Category: Diseases

Tufts Medical Center researchers find new functions of blood cell protein in transplantation

Tufts Medical Center researchers find new functions of blood cell protein in transplantation

BOSTON (August 11) – Tufts Medical Center and Tufts University scientists have found exciting, new functions of the protein angiogenin (ANG) that play a significant role in the regulation of blood cell formation, important in bone marrow transplantation and recovery from radiation-induced bone marrow failure. Since current bone marrow transplantations have significant limitations, these discoveries may lead to important therapeutic interventions to help improve the effectiveness of these treatments. The findings were published in an article, “Angiogenin promotes hematopoietic regeneration by dichotomously regulating quiescence of stem and progenitor cells,” in the August 11, 2016 issue of the journal Cell.

In the paper, the researchers show for the first time that ANG simultaneously reduces proliferation of stem cells and promotes proliferation of myeloid progenitor cells that give rise to mature myeloid cells. They further report that these two-pronged processes are accomplished by a novel molecular regulating mechanism, a first-ever such finding.

These findings have significant implications for both human stem cell transplantation and for radiation exposure. Cancer patients undergoing stem cell transplantation face two hurdles: the short-term challenge of having enough white blood cells to fight possible infections immediately following the transplant and the long-term challenge of sustaining stem cell function to maintain immunity. People exposed to large doses of radiation face challenges due to bone marrow failure induced by such exposures.

“We knew that ANG was involved in promoting cell growth so it was not unexpected to find that ANG stimulates proliferation of myeloid progenitor cells,” said Guo-fu Hu, PhD, Investigator in the Molecular Oncology Research Institute at Tufts Medical Center, and the paper’s senior author. “But it was surprising to find that ANG also suppresses growth of stem cells and that it accomplishes these divergent promotion or suppression functions through RNA processing events specific to individual cell types. Our discoveries suggest considerable therapeutic potential.”

Dr. Hu also serves as faculty in the Biochemistry; Cell, Molecular & Developmental Biology; and Cellular & Molecular Physiology programs at the Sackler School of Graduate Biomedical Sciences at Tufts.

In a series of experiments, the team from Tufts MC and the Sackler School at Tufts, which collaborated with scientists at Massachusetts General Hospital, isolated and described the divergent regulatory functions of ANG. They demonstrated how ANG stimulates proliferation of myeloid progenitor cells. They showed how ANG maintains stem cells by inducing a state of quiescence, or cellular dormancy, the first known evidence of ANG’s suppressive activity. Quiescence preserves stem cells over time so that they will be available in the future to help maintain immunity.

In another novel finding, the team demonstrated that ANG achieves these dual functions by inducing RNA processing that is different in various cell types. In hematopoietic stem/progenitor cells, ANG induces processing of a specific type of RNA (tiRNA) that is quiescence-related whereas in myeloid progenitor cells, ANG induces processing of a specific type of RNA (rRNA) that is proliferation related. tiRNA is a type of small RNA that suppresses global protein synthesis, while rRNA or ribosomal RNA is a type of RNA molecule that enhances protein synthesis.

“Proper blood cell production is dependent on functioning hematopoietic stem and progenitor cells that are destroyed during conditioning procedures for transplantation or following bone marrow injury,” said the study’s first author Kevin A. Goncalves, who performed this research as part of his PhD studies in cellular and molecular physiology at the Sackler School. “Our study demonstrates that ANG regulates critical functions of both clinically-relevant cell types.”

In further studies, the researchers tested the capacity of ANG to prevent and mitigate radiation-induced bone marrow failure, and in pre-clinical models, they found that survival following radiation exposure was increased after treatment with recombinant ANG protein.

A complementary paper, “Proximity-Based Differential Single-Cell Analysis of the Niche to Identify Stem/Progenitor Cell Regulators,” published online on August 11, 2016 in the journal Cell Stem Cell, reports the discovery and confirmation of ANG as a niche regulator.

Additional authors are Shuping Li, MD, PhD, Miaofen G. Hu, MD, PhD from Tufts Medical Center; Hailing Yang, PhD, a recent graduate of the Sackler School; and Lev Silberstein, PhD and Nicolas Severe, PhD from Massachusetts General Hospital and Harvard University. David Scadden, MD, also from Massachusetts General Hospital and Harvard University is co-corresponding author.

This study was supported by the National Institutes of Health, specifically the National Cancer Institute (award R01CA105241), the National Institute of Neurological Disorders and Stroke (award R01NS065237), the National Heart, Lung, and Blood Institute (awards R01HL097794 and F31HL128127), and the National Institute of Diabetes and Digestive and Kidney Diseases (award R01DK050234); the United States Department of Defense (W81XWH-15-1-02070); the National Natural Science Foundation of China (81272674); the Leukemia & Lymphoma Research UK/Leukemia & Lymphoma Society fellowships; a Sackler Dean’s Fellow award; and a Sackler Families Collaborative Cancer Biology award.

