The hypothesis of this FDA-IRB approved open-label pilot trial was that patients with ASD and mt dysfunction would improve clinically and/or biochemically following treatment with a combination of carnitine, coenzyme Q10 and alpha-lipoic acid (MitoCocktail).
The aims of this study were to examine the effects of the Booroola FecB gene on ovarian development and reproductive hormones (FSH, LH and inhibin) at days 90, 100, 120 and 135 of gestation (term = 147 days). The effects of litter size were eliminated by transferring equal numbers of homozygous BB and control (++) embryos to recipient ewes. The ovary, but not the body, pituitary, adrenal, kidney or thymus, was heavier (P < 0.05) in BB compared with ++ fetuses at day 90 but not thereafter. In the ovary, gene-specific differences were observed in the total number of germ cells present at days 90 (P< 0.01) and 135 (P < 0.05) with the same tendency being noted at day 100 (P < 0.07); at all of these ages the mean numbers of germ cells in the BB genotype exceeded those in ++ animals. Gene-specific differences were observed in the numbers of oogonia and isolated oocytes at day 90 (i.e. BB > ++), in the number of primordial follicles at days 100 (BB > ++) and 135 (BB > ++), and also in the number of primary or secondary follicles (++ > BB) at day 135. At each gestational age examined no differences were noted with respect to the plasma concentrations of FSH, LH or inhibin between the BB and ++ fetuses. However, the highest mean plasma concentrations of FSH and LH occurred at days 90 and 100 of gestation, which coincided with the first developing primary follicles. Collectively, the results from this and previous studies show that the different effects of the FecB gene in germ cell development in early gestation continue throughout fetal development independently of litter size. Moreover, during the growth of the first primary and secondary follicles at days 100 and 120, respectively, there are no differences in the plasma concentrations of FSH, LH and inhibin with respect to Booroola genotype.
The Inverdale gene (fecX'), located on the X chromosome, is a major gene affecting the ovulation rate of sheep. At each ovulation, ewes heterozygous (1+) for the I gene ovulate, on average, one more egg than noncarriers (++), whereas ewes that are homozygous (II) for this gene are infertile and have “streak” ovaries. Since formation of the ovary occurs in fetal life, it is possible that the fecX' gene influences ovarian development before birth. The aims of this study were to examine the effects of the I gene on germ cell development, follicular formation and growth, and plasma gonadotropin concentrations at 5 different days of gestation (i.e., Days 40, 90, 105, 120, and 135) and also in adult life. The results suggest that one copy of the X-linked mutation in female fetuses leads to a retardation of germ cell development at Days 40 and 90 of gestation. However, from Day 105 of gestation, follicular formation and growth appear normal. By contrast, in females with two copies of the X-linked mutation, germ cell development and follicular formation appear normal, but thereafter follicular growth from the primary stage of development is impaired. During fetal life the plasma concentrations of FSH and LH, although not measurable at Day 40, were similar between all the genotypes at Day 105, 120, and 135 of gestation. The only exception was for LH at Day 90 in the + and II animals: in ewes with these genotypes the plasma concentrations of LH were similar but significantly lower (p < 0.01) than in the + + genotype. In adult animals the plasma concentrations of FSH and LH were not different between the ++ and I+ genotypes, reflecting similar levels of ovarian follicular activity. However, in adult II animals, the plasma concentrations of FSH and LH were significantly higher (both p < 0.01) than in the ++ and I+ genotypes, reflecting the absence of normal secondary and antral follicles. In summary, these data show that the I gene affects ovarian development before birth and that the nature of the effect is influenced by whether the female fetus is a homozygous or heterozygous carrier of the X-linked mutation.
