SJL Mice Exposed to Cuprizone Intoxication Reveal Strain and Gender Pattern Differences in Demyelination

It may state two separate claims as one.

Continuous exposure of C57BL/6 mice to cuprizone results in two cycles of demyelination and remyelination, followed by chronic demyelination from which animals do not recover.

“In contrast, the continuous exposure of C57BL/6 mice to cuprizone results in a pattern of two cycles of demyelination and remyelination, followed by chronic demyelination from which animals do not recover 36, 39.”

• cites [36] 36. Mason JL, Langaman C, Morell P, Suzuki K, Matsushima GK (2001) Episodic demyelination and subsequent remyelination within the murine central nervous system: changes in axonal calibre. Neuropathol Appl Neurobiol 27:50–58. [DOI] [PubMed] [Google Scholar] sourceNot checked — no full text of the source
• cites [39] 39. Matsushima GK, Morell P (2001) The neurotoxicant, cuprizone, as a model to study demyelination and remyelination in the central nervous system. Brain Pathol 11:107–116. [DOI] [PMC free article] [PubMed] [Google Scholar] sourcePartly supported

  The paper’s summary passage describes cuprizone-induced demyelination in C57BL/6 mice and oligodendroglial progenitor activity despite continued exposure. It does not describe two cycles of demyelination and remyelination or establish that the animals cannot recover; it instead reports almost complete remyelination when cuprizone is withdrawn. The indexed passages provide no page number for this passage. (LLM, conf=0.82)

  Experimental — accuracy not yet measured

Probably not a substantial claim. The paper’s conclusions may not depend on it.

There are many examples of regional differences in dysmyelination caused by genetic manipulation of mice between areas such as the optic nerve, spinal cord, cerebellum and corpus callosum.

“There are many examples of regional differences in dysmyelination caused by genetic manipulation of mice between areas such as the optic nerve, spinal cord, cerebellum and corpus callosum.”

• cites [11] 11. Chun SJ, Rasband MN, Sidman RL, Habib AA, Vartanian T (2003) Integrin‐linked kinase is required for laminin‐2‐induced oligodendrocyte cell spreading and CNS myelination. J Cell Biol 163:397–408. [DOI] [PMC free article] [PubMed] [Google Scholar] sourcePartly supported

  The Results section, “Ultrastructural analysis of dy/dy mice: regional differences” (page unavailable), reports dysmyelination in the optic nerve and corpus callosum but not the spinal cord of mutant mice. The Discussion, “Regional differences” (page unavailable), also mentions a similar pattern in Fyn-knockout mice. Our copy does not document cerebellar differences or substantiate the broader assertion that there are many examples. (LLM, conf=0.85)

  Experimental — accuracy not yet measured
• cites [28] 28. Lee KK, De Repentigny Y, Saulnier R, Rippstein P, Macklin WB, Kothary R (2006) Dominant‐negative beta1 integrin mice have region‐specific myelin defects accompanied by alterations in MAPK activity. Glia 53:836–844. [DOI] [PubMed] [Google Scholar] sourceNot checked — no full text of the source

Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

BALB/cJ mice treated with 0.2% cuprizone have a similar pattern of demyelination in the corpus callosum but less demyelination and more microglia activation in the cortex compared with C57BL/6 mice.

“The BALB/cJ mice were reported to have a similar pattern of demyelination in the corpus callosum, but less demyelination and more microglia activation in the cortex as compared with C57BL/6 mice.”

• cites [48] sourceSupported

Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

Laminin-deficient dystrophia muscularis mice exhibit hypomyelination in the corpus callosum and optic nerve, but not the spinal cord.

“For example, laminin‐deficient dystrophia muscularis mice exhibit hypomyelination in the corpus callosum and optic nerve, but not the spinal cord (11)”

• cites [11] 11. Chun SJ, Rasband MN, Sidman RL, Habib AA, Vartanian T (2003) Integrin‐linked kinase is required for laminin‐2‐induced oligodendrocyte cell spreading and CNS myelination. J Cell Biol 163:397–408. [DOI] [PMC free article] [PubMed] [Google Scholar] sourceSupported

Probably not a substantial claim. The paper’s conclusions may not depend on it.

Strain differences have been reported for cortical demyelination induced by cuprizone.

“Recently, strain differences have been reported for cortical demyelination induced by cuprizone.”

• cites [48] sourceSupported

It may state two separate claims as one.

SJL mice demyelinate partially at midline, whereas C57BL/6 mice show robust demyelination, particularly at week 5.

“We found SJL mice demyelinate partially at midline (Figure 2A), whereas C57BL/6 mice show robust demyelination, particularly at week 5 2, 23, 35.”