Cell types like astrocytes regulate metabolic processes  Discovery of a brain sugar switch

Cell types like astrocytes regulate metabolic processes Discovery of a brain sugar switch

Researchers at the Technical University of Munich (TUM) discovered that our brain actively takes sugar from the blood. Prior to this, researchers around the world had assumed that this was a purely passive process. An international team led by diabetes expert Matthias Tschöp reported in the journal ‘Cell’ that transportation of sugar into the brain is regulated by so-called glia cells that react to hormones such as insulin or leptin; previously it was thought that this was only possible for neurons.

The rapid rise in obesity and the associated spread of type 2 diabetes represent an enormous challenge for our society. No efficient and safe medicines to prevent or stop this development are available. The failure to develop adequate treatments is thought to be primarily due to the fact that the molecular machinery controlling systemic metabolism still remains mostly unknown.

METABOLIC CONTROL: FUEL FOR THE HEADQUARTERS

Matthias Tschöp of the Chair for Metabolic Diseases at TUM and Director of the Division of Metabolic Diseases and also of the Helmholtz Diabetes Center (HDC) at Helmholtz Zentrum München, is investigating how control centers in the brain remotely control our metabolism in order to adjust optimally to our environment. The brain has the highest sugar consumption of all organs and also controls for example hunger feelings.

“We therefore suspected that a process as important as providing the brain with sufficient sugar was unlikely to be completely random,” so Dr. Cristina García-Cáceres, neurobiologist at the HDC and the study’s lead author. “We were misled by the fact that nerve cells apparently did not control this process and therefore first thought it to occur passively. Then we had the idea that glia cells such as astrocytes*, which had long been misunderstood as less important ‘support cells’, might have something to do with transporting sugar into the brain.”

The scientists therefore first examined the activity of insulin receptors on the surface of astrocytes, molecular structures which respond to insulin to influence cell metabolism. Here they found that if this receptor was missing on certain astrocytes the result was less activity in neurons that curb food uptake (proopiomelanocortin neurons).

At the same time, adaption of metabolism to challenges like sugar intake became impaired. With the help of advanced imaging technologies such as positron emission tomography, the scientists were able to show that hormones such as insulin and leptin act specifically on ‘support’ glia cells to regulate sugar intake into the brain, like a ‘sugar switch’. Without insulin receptors, astrocytes became less efficient in transporting glucose into the brain, particularly in the area of the satiety centers, which are located in the hypothalamus.

A PARADIGM SHIFT

“Our results showed for the first time that essential metabolic and behavioral processes are not regulated via neuronal cells alone and that other cell types in the brain, such as astrocytes, play a crucial role,” explains study leader Matthias Tschöp, who also heads the drug discovery division at the German Center for Diabetes Research (DZD). “This represents a paradigm shift and could help explain why it has been so difficult to find sufficiently efficient and save medicines for diabetes and obesity until now.”

According to the scientists, numerous new studies will now be necessary to adjust the old model of purely neural control of food intake and metabolism with a concept where astrocytes and possibly even immune cells in the brain also play a crucial role. Once there is a better understanding of the interaction between these various cells, the idea is to find ways and substances that modulate pathways on multiple cell types to curb sugar addiction and ultimately provide better treatment to the growing number of obese and diabetic individuals. “We have a lot of work ahead of us,” states García-Cáceres, “but at least now we have a better idea where to look.”

BACKGROUND:

* Astrocytes are the most common cells in the brain. One of their jobs is to form the blood-brain barrier by enclosing the blood vessels that run in the brain and selectively allowing only certain substances through to the nerve cells.

Just recently the scientists had already shown that astrocytes react to leptin, a metabolic hormone (Kim et al., 2014). This is an important factor for satiety. Because now both leptin and insulin have been shown to influence astrocytes, the researchers propose to develop a new model which, in addition to the neurons, also takes into account the astrocytes as the adjustors of the metabolism and the feeling of hunger. They hope that the more detailed view this produces will provide new perspectives for drug development.

2 Polio Paralysis Cases in Nigeria Set Back Eradication Effort

2 Polio Paralysis Cases in Nigeria Set Back Eradication Effort

In a serious setback to the drive to eradicate polio from the world, two cases of paralysis caused by the virus have been detected in northeast Nigeria, the World Health Organization announced Thursday.

The discovery dashed the hopes of global health authorities to be able to declare the continent polio-free soon. Nigeria’s last case of wild polio virus was reported in July 2014. The continent’s last was reported in Somalia a month after that. The W.H.O. requires three years with no confirmed cases before declaring a region polio-free.

“We are deeply saddened by the news,” said Dr. Matshidiso Moeti, the W.H.O. regional director for Africa. “The overriding priority now is to immunize all children around the affected area.”

Polio paralyzes only about one child of every 200 infected, and in dangerous or remote regions, many cases of paralysis are never detected, so health authorities assume the virus is far more widespread than two cases would suggest.

Until Thursday, the last known cases of paralysis caused by “wild” virus were all in Pakistan and Afghanistan. (Vaccination in many countries is still done with oral drops containing weakened live virus, which sometimes mutates to become more dangerous and start outbreaks of “vaccine-derived polio,” which also can paralyze. While alarming, those outbreaks can usually be brought under control quickly with further vaccination.)

