Influenza vaccine deemed safe for pregnant women

Photo credits: Neville F. Hacker, Joseph C. Gambone, and Calvin J. Hobel

Movies often depict ill pregnant women sacrificing their own well-being to birth a healthy child. However, a research team of Buenos Aires, Argentina has recently proven women at risk of influenza A/H1N1 do not have to make that choice. The MF59 adjuvant A/H1N1 influenza vaccine does not increase the risk of adverse perinatal events.

The influenza pandemic swoops around every year causing more deaths than an expected virus should. In the past, A/H1N1 in pregnant women has been associated with higher hospital admissions, dangerous perinatal outcomes, a rise in perinatal mortality, and early births by about four fold. An H1N1 vaccine using MF59 as the adjuvant (the 2nd punch in a 1,2 combo) was developed in 1997. However, it was seldom prescribed for women nearing birth because of the lack of data detailing the risks. This study attempts to prove that MF59 adjuvant vaccines for H1N1 influenza do not increase risk of malignant perinatal and/or maternal events.

This cross-sectional multi-center study spanned 49 hospitals in the public healthcare sector of Argentina (which handles 15% of live births in all of Argentina). Between September 2010 and May 2011, 30,448 mothers (7,293 vaccinated with H1N1 adjuvant during pregnancy) and 30,769 newborns participated. Mothers were surveyed up to day seven after delivery. Of the vaccinated women, 39.4%, 48.6%, and 10.1% received vaccination during the first, second, and third trimester respectively (1.9% were unknown).

When comparing the vaccinated and non-vaccinated women, it seems those who received the adjuvant had an overall lower incidence of perinatal events. Specifically, in vaccinated women, the following events were seen as reduced:

– Premature birth: 24.6% reduction (P < 0.01)
– Low birth weight: 28.9% reduction (P < 0.01)
– Perinatal mortality: 36.4% reduction (P < 0.01)
– APGAR score < 7: 20% reduction (P = 0.018)

However, maternal complications during pregnancy noted were on par between both groups of women. Analysis of preterm+low birth weight+perinatal mortality rates between the groups led to an odds ration of 0.80 with 95% CI from 0.72 to 0.89 comparing vaccinated to non-vaccinated women.

The A/H1N1 vaccine adjuvant was not linked to any major complications for mother or child during the perinatal period. Perhaps now more women will be able to receive this vaccination when needed without experiencing that surreal moment of “My babies life…or mine?”. (Of course my dramatics here are unnecessary, but the study has proven this vaccine safe)

Reference:
F. Rubinstein, P. Micone, A. Bonotti, V. Wainer, A. Schwarcz, F. Augustovoski, A. Pichon Riviere, A. Karolinski. Influenza A/H1N1 MF59 adjuvanted vaccine in pregnant women and adverse perinatal outcomes: multicentre study. British Medical Journal, 2013.
http://dx.doi.org/10.1136/bmj.f393

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Chronic stress tied to impaired memory

Stress ball can’t remember what it did yesterday, so now it’s stressed.
Image courtesy of trasik555

Stress is a natural occurrence in life; however, chronic stress has been proven detrimental to one’s physical well being and here mental well-being. Researchers of the University of Minho, Portugal deemed chronic stress the cause of cortico-limbic impairment and (resulting) long-term memory block.

The cortico-limbic system consists of the amygdala, anterior thalamic nuclei, cerebrum, diencephalon, fornix, hippocampus, limbic cortex, midbrain, and septum. This string of brain controls behavior, emotion, long-term memory, motivation, and olfaction. Longer term memory itself is based on long term potentiation (LTP). This is basically a set of neurons firing consistently on a region increasing the neural receptors of the neuron across the synapse and that particular synapse’s strength. This concept ties closely to the electrical activity of the region.

This study measured the spectral coherence (synchronous electrical pattern) of the ventral hippocampus (vHIP) and medial prefrontal cortex (mPFC) as representers of the cortico-limbic system (vHIP and mPFC are linked by monosynaptic connection) in rats subject to no stress, short term stress (STS), or chronic unpredictable stress (CUS). The CUS group was exposed to 28 days of stress (1 hour/day) while the STS group only 6. Stressors were randomly chosen out of: 18°C water, overcrowding, exposure to hot air stream, noise, or shaking.

The study worked to prove stress induced dysfunction of the cortico-limbic system was due to regions of the brain being out of phase (out of sync) in neuronal firing patterns.

