The straw that broke the monkey's back

Citation: Togawa D, Kovacic JJ, Bauer TW, Reinhardt MK, Brodke DS, Lieberman IH. Radiographic and histologic findings of vertebral augmentation using polymethylmethacrylate in the primate spine: percutaneous vertebroplasty versus kyphoplasty. Spine. 2006 Jan 1; 31(1):E4-10.

Summary of Experiment: Compression fractures are a common and very painful complication of osteoporosis and some traumatic injuries. The two procedures most commonly used to stabilize this type of fracture in people are vertebroplasty and kyphoplasty.

Six elderly female baboons were used to test the efficacy and rate of complications of these two procedures (two vertebrae each). Necrosis, foreign body reaction and leaking in those vertebrae were compared to holes that were created but not stabilized (two vertebrae) and one unaltered vertebrae. Analgesics and IV fluids were administered after surgery. Animals were checked twice per day for “abnormalities.” Three animals were killed “according to AVMA guidelines” 24 hours post surgery, and the other three at six months.

My Notes:

• The efficacy and rate of leaking complications of both procedures among people receiving these same two procedures were tested in a 2002 study, which was not cited. My search revealed nearly 100 papers that compare some aspect of these two procedures in human subjects.


• They fail to mention that baboons aren’t bipedal. The fact that the animals don’t walk upright and would be less susceptible to either compression fractures or vertical compression/stress during recovery has apparently been overlooked.


• These baboons did not have osteoporosis.


• Despite the fact that the entire spine was removed after the animals were killed, they forgot to remove of the vertebroplasty bones for examination.

Quote from the article:

“Unfortunately… bone mineral density of the baboons was much greater than that of human osteoporotic patients so that we were not able to expand the bone tamps to the same degree as is often achievable in humans. This fact may have artificially increased the risk of cement leak in both procedures. Some of the findings in the current study may not be supported in the patients with osteoporotic vertebral compression fractures because of these limitations. Moreover, the baboon vertebrae are morphologically different to human vertebrae (taller height in proportion than human vertebrae), so it is difficult to simulate human osteoporotic vertebral compression fracture. Future studies should attempt to induce more significant osteoporosis in other models using diet, pharmacologic, and surgical (i.e., oophorectomy) means.”

Why is the fact that they didn't have osteoporosis unfortunate?

So the authors admit it’s a crappy model, and everyone knows that there is a sea of human research data, but these people want to do more experiments on monkeys anyway?

Author Affiliations:
Cleveland Clinic Spine Institute, Cleveland, OH
Departments of Orthopaedic Surgery and Anatomic Pathology, Cleveland
Clinic Foundation, Cleveland, OH
Department of Orthopaedic Surgery, University of Utah, Salt Lake City, UT.

Funding acknowledged: Funds from “Kyphon Inc.” This competing interest was declared.

Sick and tired of being sick and tired

Citation: Vulliemoz NR, Xiao E, Xia-Zhang L, Ferin M, Wardlaw SL. Melanocortin modulation of inflammatory cytokine and neuroendocrine responses to endotoxin in the monkey. Endocrinology. 2006 Jan 12; [Epub ahead of print]

Summary of Experiment: Primates were sedated and placed in primate chair overnight. Blood was drawn at 8 am and then saline or one of three experimental agents was injected. At 10 am, animals were injected with enough E. coli to induce a significant immune response and “sickness behaviors.” Blood was taken every 30-60 minutes for the next 7 hours. This experiment was performed 3 times with 3 weeks recovery between sessions. Immune and stress responses were measured. Baselines were taken by performing the procedure without the E. coli injection (x3). Immune and stress responses were measured. Short term reaction was studied by putting primates in chairs the morning of the experiment (0800), given saline or experimental agent for a longer period (until 1300), then given E. coli and monitored until 1800. This experiment was performed 3 times with 3 weeks recovery between sessions.

Some of the agents affected aspects of the immune response that increase and decrease inflammation. The way the stress system (The “HPA axis”) responds to these inflammation messengers was also affected.

My Notes:

• There is no mention of managing the “sickness behaviors” in these monkeys. E. coli can be horrid. Symptoms include intense abdominal pain, bloody diarrhea, fever, loss of appetite, vomiting and dehydration.
• In the discussion, they address the fact that animals used in both parts of the experiment responded differently to phase two than “fresh” animals. The drugs tested could have long-term effects on the immune or hormone systems, or interact with one another when one agent is administered after the other.
• Authors mention that their results mirror rodent studies – Wardlaw also does rodent experiments. It's not clear why they are repeating work in primates.

Author Affiliation: Departments of Medicine and Obstetrics and Gynecology, Columbia University College of Physicians and Surgeons, New York, NY 10032

Funding Acknowledged: NIH Grant MH55708 (Looks like ~ $1.7Mover five years)

Toxic relationships

Citation: Gestational and lactational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin affects social behaviors between developing rhesus monkeys (Macaca mulatta). T Negishi, H Shimomura, T Koyama, K Kawasaki, Y Ishii, S Kyuwa, M Yasuda, Y Kuroda, and Y Yoshikawa Toxicol Lett, Jan 2006; 160(3): 233-44.