Emerging research suggests that mitochondrial (mt) dysfunction is important in the pathogenesis of autism spectrum disorder (ASD). The hypothesis of this open-label pilot trial was that patients with ASD and mt dysfunction would improve clinically and biochemically following treatment with combination of carnitine, coenzyme Q10 and alpha-lipoic acid (MitoCocktail) . Participants fulfilled diagnostic criteria for ASD and had abnormal buccal swab mt RCC (respiratory chain complexes) I and/or IV activity. Eleven patients aged 5-12 years, received MitoCocktail daily for 3 months. Behavioral outcome was evaluated with Autism Diagnostic Observation Schedule (ADOS-2), Autism Spectrum Rating Scale (ASRS) and Aberrant Behavior Checklist (ABC) at baseline (T1), 3 months into treatment (T2), and 3 months post-treatment (T3). Three scores from ADOS-2, 3 from ASRS, and 5 from ABC were contrasted at T1, T2 and T3. RCC I and IV were measured across these time points. For statistical analysis paired t-tests were used. RCC I/IV ratio was significantly (p<0.02) reduced during MitoCocktail treatment. All subjects showed at least one sign of metabolic improvement, which waned 3 months post-treatment in 7/11 participants. All of the 11 total or subscale mean scores improved from T1 to T2. Significant changes were observed for Unusual Behavior subscale from ASRS (p<0.006), Lethargy subscale from ABC (p <0.01), and Inappropriate Speech subscale from ABC (p<0.02). From T2 to T3, scores worsened on these three subscales being significant for Lethargy (p<0.01) and Inappropriate Speech (p<0.007). This small pilot study supports the hypothesis that MitoCocktail may have a therapeutic benefit in ASD.
In female fetuses the Booroola gene (FecBB) is known to affect germ cell development and consequently the pattern of ovarian follicular growth during fetal and post-natal life. However in males, the role of this gene during fetal development is unknown. The aims of the study reported here were to examine the effects of the FecBB gene on development of male fetuses with respect to body and organ mass (for example, pituitary gland, adrenal and mesonephros), testes development, including numbers of germ cells, and also the plasma concentrations or tissue contents of the reproductive hormones (FSH, LH and testosterone) at days 40, 55, 75, 90 and 135 of gestation. The FecBB gene was found to influence litter size, bodymass, crown–rump length and testis mass at most stages of gestation. Some effects were also noted on the mesonephros at days 40 and 55 and on the pituitary and adrenal at days 90 or 135 of gestation. However, the FecBB gene was not observed to have an effect on the patterns of germ cell development, on pituitary content or plasma concentrations of immunoreactive or bioactive FSH or immunoreactive LH or testicular content of testosterone. When embryo transfer experiments were performed to eliminate the effects of litter size at days 40, 90 and 135 of gestation nearly all of the differences in bodymass, crown–rump length and organ mass disappeared. The only exception to this was at day 90 when bodymass continued to be lighter and crown–rump lengths smaller in the BB/B + fetuses compared with the ++ fetuses; the significance of this finding remains unknown. It is concluded that for Booroola male fetuses there are no direct effects of the FecBB gene on pituitary gonadotrophin function or testicular development after sexual differentiation. Moreover, although there may be temporal differences around day 90 of gestation, there are no long-term, direct effects of the FecBB gene on total body, adrenal, testis or pituitary mass. Collectively these findings for the male are similar to those for female fetuses except with regard to germ cell development.
