Age-related complexity and coupling of children's sitting posture

This study tested the hypothesis that postural complexity increases as the coupling across the axes of motion decreases as children get older. Children aged 6 and 10 years and young adults (18-23 years) were seated on a wooden box placed atop a force platform that recorded their mediolateral and anteroposterior center of pressure (COP) motion with their feet supported and unsupported. The COP path length and complexity decreased with age, and this was paralleled by an increase in relative phase entropy across the axes of sway motion. The postural sway of the younger children was dominated by slower fluctuations that were more tightly coupled across the axes of motion than the adults. The findings support the postulation that the development of children's sitting posture is characterized by increased freedom in postural coordination that realizes a more loosely coupled but adaptive postural motion with a reduced amount of sway.     

PARP inhibitor rucaparib induces changes in NAD levels in cells and liver tissues as assessed by MRS

Poly(adenosine diphosphate ribose) polymerases (PARPs) are multifunctional proteins which play a role in many cellular processes. Namely, PARP1 and PARP2 have been shown to be involved in DNA repair, and therefore are valid targets in cancer treatment with PARP inhibitors, such as rucaparib, currently in clinical trials. Proton magnetic resonance spectroscopy (¹H‐MRS) was used to study the impact of rucaparib in vitro and ex vivo in liver tissue from mice, via quantitative analysis of nicotinamide adenosine diphosphate (NAD⁺) spectra, to assess the potential of MRS as a biomarker of the PARP inhibitor response. SW620 (colorectal) and A2780 (ovarian) cancer cell lines, and PARP1 wild‐type (WT) and PARP1 knock‐out (KO) mice, were treated with rucaparib, temozolomide (methylating agent) or a combination of both drugs. ¹H‐MRS spectra were obtained from perchloric acid extracts of tumour cells and mouse liver. Both cell lines showed an increase in NAD⁺ levels following PARP inhibitor treatment in comparison with temozolomide treatment. Liver extracts from PARP1 WT mice showed a significant increase in NAD⁺ levels after rucaparib treatment compared with untreated mouse liver, and a significant decrease in NAD⁺ levels in the temozolomide‐treated group. The combination of rucaparib and temozolomide did not prevent the NAD⁺ depletion caused by temozolomide treatment. The ¹H‐MRS results show that NAD⁺ levels can be used as a biomarker of PARP inhibitor and methylating agent treatments, and suggest that in vivo measurement of NAD⁺ would be valuable.     

The tuberculosis challenge in a rural South African HIV programme

Background  

South Africa remains the country with the greatest burden of HIV-infected individuals and the second highest estimated TB incidence per capita worldwide. Within South Africa, KwaZulu-Natal has one of the highest rates of TB incidence and an emerging epidemic of drug-resistant tuberculosis.     

Randomized controlled study of digestive enzyme activity following trophic feeding

A randomized, controlled, prospective study of 80 preterm infants of birthweight less than 1750 g requiring ventilatory support was performed. While ventilatory support was required group TF (39 infants) received trophic feeding (0.5-1 ml h -1 ) along with parenteral nutrition, whereas group C (41 infants) received parenteral nutrition alone. When ventilatory support was no longer required milk feeds were started in group C and then increased in both groups until full milk feeds were established. The ratio of lactase to sucrase activity (L:S ratio) was measured in aspirated proximal intestinal fluid on 3 occasions: immediately after ventilatory support was withdrawn (T0), 7 days later (T7) and 14 days later (T14). On the same 3 occasions faecal chymotrypsin activity was measured. The mean difference (95% confidence interval) L:S ratio was significantly higher in group TF at both T0 and T14, 1.8 (0.03, 3.57) and 0.78 (0.2, 1.35) U l -1 , respectively. There was no significant difference in faecal chymotrypsin concentration.

Conclusion : Trophic feeding alters relative intestinal disaccharidase activity, probably by inducing lactase production, but has no effect on pancreatic chymotrypsin activity.     

Cumulative lifetime incidence of extracolonic cancers in Lynch syndrome: a report of 121 families with proven mutations

Lynch syndrome or hereditary non-polyposis colorectal cancer is caused by mutations of DNA mismatch repair (MMR) genes. The extracolonic tumour spectrum includes endometrial, ovarian, gastric, small bowel, pancreatic, hepatobiliary, brain, and urothelial neoplasms. Families were referred on the basis of clinical criteria. Tumour immunohistochemistry and microsatellite testing were performed. Appropriate patients underwent sequencing of relevant exons of the MMR genes. Proven and obligate mutation carriers and first-degree relatives (FDRs) with a Lynch syndrome spectrum cancer were considered mutation carriers, as were a proportion of untested, unaffected FDRs based on the proportion of unaffected relatives testing positive in each age group. Kaplan–Meier analysis of risk to 70 years was calculated. One hundred and eighty-four Lynch syndrome spectrum extracolonic cancers in 839 proven, obligate, or assumed mutation carriers were analysed. Cumulative risk for females of an extracolonic tumour is 47.4% (95% CI 43.9–50.8). The risk to males is 26.5% (95% CI 22.6–30.4). There was no reduction in gynaecological malignancies due to gynaecological screening (examination, transvaginal ultrasound scan, hysteroscopy and endometrial biopsy). Males have a higher risk of gastric cancer than females (p = 0.0003). Gastric cancer risk in those born after 1935 does not justify surveillance. These penetrance estimates have been corrected for ascertainment bias and are appropriate for those referred to a high-risk clinic.     