In measuring local field potentials, rats exposed to CUS showed increased power activity in the vHIP and mPFC as compared to STS induced rats and no stress controls. With this increased activity, a decrease in spectral coherence was seen between these two brain regions. The CUS rats had nearly a 50% decrease in phase coherence, while STS rats showed a roughly 20% drop as compared to controls.

Furthermore, LTP was seen as impaired in mice subject to stress. This was tested using the  Morris water maze to test spatial reference memory. Time to reach the platform was 65s (day one) and 30s (day four) compared to 50s (day one) and 20s (day four) of CUS and control rats respectively.

These results show chronic stress heavily disrupts coherence of regions of the cortico-limbic system, throws off neuronal interplay, and impairs cognitive function that relies on these out-of-sync areas, specifically memory. I guess that means my stressed friends might have aced their finals had they studied in a sauna…maybe.

Reference:
João Filipe Oliveira, Nuno Sérgio Dias, Mariana Correia, Filipa Gama-Pereira, Vanessa Morais Sardinha, Ana Lima, Ana Filipa Oliveira, Luís Ricardo Jacinto, Daniela Silva Ferreira, Ana Maria Silva, Joana Santos Reis, João José Cerqueira, Nuno Sousa. Chronic stress disrupts neural coherence between cortico-limbic structures. Frontiers in Neural Circuits, 2013.
http://dx.doi.org/10.3389/fncir.2013.00010

Heart failure preventive induces heart failure in mice

Photo courtesy of Cardiomegaly

Who says too much growth and nutrition is a bad thing? The human heart does first and foremost. Past research has set out to prove limiting the amount of fatty acid derivative entering the mitochondria of the heart is protective in that it prevents cardiac hypertrophy and heart failure. However, researchers of the Sanford-Burnham Medical Research Institute believe carnitine palmitoyltransferase 1 (CPT1) inhibition (lowered ß-oxidation) actually exacerbates cardiac hypertrophy and induces heart failure. This study proved their assumptions correct using CPT1b+/- knockout mice.

CPT1b is the main isoform of CPT1 found in the heart and works to assist long chain acetyl-CoA’s (from fatty acid metabolism) entrance into the mitochondria for ß-oxidation. ß-oxidation is an important contributor of energy to the heart as so is glucose oxidation (70:30 energy contribution).

Cardiac hypertrophy is a thickening of the heart resulting in a decrease in the volume of its chambers. This can occur naturally in athletes or due to a physiological impairment in non-athletes.

In this study, CPT1b+/- mice were subjected to transverse aorta constriction (TAC) induced pressure-overload and analyzed for accompanying cardiac problems. Basically cardiac thickening was forced on the wild type/control mice and the CPT1b+/- mice.

At baseline, no cardiac abnormalities was seen in either mouse cohort. After inducing TAC, most CPT1b+/- mice died after two weeks, while their wild type companions survived. Additionally, higher rates of cardiomyocyte (heart cell) apoptosis was seen in the knockout mice than wild type. Following, triglyceride levels were measured in the post-mortem hearts of mice. Again, the  CPT1b+/- mice showed higher levels of lipids (Oil-red-O staining) than the normal mice.

CPT1b deficiency in hearts has been shown to exacerbate hypertrophy and heart failure, increase cellular suicide, and raise lipotoxicity. Therefore, caution should be taken with clinical prescription of drugs inhibiting cardiac CPT1.

Reference:
Lan He, Teayoun Kim, Qinqiang Long, Jian Liu, Peiyong Wang,Yiqun Zhou, Yishu Ding, Jeevan Presain, Philip A. Wood, Qinling Yang. Carnitine Palmitoyltransferase-1b (CPT1b) Deficiency Aggravates Pressure-Overload-Induced Cardiac Hypertrophy due to Lipotoxicity. DOI: 10.1161/CIRCULATIONAHA.111.075978
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3484985/

Diabetes drug used to treat lung cancer

From left to right: Tumor (dark purple) reduction due to phenformin treatment.

From left to right: Tumor (dark purple) reduction due to phenformin treatment.

Personalized treatment is a growing genre of cancer therapy. Researchers of the Salk Institute for Biological Studies and UCLA recently treated lung cancer with a specific metabolic mutation, KRAS LKB1 deficiency, with a derivative of a drug originally FDA approved for diabetic therapy, phenformin.

The LKB1 enzyme normally is activated in response to low cellular energy. The enzyme lets the cell know it is metabolizing inefficiently, so the cell can correct itself before starving to death. However, 20% of non-small cell lung cancers (NSCLC) have a mutation resulting in LKB1 inhibition or very little effective LKB1 produced. This is the second most common mutation in NSCLC. Following, “the tumor cell loses the ability to regulate its energy consumption, similar to a car losing its breaks,” David Shackelford.