As recently as 2012, Nigeria accounted for more than half of all polio cases worldwide. Interrupting polio transmission in Africa was considered a major public health triumph. Only two diseases — smallpox and rinderpest, a veterinary disease — have ever been eradicated from the earth, and in both of them the last cases were found in Africa. The last few hundred cases of Guinea worm, or dracunculiasis, the only other disease as close to eradication as polio is, are also confined to Africa.

Genetic sequencing of the Nigerian virus suggests that the new cases were caused by a wild strain last detected in Borno State, Nigeria, in 2011, which implies that it circulated for five years without being detected. Raids by Boko Haram, the Islamic fundamentalist militia — including the kidnapping of 200 schoolgirls in Chibok two years ago — as well as fighting between Boko Haram and the Nigerian Army have made many areas off limits for vaccinators and surveillance specialists.

Massacres and fighting have driven thousands from their home villages. “That fluid movement of population complicates understanding of exactly where they’ve ended up,” said John F. Vertefeuille, director of polio eradication for the Centers for Disease Control and Prevention in Atlanta.

“This is a setback, but we need to double our effort to make sure we interrupt transmission,” he added.

Advances by the Nigerian Army this year have opened up new areas in Borno that were formerly off limits, and a case of paralysis caused by mutant polio vaccine was detected in March, prompting the increased surveillance that led to the discovery of the newest cases, Dr. Vertefeuille said.

The Bill and Melinda Gates Foundation has taken over much of the cost of the polio eradication drive from Rotary International, which began it in 1988. The cost has recently been over $1 billion a year. In a statement, the foundation said it was “deeply concerned” about the Nigeria cases but “remained strongly committed to supporting partners, governments and communities until the job is done.”

With Congress Deadlocked, White House Diverts Funds to Fight Zika

With Congress Deadlocked, White House Diverts Funds to Fight Zika

WASHINGTON — The Obama administration on Thursday said it was shifting $81 million away from biomedical research and antipoverty and health care programs to pay for the development of a Zika vaccine, resorting to extraordinary measures because Congress has failed to approve new funding to combat the virus.

Sylvia Mathews Burwell, the secretary of health and human services, told members of Congress in a letter that without the diverted funds, the National Institutes of Health and the Biomedical Advanced Research and Development Authority would run out of money to confront the mosquito-borne illness by the end of the month. That would force the development of a vaccine to stop at a critical time, as locally acquired cases of Zika infection increase in Miami.

As of last week, 7,350 cases of Zika had been reported in the United States, most in Puerto Rico, according to the Centers for Disease Control and Prevention. Ms. Burwell said that 15 infants had been born with Zika-related birth defects. The virus can cause abnormal brain development and other serious defects in children born to infected mothers.

The local spread of the illness in the continental United States, with the first cases reported late last month, has raised the political stakes surrounding the federal government’s response. Hillary Clinton on Tuesday made a campaign stop in Wynwood, the Miami neighborhood that has had a rash of locally transmitted Zika cases, and pressed Congress to return from its five-week break to approve emergency funding to fight the virus.

President Obama and congressional Republicans have been at odds for most of the year over Zika. In February, Mr. Obama requested $1.9 billion in emergency funding. Republicans balked, demanding a more detailed accounting of where the money would go.

Lawmakers have feuded for months over how much money should be earmarked and how it should be spent. Last month, Democrats blocked consideration of a Republican measure that would have allocated $1.1 billion to fight Zika but included provisions that would have banned funding for Planned Parenthood to provide contraception related to the virus, which can be sexually transmitted.

The deadlock prompted the White House in April to shift $589 million in Ebola funding to the Zika effort, about two-thirds of it designated for domestic use. On Thursday, Ms. Burwell said that her department had used most of that money, and that it would be gone by the end of August.

“The failure to pass a Zika emergency supplemental has forced the administration to choose between delaying critical vaccine development work and raiding other worthy government programs to temporarily avoid these delays,” Ms. Burwell wrote.

Democrats seized on the announcement to berate Republicans for failing to provide additional money for Zika. At a news conference, Representative Nancy Pelosi of California, the minority leader, called on Representative Paul D. Ryan, the House speaker, to bring Congress back to advance such a measure.

“Every possible option is being exhausted, and now we’re going into the National Institutes of Health, which is supposed to be a priority,” Ms. Pelosi said.

Aides to Mr. Ryan said that shifting the funds was a long-overdue step that the Obama administration had delayed to squeeze maximum political advantage out of the Zika issue.

The National Institutes of Health announced last week that it had begun clinical trials of a Zika vaccine on 80 human subjects, and hoped to begin a second phase in “Zika-endemic countries” in early 2017. But without more funding now, officials said Thursday, the research would halt in its tracks.

Ms. Burwell said she would transfer to the Zika efforts $34 million in N.I.H. funds that had been designated to find treatments for other diseases, including cancer and diabetes.

Another $47 million will be transferred to the Biomedical Advanced Research and Development Authority, which supports the development of drugs and vaccines to respond to public health emergencies. That money will come out of a variety of accounts, including $19 million from a program that supplies heating oil subsidies for low-income families and $4 million from substance abuse programs such as those for opioid addiction.

