ugandan Academy of Science.

Existing research

The academy looked at several scientific studies with different focus areas that have all provided converging findings. These include family and twin studies. The studies have shown that homosexuality has both a heritable and an environmental component.

Family studies have shown that homosexual men have more older brothers than heterosexual men. Homosexual men are also more likely to have brothers that are also homosexual. Similarly, family studies show that lesbian women have more lesbian sisters than heterosexual women.

Studies on identical twins are important as identical twins inherit the same genes. This can shed light on a possible genetic cause. Studies on twins have established that homosexuality is more common in identical (monozygotic) twins than in non-identical (dizygotic) twins. This proves that homosexuality can be inherited.

However, the extent of the inheritance between twins was lower than expected. These findings contribute to the notion that although homosexuality can be inherited, this does not occur according to the rules of classical genetics. Rather, it occurs through another mechanism, known as epigenetics.

Epigenetics likely to be an important factor

Epigenetics relates to the influence of environmental factors on genes, either in the uterus or after birth. The field of epigenetics was developed after new methods were found that identify the molecular mechanisms (epi-marks) that mediate the effect of the environment on gene expression.

Epi-marks are usually erased from generation to generation. But under certain circumstances, they may be passed on to the next generation.

Normally all females have two X-chromosomes, one of which is inactive or “switched off” in a random manner. Researchers have observed that in some mothers who have homosexual sons there is an extreme “skewing” of inactivation of these X-chromosomes. The process is no longer random and the same X-chromosome is inactivated in these mothers.

This suggests that a region on the X-chromosome may be implicated in determining sexual orientation. The epigenetics hypothesis suggests that one develops a predisposition to homosexuality by inheriting these epi-marks across generations.

External environmental factors such as medicinal drugs, chemicals, toxic compounds, pesticides and substances such as plasticisers can also have an impact on DNA by creating epi-marks.

These environmental factors can also interfere with a pregnant woman’s hormonal system. This affects the levels of sex hormones in the developing foetus and may influence the activity of these hormones.

Future studies will determine whether these factors may have a direct impact on areas of the developing brain associated with the establishment of sexual orientation.

Looking to evolution

From an evolutionary perspective, same-sex relationships are said to constitute a “Darwinian paradox” because they do not contribute to human reproduction. This argument posits that because same-sex relationships do not contribute to the continuation of the species, they would be selected against.

If this suggestion were correct same-sex orientations would decrease and disappear with time. Yet non-heterosexual orientations are consistently maintained in most human populations and in the animal kingdom over time.

There also appear to be compensating factors in what is known as the “balancing selection hypothesis”, which accounts for reproduction and survival of the species. In this context, it has been demonstrated that the female relatives of homosexual men have more children on average than women who do not have homosexual relatives.

Future studies

The academy found that a multitude of scientific studies have shown sexual orientation is biologically determined. There is not a single gene or environmental factor that is responsible for this – but rather a set of complex interactions between the two that determines one’s sexual orientation.

However, more evidence is leading investigators to a specific region on the X-chromosome, and possibly a region on another chromosome.

The identification of these chromosomal regions does not imply that homosexuality is a disorder – nor does it imply that there are mutations in the genes in these regions, which still remain to be identified. Rather, for the first time, it suggests that there is a specific region on a chromosome that determines sexual orientation.

Although research has not yet found what the precise mechanisms are that determine sexual orientation – which may be heterosexual, homosexual, bisexual or asexual – the answers are likely to come to the fore through continued research. These findings will be important for the field of genetics and, more importantly, for those attracted to others of the same sex and society as a whole.

This article draws from the ASSAf report.

Michael Sean Pepper is Director of the Institute for Cellular and Molecular Medicine at University of Pretoria.
Beverley Kramer is Assistant Dean: Research and Postgraduate Support in the Faculty of Health Sciences at University of the Witwatersrand.

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For most of the common cancers, a major cause has been identified: smoking causes 90% of lung cancer worldwide, hepatitis viruses cause most liver cancer, H pylori bacteria causes stomach cancer, Human papillomavirus causes almost all cases of cervical cancer, colon cancer is largely explained by physical activity, diet and family history.

But for breast cancer, there is no smoking gun. It is almost unique among the common cancers of the world in that there is not a known major cause; there is no consensus among experts that proof of a major cause has been identified.

Yet, breast cancer is the most common form of cancer in women worldwide. The risk is not equally distributed around the globe, though. Women in North America and Northern Europe have long had five times the risk of women in Africa and Asia, though recently risk has been increasing fast in Africa and Asia for unknown reasons.

Is diet to blame?

Up until about 20 years ago, we thought it was all about diet. As people abandon their local food sources and begin to eat highly processed foods with lots of fats, the hypothesis went, breast cancer was thought to be more likely to develop.

This hypothesis was logical because when researchers analyzed countries’ per capita fat consumption and breast cancer mortality rates, they found a strong correlation. In addition, rats fed a high-fat diet are more prone to breast tumors.