The metabolic regulator phenformin attacks the mitochondria of affected cells and lowers the available energy. This pushes the cell into a state of needing LKB1 to correct its energy consumption. However, NSCLC lacking the LKB1 gene cannot correct and eventually apoptose, commit cellular suicide.

Using advanced stage lung cancer genetically modified mice with the mutation to the KRAS LKB1 gene (and similar KRAS mutations as controls), phenformin’s effect on tumor size and mouse survival was studied.

Mice given phenformin showed 30% decreased tumor area according to red pixel count of morphometric analysis after three weeks of treatment. In analyzing tumor cells specifically, their apoptotic rate was increased significantly. Therefore, the tumor cells were dying and shrinking cancer impact. Accompanying, an average of 35% increased survival of mice was seen when treated with phenformin in mice with the KRAS LKB1 mutation as seen in figure 5 A & B of the article.

The tumor reduction was definitely significant in the mice introduced to phenformin. It’s also noteworthy that phenformin had little to no effect on normal cells because they had functioning LKB1 and could correct any drug induced metabolic imbalance. This drug treatment would work well as an adjuvant to surgical removal of the bulk of tumors to clean out any remaining cancer.

Because phenformin is already FDA approved, clinical trials showing it’s anti-cancer effects in humans are all that is needed to bring this treatment to life. Pharmacies may see phenformin in the cancer treatment aisle sooner than most drugs even reach clinical trials.

Reference:
David B. Shackelford1, Evan Abt, Laurie Gerken, Debbie S. Vasquez, Atsuko Seki, Mathias Leblanc, Liu Wei, Michael C. Fishbein, Johannes Czernin, Paul S. Mischel3, Reuben J. Shaw. LKB1 Inactivation Dictates Therapeutic Response of Non-Small Cell Lung Cancer to the Metabolism Drug Phenformin. Cancer Cell, 2013.
http://dx.doi.org/10.1016/j.ccr.2012.12.008

“Junk” inhibition protects the heart from heart attack

Photo by Chelsee Tysoe

Heart attacks are dangerous because of the hypoperfusion, low blood flow, to heart cells and cascaded cell damage caused by reactive oxygen species and cell waste once reperfusion occurs. Researchers of the Scripps Research Institute of Florida found that by inhibiting c-jun-N-terminal Kinase (JNK or “junk”), the ischemic/reperfusion induced cardiomyocyte death could be prevented.

A heart attack causes an occlusion of blood vessels leading to the heart and results in low oxygen delivered to cardiomyocytes. As the cells are delivered less and less oxygen, a switch is made to anaerobic metabolism. Following, the cell membranes are broken down by lipases and calcium is allowed to freely rush into the cell. This causes the generation of free radicals (FR), reactive oxygen species (ROS), and the release of toxins/apoptotic factors into the cell (not to mention mitochondrial dysfunction). This dangerous process is exacerbated by the treatment of ischemia by restoring blood flow. This is because the toxins, FRs, and ROSs are rapidly shuttled to the cells and nearby tissues causing cell death.

Previous studies have shown that JNK plays a major role in the (dysfunctional) mitochondrial signaling to release FRs and ROSs; therefore, this group tested the effect of blocking that signaling or inhibiting JNK all together in vivo using rats.

Inducing heart attack in the rats and introducing 5 mg/kg of SR-3306 (JNK inhibitor) reduced ischemic/reperfusion injury by 34%. Cardiomyocyte apoptosis was also seen as reduced 4-fold by SR-3306.

Blocking JNK signaling via mitochondria effectively reduced heart attack damage to heart cells and the surrounding tissue. It seems blocking this junk induced pathway will prove useful in protecting hearts and saving lives.

Reference:
Jeremy W. Chambers, Alok Pachori, Shannon Howard, Sarah Iqbal, Philip V. LoGrasso. Inhibition of JNK Mitochondrial Localization and Signaling is Protective Against Ischemia-
Reperfusion Injury in Rats. The Journal of Biological Chemistry, 2012.
http://dx.doi.org/10.1074/jbc.M112.406777

The nose of a mole sheds new light on mammalian touch

Star-nosed mole

Star-nosed mole

Researchers of Vanderbilt and Berkeley of the United States recently dug around the star of the star-nosed mole to see what could be learned about mammalian mechanoreception, sense of touch.