Even then, Ms. Burwell said, the additional money will last only through next month, at which point agencies would have to “severely curtail many of their critical efforts” against Zika without action from Congress.

In the last four months, the Centers for Disease Control and Preventionspent $60 million to help states protect pregnant women, $25 million to strengthen their Zika preparedness and response plans, and $16 million to help them create data-collection systems to quickly detect microcephaly and other Zika-related syndromes.

Incidence of Neonatal Abstinence Syndrome

Incidence of Neonatal Abstinence Syndrome

Neonatal abstinence syndrome (NAS) is a postnatal drug withdrawal syndrome that occurs primarily among opioid-exposed infants shortly after birth, often manifested by central nervous system irritability, autonomic overreactivity, and gastrointestinal tract dysfunction (1). During 2000–2012, the incidence of NAS in the United States significantly increased (2,3). Several recent publications have provided national estimates of NAS (2,3); however, data describing incidence at the state level are limited. CDC examined state trends in NAS incidence using all-payer, hospital inpatient delivery discharges compiled in the State Inpatient Databases of the Healthcare Cost and Utilization Project (HCUP) during 1999–2013. Among 28 states with publicly available data in HCUP during 1999–2013, the overall NAS incidence increased 300%, from 1.5 per 1,000 hospital births in 1999, to 6.0 per 1,000 hospital births in 2013. During the study period, significant increases in NAS incidence occurred in 25 of 27 states with at least 3 years of data, with annual incidence rate changes ranging from 0.05 (Hawaii) to 3.6 (Vermont) per 1,000 births. In 2013, NAS incidence ranged from 0.7 cases per 1,000 hospital births (Hawaii) to 33.4 cases per 1,000 hospital births (West Virginia). The findings underscore the importance of state-based public health programs to prevent unnecessary opioid use and to treat substance use disorders during pregnancy, as well as decrease the incidence of NAS.

NAS is a postnatal withdrawal syndrome that comprises a constellation of symptoms in newborns, including central nervous system irritability (e.g., tremors, increased muscle tone, high-pitched crying, and seizures), gastrointestinal dysfunction (e.g., feeding difficulties), and temperature instability (1). Although other substances have been implicated, NAS is most often attributed to in utero opioid exposure. This exposure can result from maternal prescription opioid use, which has increased nationally in recent years (2,4), nonmedical opioid use, or medication-assisted treatment, which is long-term treatment with a longer acting but less euphoric opioid under medical supervision for opioid use disorder. Data on long-term developmental outcomes related to opioid exposure during pregnancy and NAS are limited.

The State Inpatient Databases include de-identified administrative data from all hospital inpatient discharges in a given state, regardless of payer. Data from State Inpatient Databases are compiled by state partners and then translated into a uniform format as part of HCUP, which is sponsored by the Agency for Healthcare Research and Quality. This analysis includes data from 28 states* whose data for 1999–2013 were publicly available on HCUP’s online central distributor (https://www.hcup-us.ahrq.gov/tech_assist/centdist.jsp). Consistent with previous methodology (2,3), in-hospital births were identified using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes V30.X–V39.X ending in 00 or 01 (indicating single or multiple live born infants), among all hospital discharge records during 1999–2013. Discharge records that did not have a principal or secondary diagnosis code indicating a hospital birth, or that indicated a transfer from another acute care hospital or health care facility, were excluded. Cases of NAS were identified with ICD-9-CM code 779.5 (drug withdrawal syndrome in a newborn). Cases of possible iatrogenic withdrawal, resulting from complications related to prolonged neonatal intensive care stay and not exposure during the antenatal period (ICD-9-CM codes: 765.01–765.05, 770.7, 772.1X, 779.7, 777.5X, 777.6), were excluded from the numerator.

Total incidence rates of NAS (cases per 1,000 births) were calculated for 1999 and 2013, using data available from 14 and 21 states, respectively. In addition, incidence rates of NAS were calculated for each state and year with available data during 1999–2013. Linear trends were assessed using logistic regression with NAS incidence as the outcome variable and infant birth year as the independent variable for the 27 states with at least 3 years of data. Annual incidence rate changes, which reflect average annual change in the incidence rate of NAS over time, were calculated from the beta coefficient of the infant’s birth year with a state-specific intercept for states with significant linear trends. P-values <0.05 were considered to be statistically significant.

During 1999–2013, among 29,944,574 hospital births that occurred in the 28 states included in this report, 74,576 NAS cases occurred, reflecting an overall incidence rate of 2.5 cases per 1,000 hospital births. In 1999 (the first year), 2,419 NAS cases were identified among 1,610,733 births in 14 reporting states (1.5 per 1,000 births). In 2013, 8,270 NAS cases were identified among 1,385,371 births in 21 states (6.0 per 1,000 births).