• cites [2] 2. Arnett HA, Mason J, Marino M, Suzuki K, Matsushima GK, Ting JP (2001) TNF alpha promotes proliferation of oligodendrocyte progenitors and remyelination. Nat Neurosci 4:1116–1122. [DOI] [PubMed] [Google Scholar] sourceNot checked — no full text of the source
• cites [23] 23. Hiremath MM, Saito Y, Knapp GW, Ting JP, Suzuki K, Matsushima GK (1998) Microglial/macrophage accumulation during cuprizone‐induced demyelination in C57BL/6 mice. J Neuroimmunol 92:38–49. [DOI] [PubMed] [Google Scholar] sourceNot checked — no full text of the source
• cites [35] 35. Mason JL, Ye P, Suzuki K, D'Ercole AJ, Matsushima GK (2000) Insulin‐like growth factor‐1 inhibits mature oligodendrocyte apoptosis during primary demyelination. J Neurosci 20:5703–5708. [DOI] [PMC free article] [PubMed] [Google Scholar] sourceSupported

It may state two separate claims as one.

C57BL/6 mice experience a spontaneous partial remyelination after 6 weeks and then continue to demyelinate further when exposed continuously to cuprizone.

“In addition, C57BL/6 mice experience a spontaneous partial remyelination after 6 weeks and then continue to demyelinate further when exposed continuously to cuprizone 36, 39.”

• cites [36] 36. Mason JL, Langaman C, Morell P, Suzuki K, Matsushima GK (2001) Episodic demyelination and subsequent remyelination within the murine central nervous system: changes in axonal calibre. Neuropathol Appl Neurobiol 27:50–58. [DOI] [PubMed] [Google Scholar] sourceNot checked — no full text of the source
• cites [39] 39. Matsushima GK, Morell P (2001) The neurotoxicant, cuprizone, as a model to study demyelination and remyelination in the central nervous system. Brain Pathol 11:107–116. [DOI] [PMC free article] [PubMed] [Google Scholar] sourcePartly supported

  The opening passage (section and page not supplied) describes cuprizone-induced demyelination in C57BL/6 mice and progenitor-cell activity despite continued exposure. It does not say that partial remyelination occurs after six weeks or that further demyelination follows; it describes almost complete remyelination after cuprizone is stopped. (LLM, conf=0.82)

  Experimental — accuracy not yet measured

It may state two separate claims as one.

Unlike microglia and astrocytes in C57BL/6 mice that respond vigorously to demyelination, these cell types in SJL mice have a guarded response at midline and in the lateral region, which correlates with subdued demyelination.

“Thus, unlike microglia and astrocytes in C57BL/6 mice that respond vigorously to demyelination 2, 23, 39, these cell types in SJL mice have a guarded response at midline and in the lateral region, which correlates with subdued demyelination.”

• cites [2] 2. Arnett HA, Mason J, Marino M, Suzuki K, Matsushima GK, Ting JP (2001) TNF alpha promotes proliferation of oligodendrocyte progenitors and remyelination. Nat Neurosci 4:1116–1122. [DOI] [PubMed] [Google Scholar] sourceNot checked — no full text of the source
• cites [23] 23. Hiremath MM, Saito Y, Knapp GW, Ting JP, Suzuki K, Matsushima GK (1998) Microglial/macrophage accumulation during cuprizone‐induced demyelination in C57BL/6 mice. J Neuroimmunol 92:38–49. [DOI] [PubMed] [Google Scholar] sourceNot checked — no full text of the source
• cites [39] 39. Matsushima GK, Morell P (2001) The neurotoxicant, cuprizone, as a model to study demyelination and remyelination in the central nervous system. Brain Pathol 11:107–116. [DOI] [PMC free article] [PubMed] [Google Scholar] sourcePartly supported

  The introductory overview (page not provided) says that cuprizone-induced injury in C57BL/6 mice is closely followed by microglial recruitment and myelin phagocytosis. It does not establish a vigorous astrocyte response in those mice. The citation follows the C57BL/6 clause; the subsequent observation about SJL mice is the citing authors’ comparison, not a finding attributed to this source. (LLM, conf=0.83)

  Experimental — accuracy not yet measured

Probably not a substantial claim. The paper’s conclusions may not depend on it.

In EAE, administration of estrogens leads to functional benefits.

“In EAE, administration of estrogens lead to functional benefits 5, 25, 43, 52.”

• cites [5] 5. Bebo BF Jr, Fyfe‐Johnson A, Adlard K, Beam AG, Vandenbark AA, Offner H (2001) Low‐dose estrogen therapy ameliorates experimental autoimmune encephalomyelitis in two different inbred mouse strains. J Immunol 166:2080–2089. [DOI] [PubMed] [Google Scholar] sourceSupported
• cites [25] 25. Kim S, Liva SM, Dalal MA, Verity MA, Voskuhl RR (1999) Estriol ameliorates autoimmune demyelinating disease: implications for multiple sclerosis. Neurology 52:1230–1238. [DOI] [PubMed] [Google Scholar] sourceNot checked — no full text of the source
• cites [43] sourceNot checked — no full text of the source
• cites [52] sourceNot checked — no full text of the source

Probably not a substantial claim. The paper’s conclusions may not depend on it.