By studying Japanese migrants to California, researchers found that the first generation had low risk like their parents in Japan, but then by the second and third generation, risk was as high as white American women. So, the genetics of race did not account for the stark differences in the breast cancer risk between Asia and America. This was also consistent with the idea that the change in food from the lean Asian diet to the high-fat American diet causes cancer. So it all made sense.

Until it didn’t.

Diet studies find that fat is not the answer

Starting in the mid-1980s, large, well-done prospective studies of diet and breast cancer began to be reported, and they were uniformly negative. Fat in the diet of adult women had no impact on breast cancer risk at all.

This was very surprising – and very disappointing. The evidence for other aspects of diet, like fruits and vegetables, has been mixed, though alcohol consumption does increase risk modestly. It is also clear that heavier women are at higher risk after menopause which might implicate the total amount of calories consumed if not the composition of the diet.

There is a chance that early life dietary fat exposure, even in utero, may be important, but it’s difficult to study in humans, so we don’t know much about how it might relate to breast cancer risk later in life.

If diet is not the major cause of breast cancer, then what else about modernization might be the culprit?

Two kinds of risk factors: what we can modify, and what we can’t

The factors shown to affect a woman’s risk for developing breast cancer fall into two categories. First, those that cannot be easily modified: age at menarche, age at birth of first child, family history, genes like BRCA1. And second, those that are modifiable: exercise, body weight, alcohol intake, night-work jobs.

The role of environmental pollution is controversial and also difficult to study. The concern about chemicals, particularly endocrine disruptors, started after the realization that such chemicals could affect cancer risk in rodent models. But in human studies the evidence is mixed.

Because child bearing at a young age and breast feeding reduce risk, the incidence throughout Africa, where birth rates tend to be higher, and where women start their families at younger ages, has been lower.

Death rates, however, from breast cancer in sub-Saharan Africa are now almost as high as in the developed world despite the incidence still being much lower. This is because in Africa, women are diagnosed at a later stage of disease and also because there are far fewer treatment options.

The question is whether the known risk factors differ enough between the high-risk modern societies and the low-risk developing societies to account for the large differences in risk. The answer: probably not. Experts think that less than half the high risk in America is explained by the known risk factors, and that these factors explain very little of the difference in risk with Asia.

A related question is whether the high risk in America and Northern Europe is due to a combination of many known exposures, each of which affects risk a little bit, or mostly due to a major cause that has so far eluded detection. And maybe some of the known risk factors have a common cause which we don’t yet understand.

Are we just finding more cancer?

Since the 1980s, screening by mammography has accounted for some of the increase in incidence in the modern world compared to the developing world, but not nearly enough to explain the entire difference. About 20% of the cancers found by mammography are now believed to be of a type that would never have progressed beyond the very small early stage that mammography can detect. But the problem is that we can’t tell which are the benign ones and which are not.

What about electric light?

Electric light is a hallmark of modern life. So, maybe the introduction and increasing use of electricity to light the night accounts for a portion of the worldwide breast cancer burden.

This might be because our circadian rhythm is disrupted, which affects hormones that influence breast cancer development. For example, electric light at night can trick the body into daytime physiology in which the hormone melatonin is suppressed; and melatonin has been shown to have a strong inhibitory effect on human breast tumors growing in rats.

The theory is easy to state but difficult to test in a rigorous manner. Studies have shown that night-working women are at higher risk than day-working women, which was the first prediction of the theory.

Other predictions are that blind women would be at lower risk, short sleepers would be at higher risk, and more highly lighted communities at night would have higher breast cancer incidence. Each of these has some modest support though none are conclusive. What we do know is that electric light in the evening or at night can disrupt our circadian rhythms, and whether this harms our long term health, including risk of breast cancer, is not yet clear.

Whatever is going on, it’s important to find answers because breast cancer has become a scourge that now afflicts women all over the world in very large numbers, at almost two million new cases this year alone.

This article was originally published on The Conversation.
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The number of people with insurance coverage for alcohol and drug abuse disorders is about to explode at a time there’s already a severe shortage of trained behavioral health professionals in many states.

Until now, there’s been no data on just how severe the shortage is and where it’s most dire.  Jeff Zornitsky of the health care consulting firm Advocates for Human Potential (AHP) has developed the first measurement of how many behavioral health professionals are available to treat millions of adults with a substance use disorder, or SUD, in all 50 states.

Zornitsky’s “provider availability index” – the number of psychiatrists, psychologists, counselors and social workers available to treat every 1,000 people with SUD – ranges from a high of 70 in Vermont to a low of 11 in Nevada. Nationally, the average is 32 behavioral health specialists for every 1,000 people afflicted with the disorder.  No one has determined what the ideal number of providers should be, but experts agree the current workforce is inadequate in most parts of the country.

“Right now we’re in a severe workforce crisis,” said Becky Vaughn, addictions director for the industry organization National Council for Behavioral Health.  The shortage has consequences, she said. “When people need help for addictions, they need it right away. There’s no such thing as a waiting list. If you put someone on a waiting list, you won’t be able to find them the next day.”

The shortage of specialists threatens to stall a national movement to bring the prevention and treatment of SUD into the mainstream of American medicine at a time when millions of people with addictions have a greater ability to pay for treatment thanks to insurance.