Moles are generally creatures that spend most time underground and therefore have terrible vision. To make up for this they have an excellent sense of touch. The star-nosed mole is classified as an animal with the highest density of touch neurons in one area of any animal on the planet. The star of this creature is where most of the touch receptors are housed. For this reason, this group wanted to test the microbiological and genetic components that make this organ so great for mechanoreception in order to learn about mammalian parallels.

The enhanced tactical acuity of the star led researchers to believe the ability of the mole to detect noxious stimuli of thermal and/or chemical root may be impaired. The enhancement of one sense may come at the expense of another so to speak. This was tested by applying capsaicin to the hind-paw of the mole and mice followed by application to mole nose. The first test elicited a nocifensive response in both mole and mouse, but no behavioral response was seen when applied to mole star.

RNA sequencing revealed a lack of TRPA1 and TRPV1 in the group of neurons immediately associated with the star-nose, but a 10 fold higher detection of these molecules in neurons outside the nose proximity. The aforementioned molecules are associated with nociception, or detection of pain.

Furthermore, 20 fold higher levels of Cnga2 and Cnga4, molecules associated with touch detection, were found in the ganglia associated with the nose (trigeminal ganglia) than found outside the area (dorsal root ganglia). A related ion channel, Fam 38a (Piezo1), was found to be expressed in trigeminal ganglia and dorsal root ganglia. Fam38a was found as a parallel to mouse Piezo1.

The group concluded that genes found to be associated with expression of mechanoreceptor stimuli as well as CNG and Piezo1 ion channels played roles in various aspects of mechano-transduction. Studying animals at the extremes of sensory perception can aid in understanding the senses further. In this case, researchers were guided closer to the answer of “how do humans feel” by a star not in the sky, but on a mole.

Reference:
Kristin A. Gerhold equal contributor,

Maurizio Pellegrino equal contributor,

Makoto Tsunozaki, Takeshi Morita, Duncan B. Leitch, Pamela R. Tsuruda, Rachel B. Brem, Kenneth C. Catania, Diana M. Bautista. The Star-Nosed Mole Reveals Clues to the Molecular Basis of Mammalian Touch. PLoS ONE, 2013

Mutations for cancer begin before cancer

Cancer cells mid-division. Photo courtesy of The Telegraph

Cancer cells mid-division.
Photo courtesy of The Telegraph

Cancer can prove one of the nastiest diseases to crop up in one’s body due to it remaining hidden until it has already metastasized and spread around the system. A Baltimore/Boston collaboration of researchers set out to prove over half of the somatic mutations that make up a tumor are present before “tumor growth” of self-renewing tissues even starts.

Tumors form as the result of genetic mutations in which more cell replication and division happens than cell death. This causes the overgrowth of cells resulting in cancerous masses. Cancers aren’t caused by a single mutation, however. Many things must go wrong in cells before they get out of control. The basis of this study was to see how many passenger mutations (those that do not affect cell growth) actually occur before the tumor is initiated (by driver mutations) and whether or not this was affected by patient age.

To test, data was analyzed from The Cancer Genome Atlas and the International Cancer Genome Consortium of 676 patients with chronic lymphocytic lekemia (CLL), uterine corpus endometrioid carcinoma, colorectal cancer, or pancreatic cancer. The researchers first found that the total number of somatic mutations found in these cancers increased with patient age (at diagnosis) (P<0.01). The mutation to age correlation was independent of cancer stage.

The results further indicated that over 50% of passenger mutations developed before a single driver mutation in median aged patients. Using the regression data shown in the article, the number of somatic mutations at the earliest stage of cancer detection (after 25 years for colorectal, after 7 years for leukemia, and after 10 years for uterine) was estimated as 5.86, 33.3, and 50.2 in the different cancers. This suggested 68%, 57%, and 51% respectively of the somatic mutations happened before the tumors initiated.

Finally, the mutations rates were estimated, but did not deviate much from that of normal cells and bacteria.

The results from this study showing that the number of somatic mutations in a patient are age dependent and that a large number of these mutations appear before cancer growth begins are relevant for current genome-cancer studies. From this data, it may be possible to predict a cancer’s appearance before it even starts.

Catching cancer early is one of the most important keys to stopping it. This project is a step closer to faster cancer detection and elimination.

Reference:
Cristian Tomasetti, Bert Vogelstein, Giovanni Parmigiani. Half or more of the somatic mutations in cancers of self-renewing tissues originate prior to tumor initiation. PNAS, 2013.