In MS there is a clear protection from relapse during the third trimester of pregnancy when several hormones, especially sex steroids, reach a peak.

“In MS there is a clear protection from relapse during the third trimester of pregnancy when several hormones, especially sex steroids, reach a peak (12).”

• cites [12] 12. Confavreux C, Hutchinson M, Hours MM, Cortinovis‐Tourniaire P, Moreau T (1998) Rate of pregnancy‐related relapse in multiple sclerosis. Pregnancy in Multiple Sclerosis Group. N Engl J Med 339:285–291. [DOI] [PubMed] [Google Scholar] sourcePartly supported

  The Results and Conclusions report that relapse rates in women with MS declined especially in the third trimester. The paper’s discussion proposes an immunologic explanation, but the passages in our copy do not say that hormones, particularly sex steroids, peak then; searches for those terms found no support for that part of the sentence. Page numbers were not provided for these passages. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

It may state two separate claims as one.

Female SJL mice were partially resistant to demyelination, whereas male SJL mice were more severely demyelinated.

“Importantly, female mice were partially resistant to demyelination, whereas male mice were more severely demyelinated.”

It may state two separate claims as one.

SJL mice did not readily demyelinate at the midline within the corpus callosum but showed greater demyelination immediately lateral to midline.

“The SJL mice did not readily demyelinate at the midline within the corpus callosum but showed greater demyelination immediately lateral to midline.”

It may state two separate claims as one.

In female SJL mice, demyelination showed a slow, delayed course, moderate from weeks 3 through 6, and did not reach a statistically significant difference from untreated until week 7.

“Equally important in female SJL mice, demyelination showed a slow, delayed course of demyelination (Figure 2B), which is moderate from weeks 3 through 6 and does not reach a statistically significant difference from untreated until week 7 (P < 0.001).”

It may state two separate claims as one.

During continuous exposure to cuprizone, demyelination in SJL mice was not complete and appeared to plateau after week 7.

“During continuous exposure to cuprizone, demyelination was not complete and appeared to plateau after week 7.”

It may state two separate claims as one.

The midline corpus callosum showed only partial demyelination and remyelination was not observed during the course of cuprizone administration.

“The midline corpus callosum showed only partial demyelination and remyelination was not observed during the course of cuprizone administration.”

The quote only partly states this claim.

In the lateral regions of the corpus callosum, a gradual depletion of mature oligodendrocytes is observed in both male and female SJL mice, beginning at week 3, compared with untreated mice.

“In the lateral regions of the corpus callosum, a gradual depletion of mature oligodendrocytes is observed in both male and female mice, beginning at week 3, compared with untreated mice (P < 0.01; Figure 3B).”

It may state two separate claims as one.

Very little demyelination was induced by 0.1% cuprizone, not significantly different from untreated.

“Very little demyelination was induced by 0.1% cuprizone, not significantly different from untreated.”

It may state two separate claims as one.

Over half of the animals from the 0.3% or greater cuprizone groups succumbed to the higher doses, similar to C57BL/6 mice.

“Over half of the animals from these groups succumbed to the higher doses, similar to C57BL/6 mice.”

It may state two separate claims as one.

Mild demyelination was detected in male SJL mice beginning at week 3, reaching statistical significance compared with untreated mice at weeks 5 and 6.

“Mild demyelination was detected in male SJL mice beginning at week 3, reaching statistical significance compared with untreated mice at weeks 5 and 6 (P < 0.05).”

It may state two separate claims as one.

Female SJL mice have more oligodendrocytes than male counterparts at all time points in the lateral regions, and this gender effect is highly significant.

“Female mice have more oligodendrocytes than male counterparts at all time points, and this gender effect is highly significant (P < 0.0001).”

It may state two separate claims as one.

More robust demyelination was observed in male SJL mice at week 7, reaching a plateau through week 10.

“More robust demyelination was observed in males at week 7 (P < 0.001), reaching a plateau through week 10.”

It may state two separate claims as one.

Unlike male C57BL/6 mice, which show three cycles of demyelination over 13 weeks, SJL mice appear to demyelinate gradually once during these time points, and the demyelination is incomplete.

“Thus, unlike male C57BL/6 mice, which show three cycles of demyelination while on continuous exposure to cuprizone over 13 weeks (36), SJL mice appear to demyelinate gradually once during these time points; however, the demyelination is incomplete.”

• cites [36] 36. Mason JL, Langaman C, Morell P, Suzuki K, Matsushima GK (2001) Episodic demyelination and subsequent remyelination within the murine central nervous system: changes in axonal calibre. Neuropathol Appl Neurobiol 27:50–58. [DOI] [PubMed] [Google Scholar] sourceNot checked — no full text of the source

It may state two separate claims as one.

The number of mature oligodendrocytes at midline is initially diminished at week 3 but did not reach a statistically significant difference from untreated mice until week 5.