Two Federal Laws

The Affordable Care Act for the first time requires all insurers, including Medicaid, to cover the treatment of drug and alcohol addiction.  In the past, Medicaid covered only pregnant women and adolescents in most states. Private insurance either didn’t pay for treatments or paid so little that most people could not afford to make up the difference.

For anyone with insurance coverage, the Mental Health Parity and Addiction Equity Act ensures that the duration and dollar amount of coverage for substance use disorders is comparable to coverage for medical and surgical care. Together, the two federal laws are expected to make billions of dollars available to the behavioral health care market.

Of the estimated 18 million adults potentially eligible for Medicaid in all 50 states, at least 2.5 million have substance use disorders. Of the 19 million uninsured adults with slightly higher incomes who are eligible for subsidized exchange insurance, an estimated 2.8 million struggle with substance abuse, according to the most recent national survey by the U.S. Substance Abuse and Mental Health Services Administration.

Although the federal government has acknowledged the scarcity of treatment specialists, it has failed to quantify and assess it. Other fields of health care, including mental health and primary care, are tracked by the U.S. Health Resources and Services Administration to determine which communities are “underserved.”  Without this information, it is hard to know where more behavioral health specialists are needed and when the supply of providers is expanding or shrinking in any given region.

That’s where AHP’s Zornitsky steps in. Using data from the U.S. Department of Labor’s Bureau of Labor Statistics on the current size of the labor force and its projected growth, plus Department of Health and Human Services data on the prevalence of SUD among adults, he approximates the relative adequacy of the addiction treatment workforce in each state.

“It is not perfect,” Zornitsky said of the index, “but it’s a consistent, state-based measure that allows for comparisons and tracking over time.”

Poor Pay

According to a 2013 report to Congress from the Substance Abuse and Mental Health Services Administration, the “growing workforce crisis in the addictions field” is due to a variety of factors, including stigma, an aging workforce and inadequate compensation.

The U.S. spent $24 billion on treatment of drug and alcohol disorders in 2009, the most recent year for which comprehensive data are available, according to a new study by the Pew Charitable Trusts (Pew also funds Stateline).  Sixty-nine percent of the spending came from public sources such as state and local governments, Medicaid, Medicare and federal grants. Private sources, including commercial insurance and out-of-pocket spending, made up the balance, according to the report.

Historically, reimbursement rates and consequently salaries for physicians, psychologists, social workers and counselors in the addiction field have been well below salaries for comparable professionals in other health care specialties that require the same level of education and training.

For example, the average salary for social workers in the addiction field is $38,600, compared to $47,230 in the rest of the health care industry, according to the Bureau of Labor Statistics.

As a result, too few health care workers are going into the field and too many are switching to more lucrative specialties. And because the average age of addiction specialists is higher than in other professions, demographers predict a behavioral health retirement boom in the next five years.

Between now and 2020, the addiction services field will need to fill more than 330,000 jobs to keep pace with demand, of which more than half are the result of people retiring and switching to other occupations.

Low Treatment Rates

Of the roughly 23 million Americans who suffer from drug and alcohol disorders, only 11 percent receive treatment at a specialty facility, according to the most recent National Survey on Drug Use and Health.

That compares to U.S. treatment rates as high as 80 percent for diseases such as diabetes and hypertension. Part of the reason for lack of treatment has been inability to pay. With billions in private insurance and Medicaid dollars becoming available, that is expected to change.

But questions remain about how the existing addiction services industry will manage the expansion, whether new businesses will enter the market and how many providers will take Medicaid patients. Today, only 55 percent of addiction practitioners accept Medicaid reimbursements, which tend to be lower than private insurance.

Another reason many substance abusers go without treatment is the social stigma connected with addictions and mental illness. To avoid being labeled, many hide their drug or alcohol use, and refuse to admit they have a problem. With more money available for treatment and increased public concern over the nation’s rising death toll from drug addictions, experts are hopeful the stigma will dissipate and more health care professionals will be drawn to the field.

The Affordable Care Act eventually should spur more competitive salaries for behavioral health professionals. But for now, it is complicating matters, Vaughn said. Both Medicaid and private insurers require levels of professional licensing and credentialing that were not needed when addiction services were funded primarily by federal grants. In addition, many of the mostly small providers in the industry have no business experience negotiating contracts with Medicaid managed care organizations or filing claims for Medicaid and private insurance.

It will be largely up to states to make the changes needed to develop an adequate addiction treatment workforce. The federal government has offered model licensing guidelines that define a so-called “scope of practice” for each job title in the behavioral health profession, but states will have to create licensing laws and regulations. States could also encourage more people to go into the profession by offering to repay student loans and funding local colleges.

In addition, state Medicaid agencies will need to reach out to the existing addiction industry and provide business training to enable them to file claims for the billions in new funding for drug and alcohol treatments. Most important, Vaughn said, Medicaid rates for addiction services need to be raised to provide a reimbursement benchmark that is closer to the fees paid to practitioners in other health care professions.