Data for at least 5 consecutive years were available for 27 states (Table). In 1999, NAS incidence ranged from 0.3 per 1,000 births in Iowa to 7.6 per 1,000 births in Maryland. In 2013, NAS incidence ranged from 0.7 per 1,000 births in Hawaii to 33.4 per 1,000 births in West Virginia. During 2012–2013, three of 25 states (Maine, Vermont, and West Virginia), reported NAS incidence rates >30 per 1,000 hospital births (Figure). From 1999 to 2013, the incidence of NAS significantly increased in 25 of the 27 states with at least 3 years of data included in this report (Table). NAS incidence rates did not change significantly in California and South Dakota during 1999–2013. The annual incidence rate change over 1999–2013 was lowest in Hawaii (0.05 per 1,000 births) and highest in Vermont (3.6 per 1,000 births).

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Discussion

The overall incidence of NAS in the states included in this report has increased almost 300% during 1999–2013, from 1.5 to 6.0 cases per 1,000 hospital births. This increase in NAS incidence is consistent with that reported by other studies, which have described a national increase in incidence of 383% (from 1.2 cases per 1,000 hospital births in 2000 to 5.8 cases per 1,000 hospital births in 2012) (2,3). Substantial variation in NAS incidence and trends by state exist, with incidences in 2013 ranging from 0.7 (Hawaii) to 33.4 per 1,000 births (West Virginia). Differences in NAS incidence might be caused by variations across states in opioid prescribing rates (5), prevalence of illicit opioid use, or use of the ICD-9 code that identifies NAS.

State governments partially finance and fully administer Medicaid programs, direct block-grant funds relevant to treatment of substance use disorders and maternal and child health programs, and license health care professionals. Previous research indicates that Medicaid programs were financially responsible for approximately 80% of the estimated $1.5 billion in NAS-related annual hospital charges in 2012 (3). Taken together, these factors make state-specific NAS estimates important to the formulation of public health plans to improve the health of mothers and infants affected by opioid use.

The findings in this report are subject to at least four limitations. First, the State Inpatient Databases include de-identified administrative data, and counts of NAS cases are based on information collected at the delivery hospitalization. In this analysis, only cases at the originating hospitals were counted. Cases identified as transfers from another hospital were not counted, to minimize possible duplication of counts and thus, overreporting of infants with NAS who might need a higher level of care. However, these rates are likely underestimates, as hospital administrative data identify fewer cases of NAS than does clinical reporting (6). Second, these estimates are not generalizable to births that occur outside of the hospital; however, out-of-hospital deliveries represented only 1.5% of births in 2014 (7). Third, although statistically significant annual changes in incidence rates were observed, these changes might not represent large increases in actual numbers of affected infants, depending on the birth population in each state. Finally, data are not generalizable to the entire United States, but only to the 28 states included in this report.

Primary prevention measures are important in curbing the incidence of NAS. In 2016, CDC released the Guideline for Prescribing Opioids for Chronic Pain, which recommends that clinicians 1) consider nonopioid pharmacologic therapy for chronic pain management, 2) discuss family planning and how long-term opioid use might affect future pregnancies before initiating opioid therapy in reproductive-aged women, and 3) prescribe the lowest effective dose when opioids are started (8). Individual states have implemented strategies to address the opioid epidemic and NAS. Prescription drug monitoring programs are operational or will be implemented in 49 states and the District of Columbia (www.cdc.gov/drugoverdose/pdmp) to track prescribing and dispensing of controlled prescription drugs; these programs have been shown to reduce inappropriate prescribing and overdose deaths (9). In addition, Florida, Georgia, Kentucky, and Tennessee have made NAS a reportable condition to state health departments to improve public health surveillance. Implementation of this type of passive surveillance of NAS can help states successfully target prevention and treatment measures, including access to medication-assisted treatment, the standard of care recommended by the American College of Obstetricians and Gynecologists for pregnant women with opioid use disorders (10). As part of the Protecting Our Infants Act of 2015,† CDC continues to provide technical assistance to states and American Indian tribes to improve NAS surveillance and to support implementation of effective public health measures.

Zika Cases in Puerto Rico Are Skyrocketing

Zika Cases in Puerto Rico Are Skyrocketing

SAN JUAN, P.R. — The Zika epidemic that has spread from Brazil to the rest of Latin America is now raging in Puerto Rico — and the island’s response is in chaos.

The war against the Aedes aegypti mosquito carrying the virus is sputtering out in failure. Infections are skyrocketing: Many residents fail to protect themselves against bites because they believe the threat is exaggerated.

Federal and local health officials are feuding, and the governor’s special adviser on Zika has quit in disgust.

There are only about 5,500 confirmed infections on the island, including of 672 pregnant women. But experts at the Centers for Disease Control and Prevention say they believe that is a radical undercount.

Just four cases of infection were confirmed last week in Florida. But in Puerto Rico, officials believe thousands of residents — including up to 50 pregnant women — are infected each day.

Most never get tested. Tests on donated blood, the most reliable barometer of the epidemic’s spread, show that almost 2 percent of the donors were infected in the last 10 days.

“That’s a stunning number and reflects an explosion of cases,” Dr. Thomas R. Frieden, the director of the C.D.C., said in an interview.