“As shown in Figure 3A, the number of mature oligodendrocytes at midline is initially diminished at week 3 but did not reach a statistically significant difference from untreated mice until week 5.”

It may state two separate claims as one.

From weeks 5 to 10, female SJL mice exhibited less demyelination than male counterparts, and this gender effect over the entire observed time period is significant.

“From weeks 5 to 10, female SJL mice exhibited less demyelination than male counterparts, and this gender effect over the entire observed time period is significant (two‐factor ANOVA P = 0.0305).”

The quote only partly states this claim.

There are significantly more mature oligodendrocytes in female SJL mice than male mice.

“Thus, similar to demyelination in Figure 2, there are significantly more mature oligodendrocytes in female mice than male mice.”

Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.

Similar layers that show differential demyelination in C57BL/6 mice occur in a more caudal region of the corpus callosum next to the hippocampus.

“Similar layers that show differential demyelination in C57BL/6 mice occur in a more caudal regions of the corpus callosum next to the hippocampus (data not shown) and the reason for these differences is not clear.”

Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds. It may state two separate claims as one.

129 mice have similar patterns of demyelination in the corpus callosum as C57BL/6 mice but demyelinate at a lower dose of 0.1% cuprizone.

“This may be also true for 129 mice that have similar patterns of demyelination in the corpus callosum as C57BL/6, but demyelinate at a lower dose of 0.1% of cuprizone (data not shown).”

It may state two separate claims as one.

At many time points, male SJL mice were more severely demyelinated than female SJL mice in both midline and lateral regions, and the overall gender effect was statistically significant.

“At many time points, male mice were more severely demyelinated than female mice in both midline and lateral regions, and the overall gender effect was statistically significant.”

It may state two separate claims as one.

When cuprizone administration was discontinued at week 7 and mice recovered for 3 weeks, a modest increase in oligodendrocytes was observed at both midline and lateral regions, with statistical significance only in the lateral region.

“When cuprizone administration was discontinued at week 7 and mice were allowed to recover for 3 weeks, a modest increase in oligodendrocytes was observed at both midline and lateral regions; however, statistical significance was observed only in the lateral region (Figure 3B, P < 0.05 for both male and females).”

It may state two separate claims as one.

Demyelination is only partial in SJL mice through 10 weeks of continuous cuprizone treatment, whereas full demyelination is observed at week 5 in C57BL/6 mice.

“Second, demyelination is only partial in SJL mice through 10 weeks of continuous treatment whereas full demyelination is observed at week 5 in C57BL/6.”

• Also stated in: § DISCUSSION · plain

  “One of the more striking differences in SJL mice is the lack of total demyelination during a 10‐week period of continuous exposure to cuprizone.”

It may state two separate claims as one.

Even up to week 13 of continuous cuprizone exposure, demyelination scores were approximately 0.75 for males and 1.0 for females at the lateral region, similar to week 10 scores.

“Even up to week 13 of continuous exposure to cuprizone, demyelination scores were approximately 0.75 for males and 1.0 for females at the lateral region, similar to week 10 scores in Figure 2B.”

It may state two separate claims as one.

SJL mice treated with cuprizone for 7 weeks and then allowed to recover for 3 weeks showed only slight remyelination, unlike C57BL/6 mice that remyelinate quickly upon discontinuation of cuprizone.

“Furthermore, unlike C57BL/6 mice that remyelinate quickly upon discontinuation of cuprizone, SJL mice that were treated with cuprizone for 7 weeks and then allowed to recover for 3 weeks showed only slight remyelination.”

• Also stated in: § DISCUSSION · plain

  “An additional interesting difference of SJL mice from C57BL/6 mice is the lack of robust remyelination after 3 weeks of recovery from the cuprizone diet.”

It may state two separate claims as one.

Microglia accumulation at midline in both male and female SJL mice is detected at weeks 3 and 5 and becomes statistically significant compared with untreated mice during weeks 6 through 10.

“As show in Figure 5A, microglia accumulation at midline in both male and female mice is detected at weeks 3 and 5 and becomes statistically significant compared with untreated mice during weeks 6 through 10 (P < 0.05).”

It may state two separate claims as one. The quote only partly states this claim.

After exposure to cuprizone, a higher number of astrocytes begin to populate the midline of the corpus callosum and by week 5, they appear to have reached maximal numbers in both male and female SJL mice.

“After exposure to cuprizone, a higher number of astrocytes begin to populate the midline of the corpus callosum and by week 5, they appear to have reached maximal numbers in both male and female mice (Figure 6A).”

It may state two separate claims as one.

In C57BL/6 mice, no apparent remyelination is detected in the midst of demyelination, and remyelinated axons are not detected until after complete demyelination at week 5.

“However, in C57BL/6 mice, we do not detect any apparent remyelination in the midst of demyelination, and remyelinated axons are not detected until after complete demyelination that occurs at week 5.”

It may state two separate claims as one.

During cuprizone intoxication, OPC numbers increase gradually, becoming statistically significant at the 8-week time point.