Summary of Experiment: Forty-nine pregnant monkeys were injected with different doses of dioxin every thirty days from the third week of pregnancy until 3 months after delivery. From 1-2 ears of age, the babies performed tests to assess learning ability, social skills and response to novel and stressful events. Social skills were the only variable affected, and differences decreased over time. The dioxin monkeys seemed not to be afraid of things that elicited fear in normal monkeys. This same phenomenon had already been documented in earlier papers (Schantz AND Bowman, 1989; Schantz et al., 1992). They claim that the differences between those results and their own were due to differences in the behavioral tests used.

My Notes:

• Dioxin is the most potent animal carcinogen ever tested, as well as the cause of severe weight loss, liver problems, kidney problems, birth defects, and death. We already know that dioxin causes damage to development, reproduction, and the immune and endocrine systems at infinitesimally low doses (in the low parts per trillion). Toxicological studies have not been able to establish a "threshold" dose below which dioxin does not cause harmful effects.


• The authors indicate that monkeys may be able to overcome the toxic effects of dioxin during development, because some social behaviors changed. However, it’s equally possible that the initial effect was due to novelty, and continued tests with novelty may have revealed persistent effects.


• Experiments were done at an SNBL facility. Female are housed individually most of the time, but with a male 3 days per month if they are not already pregnant.
  Babies were weaned at 13-14 months (much better than 5 months of age in the prior test), but thereafter were housed individually.


• Some of the methods were funky – they didn’t count non-responses to the test environment as a “trial,” which could lead to habituation, etc. In some tests, they are using groups of 3 and 4 monkeys, in others 28…you can’t just pick and choose like that and then argue that the statistics mean anything.


• Their conclusions are wacky:
  

  “However, the results might serve as a warning to humans of potential alterations by perinatal exposure to TCDD in developing social behaviors, and these alterations might not be necessarily considered as apparently negative effects such as learning disability and psychological disorders.”

Author affiliations: University of Tokyo

Funding acknowledged: Core Research for Evolutional Science and Technology (CREST) program of the Japan Science and Technology Agency.

Conservation of lemurs and other endemic wildlife in Madagascar

I think it's wonderful that President Marc Ravalomanana and several motivated NGOs have defined a vision for conservation in Madagascar. With most of the island's forest already gone, and many habitats in need of protection, it is an absolutely urgent situation. However, most recent news announcements out of Madagascar are about mining: gold, platinum, other metals, and even diamonds. Large scale mining, and its purported economic benefits, and biodiversity conservation just don't mix.

Sadly, I think these conservation efforts may be a day late and a dollar (or ariary ) short!

Smoking gun

Citation: TA Slotkin, KE Pinkerton, and FJ Seidler. Perinatal environmental tobacco smoke exposure in rhesus monkeys: critical periods and regional selectivity for effects on brain cell development and lipid peroxidation. Environ Health Perspect, Jan 2006; 114(1): 34-9.

The authors begin their article by citing sources that acknowledge the harm caused by “Environmental Tobacco Smoke,” i.e. second-hand smoke. The sources are 15-20 years old. Since we already know this, it was critical to perform an experiment on pregnant and nursing mother monkeys and their children.

Summary of Experiment: 15 pregnant mothers were obtained (by Duke from CaNPRC). An additional “set” of 16 monkeys was used in a second set of experiments. The 15 dams were assigned to one of three groups: breathing filtered air, breathing ETS pre- and postnatally, and breathing ETS postnatally only. Smoke from the burning end of cigarettes was “aged” and pumped into chambers that housed two monkeys for six hours each day, five days a week beginning 50 days after conception, and for both mother and infant from birth to 13 months of age. Mothers were removed from the enclosure when the babies were “weaned” at 5 months of age. For monkeys breathing only post-natal smoke, the smoke experiment began at 6 mos. At 13 months, monkeys were given ketamine and then overdosed on phenobarb.

There were no differences between groups in weight, growth, general health or “activity” pre- or postnatally. There were significant difference in the number and size of brain cells in some parts of the brain and in how tissues used oxygen.

My Notes :
These results were nothing new – they are highly duplicative of the authors own work:

“Perinatal or postnatal ETS exposure elicited two characteristic patterns of neural cellular effects, both of which resemble earlier findings for effects of prenatal nicotine exposure in rodents (Levin and Slotkin 1998; Roy et al.1998, 2002; Roy and Sabherwal 1994, 1998; Slotkin 1998, 2004; Slotkin et al. 1987b).”

And an ocean of evidence about the harmful effects of smoke in general. Despite this, they want to keep doing ETS experiments on monkeys:

“These neurochemical inferences point to the need for detailed, quantitative morphologic investigations of ETS effects on primate development paralleling those done for nicotine in rodent models (Roy et al. 1998, 2002; Roy and Sabherwal 1994, 1998).”

They favor the use of diagnostic methods available for studying and monitoring the effects of smoke on human children (available for at least ten years):

“…supports the use of nicotine metabolite measurements in fetuses and children as an appropriate predictor of outcome (Eliopoulos et al. 1996; Fried et al. 1995; Jauniaux et al. 1999; Kohler et al. 1999; Ostrea et al. 1994).”

Stop the presses!

“Translated to human ETS exposure, this finding points out the importance of reducing the exposure of young children to tobacco smoke in the home or in child care settings.”

You mean we shouldn't be giving them ciggys OR smoking around them? I thought the issue was smoking around food or office equipment!

Author Affiliations: Duke University Medical Center. Monkeys provided courtesy of CaNPRC

Funding Acknowledged: Research was supported by grants from the Philip Morris External Research Program and the National Institutes of Health (ES011634, ES05707, and RR00169).