The proportion of pregnant women testing positive for the virus has risen sevenfold since January, the agency said on Friday. Officials warned that hundreds of infants could be born with microcephaly in the coming year.

But a wave of microcephaly like Brazil’s may yet be averted for two reasons. The pregnancy rate is falling so precipitously that this year, for the first time in history, Puerto Rico will have fewer births than deaths.

Obstetricians, too, are quietly urging their infected pregnant patients to have regular ultrasounds and to consider abortion if brain damage turns up.

And damage is turning up.

In an office at the University of Puerto Rico Hospital, the gentle curves of the graph on Dr. Alberto De la Vega’s computer screen trace a horror story. They are the head circumferences of dozens of fetuses whose mothers have been infected with the Zika virus for at least a month — and almost 75 percent are below the mean; normally, only half should be.

Only one was clearly microcephalic, with the extreme shrinkage and brain damage that is the worst consequence of the infection, and that curve abruptly ends: The mother chose abortion.

“What worries me is not 100 kids with microcephaly,” said Dr. De la Vega, chief of ultrasound diagnosis at the university. “What worries me is a lot of kids affected in some way we cannot determine yet.”

“We may be facing a generation with learning and behavioral disabilities,” he said.

On the scan of a patient who had fled his office fighting back tears, he pointed out three large white spots — clumps of dead cells.

“Her fetus does not have microcephaly now,” he said, “but this is what leads to it.”

A ‘Very Dire’ Situation

Cases of Zika infection are expected to keep rising through October, and by year’s end, a quarter of the island’s population of 3.5 million will have been exposed, a “very dire” situation, said Dr. Lyle R. Petersen, the C.D.C.’s chief of vector-borne diseases and director of its fight against Zika.

In a normal year, that would mean about 8,000 infected pregnancies, but the birthrate is dropping rapidly, said Jose A. Lopez, the health department’s demographer. In past years, births normally outnumbered deaths by about 400 per month, but since January, that ratio has reversed itself, and there have been, on average, 135 more deaths than births.

The drop is partly a result of rising divorce rates and couples emigrating as the economy deteriorates, but also of “mothers delaying giving birth because of the campaign against Zika,” Mr. Lopez said.

Federal health officials have accused Congress of stoking the epidemic here by failing to appropriate $1.9 billion requested by the administration to fight the Zika virus. But the story on the ground is far more complex.

 In February, the governor’s office and the health department announced ambitious battle plans. Millions of old tires where mosquitoes breed would be collected. Cemeteries would be drained of standing water.

Septic tanks and water meters would get screens, as would all schools attended by girls old enough to get pregnant. Teams would visit pregnant women’s houses to spray larvicide and screen windows.

Some of that was done, sometimes effectively. Humacao, a town on the southeast coast with pharmaceutical and electric plants that provide a steady tax base, moved faster than most municipalities, said José L. Báez, its chief of emergency management.

Workers collected 200,000 tires, packing them into two abandoned factories. At the local historic cemetery, teams filled empty urns with sand. Spray trucks worked steadily.

But it was never enough. Discarded tires kept popping up on roadsides. Mosquitoes bred in garbage cans. Teams could not legally enter abandoned properties or even fill depressions in privately owned graves. The town’s permethrin insecticides turned out to be ineffective, and daily rains washed away previous efforts.

No cutting-edge plans like releasing genetically modified mosquitoes are ready for deployment yet. The C.D.C. lab here has developed a bucket trap that drastically cuts mosquito populations, but millions of them would be needed to cover the island.

So, as a last resort, the C.D.C. on July 6 endorsed aerial spraying to eliminate mosquitoes with an insecticide called naled.

It was a gamble. Naled failed to stop a 1987 dengue outbreak here “and there is no guarantee it will work this time,” Dr. Petersen said. “But it’s the only thing that will alter the course of this epidemic.”

Modern spray nozzles and GPS-guided planes were more accurate, he argued, and superfine mists with small amounts of naled would drift into houses where mosquitoes hid in closets. Counties in Florida and Louisiana had recently knocked down populations of the yellow-fever mosquito by up to 99 percent with naled, he and others noted.

But naled is toxic to bees, birds and fish. The insecticide is not used in flea collars because it might be picked up by children stroking pets. It is banned in the European Union.

Skepticism All Around

Puerto Rico rebelled. Protest marches drew hundreds wearing gas masks and carrying bee puppets. Top radio personalities, already angry over Congress imposing a control board to run the territory’s finances, accused federal officials of “colonialism” and reminded listeners that the military tested Agent Orange on Puerto Rico’s jungles before deploying it in Vietnam.

Medical groups joined the opposition, including the largest, the Puerto Rican College of Physicians and Surgeons. Dr. Iván González Cancel, a surgeon famous for performing the island’s first heart transplant, denounced the plan, saying: “I don’t believe in conspiracy theories, but I think this is an experiment with the C.D.C. using Puerto Rico as a laboratory.”

On July 21, a local TV station revealed that the C.D.C. had quietly imported naled. The next day, Gov. Alejandro García Padilla accused the agency of “blackmail” and emphatically killed the idea. The agency apologized, saying it was only trying to be prepared. But it was too late.