“During cuprizone intoxication, OPC numbers increase gradually, becoming statistically significant at the 8‐week time point.”

Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

SJL mice die or are lethargic at 0.3% cuprizone, and higher doses of 0.4, 0.5 and 0.6% resulted in death within the first couple of weeks.

“Similar to C57BL/6 mice (23), SJL mice die or are lethargic at 0.3%, and higher doses of 0.4, 0.5 and 0.6% resulted in death within the first couple of weeks.”

• cites [23] 23. Hiremath MM, Saito Y, Knapp GW, Ting JP, Suzuki K, Matsushima GK (1998) Microglial/macrophage accumulation during cuprizone‐induced demyelination in C57BL/6 mice. J Neuroimmunol 92:38–49. [DOI] [PubMed] [Google Scholar] sourceNot checked — no full text of the source

It may state two separate claims as one.

In the lateral regions, the microglial response was more robust, with nearly 30% more microglia/mm2 than at midline, and there was a slight decrease at week 10.

“In the lateral regions, the microglial response was more robust, with nearly 30% more microglia/mm2 than at midline, and there was a slight decrease at week 10.”

It may state two separate claims as one.

At the 0.2% cuprizone dose, liver sections showed little indication of toxicity in either gender as indicated by vacuolation or necrosis, but male mice exhibited an increase in binucleated hepatocytes compared with untreated mice, whereas females did not.

“Analysis of liver sections indicated that at the 0.2% cuprizone dose, there is little indication of toxicity in either gender as indicated by vacuolation or necrosis, but male mice do exhibit an increase in binucleated hepatocytes compared with untreated mice, whereas females do not (data not shown).”

It may state two separate claims as one.

Unlike microglia, astrocyte numbers in the lateral regions remained similar to numbers at midline and did not increase appreciably.

“Unlike microglia, astrocyte numbers in the lateral regions remained similar to numbers at midline and did not increase appreciably.”

It may state two separate claims as one. The quote only partly states this claim.

In the midline corpus callosum, microglia accumulation began by week 3 and reached statistically significant numbers compared with untreated mice by week 6, then remained unchanged through week 10, in both male and female SJL mice.

“In the midline corpus callosum microglia accumulation began by week 3 and reached statistically significant numbers compared with untreated mice by week 6, then remained unchanged through week 10, in both male and female mice.”

Probably not a substantial claim. The paper’s conclusions may not depend on it.

In C57BL/6 mice, 0.2% cuprizone is optimal to induce full demyelination of the midline corpus callosum at week 5.

“In the C57BL/6 strain, initial studies indicated that a lower dose of 0.2% of cuprizone was optimal (23) to induce full demyelination of the midline corpus callosum at week 5.”

• cites [23] 23. Hiremath MM, Saito Y, Knapp GW, Ting JP, Suzuki K, Matsushima GK (1998) Microglial/macrophage accumulation during cuprizone‐induced demyelination in C57BL/6 mice. J Neuroimmunol 92:38–49. [DOI] [PubMed] [Google Scholar] sourceNot checked — no full text of the source

Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

Men with MS may develop less inflammatory but more destructive lesions.

“This suggests that men with MS may develop less inflammatory but more destructive lesions.”

• cites [47] sourceNot checked — no full text of the source

Probably not a substantial claim.

Female SJL and ASW mice have more severe EAE than males when induced by active immunization.

“A comprehensive comparison of EAE clinical disease scores in several mouse strains revealed that female SJL and ASW have more severe EAE than males when induced by active immunization (44).”

• cites [44] sourceNot checked — no full text of the source

Probably not a substantial claim. It may be too vague to check against evidence.

The SJL strain is a logical choice for gender studies in the cuprizone model.

“The fact that SJL mice show gender differences in both the EAE and TMEV models indicates that the SJL strain is a logical choice for gender studies in the cuprizone model.”

• AssumptionRests on an assumption: Gender differences observed in the EAE and TMEV models are predictive of gender differences in the cuprizone model.

Probably not a substantial claim.

Male SJL/J mice display more severe neurological deficits than female mice in TMEV-induced demyelinating disease.

“In this model, male SJL/J display more severe neurological deficits than female mice (1).”

• cites [1] 1. Alley J, Khasabov S, Simone D, Beitz A, Rodriguez M, Njenga MK (2003) More severe neurologic deficits in SJL/j male than female mice following Theiler's virus‐induced CNS demyelination. Exp Neurol 180:14–24. [DOI] [PubMed] [Google Scholar] sourceNot checked — no full text of the source

Probably not a substantial claim.

Sections were scored blinded based on the amount of blue or pink fibers in the corpus callosum.

“Sections were scored blinded based on the amount of blue or pink fibers in the corpus callosum, on a scale of 3 (complete myelination equal to an untreated mouse) to 0 (complete demyelination, as seen during peak cuprizone demyelination).”

It may state two separate claims as one.