Introduction Lithium is a highly effective treatment in the management of Bipolar Affective Disorder (BPAD) however it is associated with increased risk of developing chronic kidney disease. There is a lack of clear guidance on alternative approaches to managing those individuals that require cessation of lithium due to progression to end stage renal disease (ESRD). Objectives We discuss two patients with BPAD on lithium therapy who have developed ESRD. In both cases, lithium was discontinued due to ESRD, with alternatives trialled. In one case, the patient continues to be managed without lithium, whereas in the second, a decision was made to recommence lithium at a low dose. We reviewed the literature to provide meaningful context to the cases. Methods Case 1 This patient with a long history of BPAD and multiple medical co-morbidities experienced progressive decline in renal function. A decision was made to cease lithium therapy with close monitoring for signs of affective relapse. The patient was stabilised using a combination of sodium valproate and quetiapine. Since cessation of lithium, the patient has required a significant increase in support from the CMHT and more frequent admissions to manage mood and anxiety symptoms that cause significant subjective distress. Results Case 2 This patient had a long history of stable BPAD, with no episodes of illness for over 30 years. Unfortunately they developed CKD and despite a significant reduction in lithium over time, they developed ESRD requiring haemodialysis. Lithium was discontinued leading to a manic relapse of BPAD requiring a prolonged admission and a combination of carbamezapine, olanzapine, escitalopram and clonazepam to stabilise their mental state. Following discharge home, their mental state failed to reach baseline and they reported significant anxiety symptoms and memory impairment. Following protracted assessment and support they were deemed unfit for renal transplant and a decision was then made by the patient, their family, nephrology and psychiatry to recommence lithium therapy whilst on haemodialysis. Their anxiety and functioning improved significantly following the reintroduction of low dose lithium, allowing the withdrawal of other neuroleptics. Conclusions Both cases required an individual approach to balance physical and mental health considerations. There are no clear markers to predict if a patient will respond to alternative mood stabilisers, nor is there a guarantee that kidney function will improve or stop declining when lithium is discontinued. Decisions should reflect patient preference and balance risks associated with relapse and of declining ESRD. Disclosure of Interest None Declared
'/%3e%3cuse xlink:href='%23a' transform='rotate(72 0 0)'/%3e%3cuse xlink:href='%23a' transform='rotate(-72 0 0)'/%3e%3cuse xlink:href='%23a' transform='scale(-1 1) rotate(72)'/%3e%3c/g%3e%3c/defs%3e%3cpath fill='%23012169' d='M0 0h1200v600H0z'/%3e%3cpath stroke='%23FFF' stroke-width='60' d='m0 0 600 300M0 300 600 0' clip-path='url(%23b)'/%3e%3cpath stroke='%23C8102E' stroke-width='40' d='m0 0 600 300M0 300 600 0' clip-path='url(%23c)'/%3e%3cpath stroke='%23FFF' stroke-width='100' d='M300 0v300M0 150h600' clip-path='url(%23b)'/%3e%3cpath stroke='%23C8102E' stroke-width='60' d='M300 0v300M0 150h600' clip-path='url(%23b)'/%3e%3cuse xlink:href='%23d' fill='%23FFF' transform='matrix(45.4 0 0 45.4 900 120)'/%3e%3cuse xlink:href='%23d' fill='%23C8102E' transform='matrix(30 0 0 30 900 120)'/%3e%3cg transform='rotate(82 900 240)'%3e%3cuse xlink:href='%23d' fill='%23FFF' transform='rotate(-82 519.022 -457.666) scale(40.4)'/%3e%3cuse xlink:href='%23d' fill='%23C8102E' transform='rotate(-82 519.022 -457.666) scale(25)'/%3e%3c/g%3e%3cg transform='rotate(82 900 240)'%3e%3cuse xlink:href='%23d' fill='%23FFF' transform='rotate(-82 668.57 -327.666) scale(45.4)'/%3e%3cuse xlink:href='%23d' fill='%23C8102E' transform='rotate(-82 668.57 -327.666) scale(30)'/%3e%3c/g%3e%3cuse xlink:href='%23d' fill='%23FFF' transform='matrix(50.4 0 0 50.4 900 480)'/%3e%3cuse xlink:href='%23d' fill='%23C8102E' transform='matrix(35 0 0 35 900 480)'/%3e%3c/svg%3e)
'/%3e%3cuse xlink:href='%23a' transform='rotate(144 450 300)'/%3e%3cuse xlink:href='%23a' transform='rotate(216 450 300)'/%3e%3cuse xlink:href='%23a' transform='rotate(288 450 300)'/%3e%3c/svg%3e)