That same week, Dr. Johnny Rullán, a former health secretary advising Governor Padilla on the epidemic, gave up his post, saying the whole atmosphere had become too vicious. Since January, he had held town meetings explaining the mosquito control plans to skeptical audiences. “I felt like a scratched record saying the same things over and over,” he said. When he endorsed aerial spraying, he was falsely accused of plotting to make millions by basing planes at a remote airport he was accused of owning. (It is owned by someone with a similar name.)

He ultimately decided the spraying would be a public relations disaster. “Any microcephaly cases that occur now will be blamed on the spray, not the virus,” he said.

He resigned and left for a vacation in Spain. “In October,” he said, “I’ll write something saying, ‘I told you.’ ”

Skepticism of the danger remains high. Local papers still refer to the “theory” that the Zika virus causes microcephaly, although the World Health Organization considers it a fact.

Seventy-two apparently healthy babies have been born to infected mothers while only one stillborn fetus has shown evidence of microcephaly, so no disturbing pictures of tiny-headed babies, like those in Brazil, have appeared. Although officials have explained that most of the 72 mothers were infected late in pregnancy, the sense that the danger is remote persists.

Alba Sanchez, 25, and nearing the end of her fourth pregnancy, attended a hospital Zika-prevention workshop wearing the skimpiest of maternity dresses. Asked if she used repellent, she wrinkled her nose.

“Never!” she said loudly. “It’s stinky. And I don’t know anyone who’s had Zika.”

Asked how she protected herself, she mimed slaps to her bare arms and legs. “I smack every one I see.”

Her husband, Jandy Vasquez, 22, a mountainous man towering over her, rolled his eyes and smiled ruefully. “I’d spray a whole can on her every day,” he said. “But she does what she wants.”

Indeed, the fight against birth defects is taking place largely in face-to-face meetings between doctors and patients like Ms. Sanchez.

Agonizing Decisions

Many obstetricians said they were urging women to put off pregnancy. And through the CDC Foundation, pharmaceutical companies like BayerAllergan and Merck have donated or discounted more than 100,000 sets of IUD’s, implants, vaginal rings and other contraceptives.

“I tell my patients: ‘If you can avoid pregnancy for one year, please do,’ ” said Dr. Carmen D. Zorrilla, founder of the University of Puerto Rico’s Maternal-Infant Studies Center, the territory’s leading maternal H.I.V. unit, which now holds workshops in Zika-related care.

The doctors also remind patients whose fetuses show signs of brain damage that abortion is available in major hospitals and, for the uninsured, through Profamilias, a reproductive-rights group.

Some religious women will say, “‘But this is God’s gift,’ ” Dr. Zorrilla said. “But at the same time, they’re afraid to have a baby they know will need assistance 24/7 for life.”

How many women are terminating pregnancies is unknown. Although the health department tabulates legal abortions, current figures are unavailable, a department spokeswoman said.

“Anecdotally, they’re on the increase,” Dr. Rullán said. “One doctor told me he did 15 in a period where he normally would have done one or two.”

Making that choice is excruciating. Danelle, a patient of Dr. De la Vega’s who agreed to be interviewed on the condition that only her middle name be used, wept as she described her predicament.

Her fetus is 23 weeks along. On sonograms, Danelle, 36, can see a face, even hair: To her, the outlines resemble a small, sleeping child, nestled against the placenta as if it were a pillow.

Danger signs have appeared since Danelle was infected with the virus in late April. The fetus’s growth abruptly slowed and is now well below normal. An enlarged brain artery indicates that too little nutrition is crossing the placenta.

Because she herself is a doctor, Danelle knows what that means: Severe mental deficits are possible. Her husband, a train dispatcher who held her hand as she spoke, “is the more positive one of us — and he’s also in denial,” she said.

“But I’m the G.I. one,” she added, using a local term for hewing strictly to the book.

She was having ultrasounds every 14 days and must decide very soon whether to abort.

“The window is closing,” she said, wiping her eyes. “I don’t sleep at night. I don’t want to do this, but I don’t want her to come into this world and then suffer.

“And when I’m not here, who’s going to take care of her?”

STUDY UNCOVERS CLUE TO DECIPHERING SCHIZOPHRENIA

STUDY UNCOVERS CLUE TO DECIPHERING SCHIZOPHRENIA

The brains of healthy relatives of people with schizophrenia may hold a clue to better understand – and ultimately treat – the devastating illness, finds new research led by a Michigan State University scientist.

The study is the first to look at the neurotransmitters glutamate and gamma-aminobutyric acidergic, or GABA, in both schizophrenia patients and healthy relatives of schizophrenia patients using a noninvasive imaging test called magnetic resonance spectroscopy.

Glutamate, which promotes the firing of brain cells, and GABA, which inhibits neural firing, work hand in hand to regulate brain function. In the past 20 years, many researchers have come to believe that glutamate and GABA play a role in schizophrenia, yet the precise relationship remains unclear and no medication for schizophrenia has hit the market specifically targeting these neurotransmitters.