Genetic factors and gender influence susceptibility to demyelinating disease in the cuprizone model.

“Thus, genetic factors and gender influence susceptibility to demyelinating disease in the cuprizone model, which may provide additional insights into the variability observed in human demyelinating diseases such as multiple sclerosis.”

• AssumptionRests on an assumption: The observed gender differences in demyelination are due to gender or genetic factors rather than other confounders.

Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

Many ICI and Swiss Webster mice lived for months on the cuprizone diet, though not all tolerated it.

“Though not tolerated by all of these mice, many of them mice lived for months on the cuprizone diet.”

• cites [8] 8. Blakemore WF (1974) Remyelination of the superior cerebellar peduncle in old mice following demyelination induced by cuprizone. J Neurol Sci 22:121–126. [DOI] [PubMed] [Google Scholar] sourceNot checked — no full text of the source
• cites [27] 27. Komoly S, Jeyasingham MD, Pratt OE, Lantos PL (1987) Decrease in oligodendrocyte carbonic anhydrase activity preceding myelin degeneration in cuprizone induced demyelination. J Neurol Sci 79:141–148. [DOI] [PubMed] [Google Scholar] sourceNot checked — no full text of the source
• cites [31] 31. Ludwin SK (1978) Central nervous system demyelination and remyelination in the mouse: an ultrastructural study of cuprizone toxicity. Lab Invest 39:597–612. [PubMed] [Google Scholar]Not checked — no full text of the source

Probably not a substantial claim. The paper’s conclusions may not depend on it.

One limitation of the LFB-PAS stain is that it cannot detect whether any remyelination is occurring during the demyelination period.

“However, one limitation of the LFB–PAS stain is that one cannot detect whether any remyelination is occurring during the demyelination period.”

It may state two separate claims as one.

The increase in oligodendrocytes indicates that SJL mice are capable of recovery from cuprizone-induced oligodendrocyte loss and correlates with the remyelination observed.

“This increase in oligodendrocytes indicates that SJL mice are capable of recovery from cuprizone‐induced oligodendrocyte loss and correlates with the remyelination observed in Figure 2A,B.”

Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

Dominant negative β1 integrin ΔC mice are hypomyelinated in spinal cord and optic nerve, but not the corpus callosum.

“whereas dominant negative β1 integrin ΔC mice are hypomyelinated in spinal cord and optic nerve, but not the corpus callosum (28).”

• cites [28] 28. Lee KK, De Repentigny Y, Saulnier R, Rippstein P, Macklin WB, Kothary R (2006) Dominant‐negative beta1 integrin mice have region‐specific myelin defects accompanied by alterations in MAPK activity. Glia 53:836–844. [DOI] [PubMed] [Google Scholar] sourceNot checked — no full text of the source

Probably not a substantial claim. It may be too vague to check against evidence. The paper’s conclusions may not depend on it. It may state two separate claims as one.

The remyelination analysis performed here is limited, and a more thorough examination to determine whether remyelination progresses further would require later time points.

“However, it should be emphasized that the remyelination analysis performed here is limited, and a more thorough examination to determine whether remyelination progresses further would require later time points.”

It may state two separate claims as one.

Female SJL mice are more resistant to oligodendrocyte loss and demyelination than male SJL mice, and this trend was observed at most time points between weeks 5 through 10.

“Thus, female SJL mice are more resistant to oligodendrocyte loss and demyelination, and this trend was observed at most of the time points between weeks 5 through 10.”

Probably not a substantial claim. The paper’s conclusions may not depend on it.

Studies of ICI and Swiss Webster mice used 0.5% to 0.6% cuprizone in their diet to induce demyelination.

“Studies of ICI and Swiss Webster mice used 0.5% to 0.6% cuprizone in their diet to induce demyelination 8, 27, 31.”

• cites [8] 8. Blakemore WF (1974) Remyelination of the superior cerebellar peduncle in old mice following demyelination induced by cuprizone. J Neurol Sci 22:121–126. [DOI] [PubMed] [Google Scholar] sourceNot checked — no full text of the source
• cites [27] 27. Komoly S, Jeyasingham MD, Pratt OE, Lantos PL (1987) Decrease in oligodendrocyte carbonic anhydrase activity preceding myelin degeneration in cuprizone induced demyelination. J Neurol Sci 79:141–148. [DOI] [PubMed] [Google Scholar] sourceNot checked — no full text of the source
• cites [31] 31. Ludwin SK (1978) Central nervous system demyelination and remyelination in the mouse: an ultrastructural study of cuprizone toxicity. Lab Invest 39:597–612. [PubMed] [Google Scholar]Not checked — no full text of the source

Probably not a substantial claim.

We could not examine SJL mice at cuprizone doses of 0.3% or greater because they are susceptible to systemic toxicity.

“Although higher doses may induce full demyelination, we could not examine SJL mice at doses of 0.3% or greater as they are susceptible to systemic toxicity.”

Probably not a substantial claim. The paper’s conclusions may not depend on it.

Swiss female mice have been reported to be resistant to cuprizone-induced demyelination.

“A final note, Swiss female mice have been reported to be resistant to cuprizone‐induced demyelination; however, the mechanism for such differences compared with male Swiss mice is not known (31).”

• cites [31] 31. Ludwin SK (1978) Central nervous system demyelination and remyelination in the mouse: an ultrastructural study of cuprizone toxicity. Lab Invest 39:597–612. [PubMed] [Google Scholar]Not checked — no full text of the source

Probably not a substantial claim. The paper’s conclusions may not depend on it.

This study did not address specific functions of microglia or astrocytes, which may also be influenced by sex hormones.

“This study did not address specific functions of microglia or astrocytes, which may also be influenced by sex hormones 9, 13, 14, 19, 26, 40).”

• cites [9] 9. Brown CM, Wright E, Colton CA, Sullivan PM, Laskowitz DT, Vitek MP (2002) Apolipoprotein E isoform mediated regulation of nitric oxide release. Free Radic Biol Med 32:1071–1075. [DOI] [PubMed] [Google Scholar] sourceNot checked — no full text of the source
• cites [13] 13. Drew PD, Chavis JA (2000) Female sex steroids: effects upon microglial cell activation. J Neuroimmunol 111:77–85. [DOI] [PubMed] [Google Scholar] sourceNot checked — no full text of the source
• cites [14] 14. Drew PD, Chavis JA, Bhatt R (2003) Sex steroid regulation of microglial cell activation: relevance to multiple sclerosis. Ann N Y Acad Sci 1007:329–334. [DOI] [PubMed] [Google Scholar] sourceNot checked — no full text of the source
• cites [19] 19. Fuller A, Yahikozawa H, So EY, Dal Canto M, Koh CS, Welsh CJ, Kim BS (2007) Castration of male C57L/J mice increases susceptibility and estrogen treatment restores resistance to Theiler's virus‐induced demyelinating disease. J Neurosci Res 85:871–881. [DOI] [PubMed] [Google Scholar] sourceNot checked — no full text of the source
• cites [26] 26. Kipp M, Karakaya S, Johann S, Kampmann E, Mey J, Beyer C (2007) Oestrogen and progesterone reduce lipopolysaccharide‐induced expression of tumour necrosis factor‐alpha and interleukin‐18 in midbrain astrocytes. J Neuroendocrinol 19:819–822. [DOI] [PubMed] [Google Scholar] sourceNot checked — no full text of the source
• cites [40] 40. Mendez P, Wandosell F, Garcia‐Segura LM (2006) Cross‐talk between estrogen receptors and insulin‐like growth factor‐I receptor in the brain: cellular and molecular mechanisms. Front Neuroendocrinol 27:391–403. [DOI] [PubMed] [Google Scholar] sourceNot checked — no full text of the source

It may state two separate claims as one.

Sex hormones have been shown to have direct effects on oligodendrocyte proliferation and maturation as well as survival.

“In addition, sex hormones have been shown to have direct effects on oligodendrocyte proliferation and maturation 21, 33 as well as survival 20, 51.”

• cites [21] 21. Ghoumari AM, Baulieu EE, Schumacher M (2005) Progesterone increases oligodendroglial cell proliferation in rat cerebellar slice cultures. Neuroscience 135:47–58. [DOI] [PubMed] [Google Scholar] sourceNot checked — no full text of the source
• cites [33] 33. Marin‐Husstege M, Muggironi M, Raban D, Skoff RP, Casaccia‐Bonnefil P (2004) Oligodendrocyte progenitor proliferation and maturation is differentially regulated by male and female sex steroid hormones. Dev Neurosci 26:245–254. [DOI] [PubMed] [Google Scholar] sourceNot checked — no full text of the source
• cites [20] 20. Gerstner B, Sifringer M, Dzietko M, Schuller A, Lee J, Simons S et al (2007) Estradiol attenuates hyperoxia‐induced cell death in the developing white matter. Ann Neurol 61:562–573. [DOI] [PubMed] [Google Scholar] sourceNot checked — no full text of the source
• cites [51] sourceNot checked — no full text of the source

Probably not a substantial claim. The paper’s conclusions may not depend on it.

Studies of dietary copper deficiency in rats indicate that females exhibit less severe symptoms of weight loss, anemia and lethality.

“Studies of dietary copper deficiency in rats indicate that females exhibit less severe symptoms of weight loss, anemia and lethality 16, 17, 18.”