According to the study, both schizophrenia patients and healthy relatives showed reduced levels of glutamate. But while the patients also showed reduced levels of GABA, the relatives had normal amounts of the inhibitory neurotransmitter.

This begs two key questions. First, if glutamate is altered, why do these relatives not show symptoms of the illness? And, second, how did healthy relatives maintain normal levels of GABA even though they, like the patients, were genetically predisposed to schizophrenia and had altered glutamate levels?

“This finding is what’s most exciting about our study,” said lead investigator Katharine Thakkar, MSU assistant professor of clinical psychology. “It hints at what kinds of things have to go wrong for someone to express this vulnerability toward schizophrenia. The study gives us more specific clues into what kinds of systems we want to tackle when we’re developing new treatments for this very devastating illness.”

The research, reported online in the journal Biological Psychiatry, involved 21 patients with chronic schizophrenia, 23 healthy relatives (the relatives were siblings of other patients with schizophrenia, not the patients in the study) and a control group of 24 healthy nonrelatives. It was performed in collaboration with researchers at the University Medical Center Utrecht in the Netherlands, where Thakkar served as a postdoctoral fellow.

Schizophrenia, which affects about 3.5 million Americans, is marked by delusions, hallucinations and other symptoms, although it is not, contrary to popular belief, split or multiple personality.

Many schizophrenia drugs regulate dopamine, another neurotransmitter in the brain, though the medication does not work for everyone. In fact, medication for schizophrenia has changed very little in the past 50 years and remains somewhat limited in its effectiveness. Many researchers believe there are multiple risk factors for the illness, including dopamine and glutamate/GABA imbalance.

The brain scan used in the study – which is conducted on a conventional MRI machine – could eventually help clinicians target more specific treatments.

“There are likely different causes of the different symptoms and possibly different mechanisms of the illness across individuals,” Thakkar said. “In the future, as this imaging technique becomes more refined, it could conceivably be used to guide individual treatment recommendations. That is, this technique might indicate that one individual would benefit more from treatment A and another individual would benefit more from treatment B, when these different treatments have different mechanisms of action.”

ROCKY MARRIAGES NOT ALWAYS BAD FOR YOUR HEALTH

ROCKY MARRIAGES NOT ALWAYS BAD FOR YOUR HEALTH

For men, an unhappy marriage may actually slow the development of diabetes and promote successful treatment once they do get the disease, finds a national study led by a Michigan State University sociologist.

Why? It may be because wives are constantly regulating their husband’s health behaviors, especially if he is in poor health or diabetic. And while this may improve the husband’s health, it also can be seen as annoying and provoke hostility and emotional distress.

“The study challenges the traditional assumption that negative marital quality is always detrimental to health,” said Hui Liu, MSU associate professor of sociology and lead investigator of the federally funded research. “It also encourages family scholars to distinguish different sources and types of marital quality. Sometimes, nagging is caring.”

Using data from the National Social Life, Health and Aging Project, Liu and colleagues analyzed survey results from 1,228 married respondents over five years. At the onset of the study, the respondents were 57 to 85 years old; 389 had diabetes at the end of the study.

Diabetes is the seventh leading cause of death in the United States. More than 29 million Americans had diabetes in 2012, or 9.3 percent of the population.

Liu, an expert in population-based health and family science, investigated the role of marital quality in diabetes risk and management and found two major gender differences:

*The most surprising finding was that, for men, an increase in negative marital quality lowered the risk of developing diabetes and increased the chances of managing the disease after its onset. Diabetes requires frequent monitoring that the wives could be prodding the husband to do, boosting his health but also increasing marital strain over time.

*For women, a good marriage was related to a lower risk of being diabetic five years later. Women may be more sensitive than men to the quality of a relationship and thus more likely to experience a health boost from a good-quality relationship, Liu said.

“Since diabetes is the fastest growing chronic condition in the United States, implementation of public policies and programs designed to promote marital quality should also reduce the risk of diabetes and promote health and longevity, especially for women at older ages,” the study says.

The study, published online in the Journals of Gerontology: Social Sciences, was co-authored by Shannon Shen, an MSU graduate, and Linda Waite, professor at the University of Chicago.

The research was partially funded by the National Institute on Aging, the National Institute of Child Health and Human Development and the Office of Behavioral and Social Sciences Research, which are all part of the National Institutes of Health.

Zika Virus

Zika Virus

Zika virus disease (Zika) is a disease caused by the Zika virus, which is spread to people primarily through the bite of an infected Aedes species mosquito. Although this virus was discovered in the mid 1900’s it has come to light in recent years due to  large outbreaks in French Polynesia and Brazil in 2013 and 2015 respectively.Although the virus is rarely found to be deadly, national health authorities have reported potential neurological and auto-immune complications of Zika virus disease. Mosquitoes and their breeding sites pose a significant risk factor for Zika virus infection. Prevention and control relies on reducing mosquitoes through source reduction (removal and modification of breeding sites) and reducing contact between mosquitoes and people. MSU-IIH believes a global task force with an interdisciplinary approach is essential for rapid control response of Zika, in order to stop the epidemic.

Zika-Virus-Infographic