• cites [16] 16. Farquharson C, Robins SP (1988) Female rats are susceptible to cardiac hypertrophy induced by copper deficiency: the lack of influence of estrogen and testosterone. Proc Soc Exp Biol Med 188:272–281. [DOI] [PubMed] [Google Scholar] sourceNot checked — no full text of the source
• cites [17] 17. Fields M, Lewis C, Scholfield DJ, Powell AS, Rose AJ, Reiser S, Smith JC (1986) Female rats are protected against the fructose induced mortality of copper deficiency. Proc Soc Exp Biol Med 183:145–149. [DOI] [PubMed] [Google Scholar] sourceNot checked — no full text of the source
• cites [18] 18. Fields M, Lewis CG, Beal T, Scholfield D, Patterson K, Smith JC, Reiser S (1987) Sexual differences in the expression of copper deficiency in rats. Proc Soc Exp Biol Med 186:183–187. [DOI] [PubMed] [Google Scholar] sourceNot checked — no full text of the source

Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

One study found an exacerbation of some copper-deficient symptoms, such as weight loss, in ovariectomized females, but no effect on severity by male or female sex hormones was detected in another study.

“One study found an exacerbation of some copper‐deficient symptoms, such as weight loss, in ovariectomized females (10) but no effect on severity by male or female sex hormones was detected in another study (16).”

• cites [10] 10. Bureau I, Gueux E, Mazur A, Rock E, Roussel AM, Rayssiguier Y (2003) Female rats are protected against oxidative stress during copper deficiency. J Am Coll Nutr 22:239–246. [DOI] [PubMed] [Google Scholar] sourceNot checked — no full text of the source
• cites [16] 16. Farquharson C, Robins SP (1988) Female rats are susceptible to cardiac hypertrophy induced by copper deficiency: the lack of influence of estrogen and testosterone. Proc Soc Exp Biol Med 188:272–281. [DOI] [PubMed] [Google Scholar] sourceNot checked — no full text of the source

Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

Female SJL mice infected with TMEV show less severe neurological deficits and a moderate (though not statistically significant) resistance to demyelination compared with males.

“Similar to our findings in the cuprizone model, female SJL mice infected with TMEV show less severe neurological deficits and a moderate (though not statistically significant) resistance to demyelination compared with males (1).”

• cites [1] 1. Alley J, Khasabov S, Simone D, Beitz A, Rodriguez M, Njenga MK (2003) More severe neurologic deficits in SJL/j male than female mice following Theiler's virus‐induced CNS demyelination. Exp Neurol 180:14–24. [DOI] [PubMed] [Google Scholar] sourceNot checked — no full text of the source

Probably not a substantial claim.

There is much evidence for a role of sex hormones in demyelination and oligodendrocyte function.

“There is much evidence for a role of sex hormones in demyelination and oligodendrocyte function.”

It may state two separate claims as one.

The difference in gender effects between EAE and cuprizone models may reflect a key difference: EAE has an autoimmune etiology, whereas cuprizone delivers a toxic injury to oligodendrocytes.

“The fact that female SJL mice show increased severity in EAE, but decreased severity in cuprizone intoxication may reflect a key difference between EAE and cuprizone models: EAE has an autoimmune etiology, whereas cuprizone delivers a toxic injury to oligodendrocytes.”

• AssumptionRests on an assumption: EAE and cuprizone models differ in that EAE has an autoimmune etiology and cuprizone delivers a toxic injury to oligodendrocytes.

It may state two separate claims as one.

In the EAE model, female SJL mice are both more susceptible to disease induction and exhibit more severe neurological deficits.

“Nevertheless, these findings of gender differences are in contrast to those in the EAE model, in which female SJL mice are both more susceptible to disease induction and exhibit more severe neurological deficits 3, 44, 53.”

• cites [3] 3. Bebo BF Jr, Vandenbark AA, Offner H (1996) Male SJL mice do not relapse after induction of EAE with PLP 139‐151. J Neurosci Res 45:680–689. [DOI] [PubMed] [Google Scholar] sourceNot checked — no full text of the source
• cites [44] sourceNot checked — no full text of the source
• cites [53] sourceNot checked — no full text of the source

It may state two separate claims as one.

The utility of both EAE and cuprizone models for the study of MS is supported by heterogeneity in MS lesions, in which type III and IV lesions suggest primary oligodendrocyte dystrophy, whereas type I and II lesions are consistent with T- or B-cell-associated autoimmune mechanisms.

“The utility of both models for the study of MS is supported by heterogeneity in MS lesions, reported by Lucchinetti et al (30), in which type III and IV lesions suggest primary oligodendrocyte dystrophy, whereas type I and II lesions are consistent with T‐ or B‐cell‐associated autoimmune mechanisms.”

• cites Lucchinetti et al (30)Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Probably not a substantial claim. It may be too vague to check against evidence.

Cuprizone intoxication of SJL mice will be a useful model to study the role of sex hormones in primary oligodendrocyte disruption.

“Cuprizone intoxication of SJL mice will be a useful model to study the role of sex hormones in primary oligodendrocyte disruption.”

It may state two separate claims as one.

SJL female mice are more resistant than males to loss of oligodendrocytes and demyelination, though there were no gender differences in microglial or astrocytic accumulation.

“Importantly, SJL female mice are more resistant than males to loss of oligodendrocytes and demyelination, though there were no gender differences in microglial or astrocytic accumulation.”