Signaling via LTbetaR on the lamina propria stromal cells of the gut is required for IgA production

Peyer's patches (PPs) and/or mesenteric lymph nodes (MLNs) are thought to be essential for immunoglobulin A (IgA) production. We found that the severe IgA deficiency in lymphotoxin-deficient (LT(-/-)) mice could be fully reversed by reconstitution with LT-expressing bone marrow, despite the absence of both LNs and PPs. The number of IgA precursors from LT(-/-) mice was not reduced, and they were able to migrate into the lamina propria (LP) of wild-type mice but not of LTbetaR(-/-) mice. Consistently, lymphoid tissue chemokines and adhesion molecules were reduced within the LP of LTalpha(-/-) and LTbetaR(-/-) mice. IgA deficiency in LTalpha(-/-) mice was reversed by the transplantation of a segment of RAG-1 (recombination-activating gene 1) deficient intestine, which confirmed the dispensability of the MLNs and PPs and the sufficiency of the LT-mediated gut microenvironment for IgA production.     

The effect of dietary restriction during development in utero on the frequency of spontaneous somatic mutations

Caloric or dietary restriction is known to be protective againstcancer in humans and in mice but the mechanism is uncertain.Given that somatic mutations are important in carcinogenesis,dietary restriction may act by changing mutation rates. Indeed,previous studies have shown that reductions in caloric intakeduring development or in adult life make mice less susceptibleto high doses of mutagens. In these studies there have beenhints that the spontaneous mutant frequency may also be reduced,but no significant decrease has been observed save in one studyof very old mice. Since the spontaneous mutant frequency isalready low, reductions from this level require the use of muchlarger sample sizes than usual and larger than those used inthe previous studies. As pre-existing mutations cannot be eliminated,it is necessary to reduce the dietary intake over a period oftime when a substantial proportion of spontaneous mutationsarise in order to see an effect. To overcome such problems,the dietary restriction in this study was applied during thetime of the highest mutation rate, early development, and manymore than the usual number of animals were studied. SWR femalemice were crossed with Muta^TMMouse males to obtain F₁ progenyfor analysis of mutant frequency. At conception, the dams wereput into two groups, one that was fed ad libitum and anotherwhich was fed 80% of the ad libitum diet. Pups were killed atbirth, DNA was extracted from the whole animal and used to measurethe mutant frequencies of the mice at the cII locus. Althoughthe weights of the pups from dams whose diet was restrictedwere significantly less than those of the ad libitum mice (P= 0.003), the litter sizes in the two groups were approximatelythe same and did not differ significantly (P = 0.13). Therewas no significant difference in the mutant frequencies in thedietarily restricted and ad libitum groups (P = 0.43). In addition,there was no significant correlation between the weights ofthe pups and their mutant frequency in either the ad libitumor dietarily restricted groups (r² = 0.14 and r² = 0.024). Nodifference was observed in mutant frequency between the ad libitumand dietarily restricted mice from litters of the same size(P = 0.61). These results indicate that the protective effectof dietary restriction on cancer rates is not mediated by analteration in the spontaneous rate of mutation but rather byanother mechanism, such as its effect on induced mutation. ¹ To whom correspondence should be addressed. Tel: +1 416 7362100; Fax: +1 416 736 5698; Email: jheddle{at}yorku.ca     

Prevalence and correlates of depression among HIV-infected and -affected older people in rural South Africa

Background

Little is known about depression in older people in sub-Saharan Africa, the associated impact of HIV, and the influence on health perceptions.

Objectives

Examine the prevalence and correlates of depression; explore the relationship between depression and health perceptions in HIV-infected and -affected older people.

Methods

In 2010, 422 HIV-infected and -affected participants aged 50+ were recruited into a cross-sectional study. Nurse professionals interviewed participants and a diagnosis of depressive episode was derived from the Composite International Diagnostic Interview (Depression module) using the International Classification of Diseases diagnostic criteria and categorised as major (MDE) or brief (BDE).

Results

Overall, 42.4% (n=179) had a depressive episode (MDE: 22.7%, n=96; BDE: 19.7%, n=83). Prevalence of MDE was significantly higher in HIV-affected (30.1%, 95% CI 24.0–36.2%) than HIV-infected (14.8%, 95% CI 9.9–19.7%) participants; BDE was higher in HIV-infected (24.6%, 95% CI 18.7–30.6%) than in HIV-affected (15.1%, 95% CI 10.3–19.8%) participants. Being female (aOR 3.04, 95% CI 1.73–5.36), receiving a government grant (aOR 0.34, 95% CI 0.15–0.75), urban residency (aOR 1.86, 95% CI 1.16–2.96) and adult care-giving (aOR 2.37, 95% CI 1.37–4.12) were significantly associated with any depressive episode. Participants with a depressive episode were 2–3 times more likely to report poor health perceptions.

Limitations

Study limitations include the cross-sectional design, limited sample size and possible selection biases.

Conclusions

Prevalence of depressive episodes was high. Major depressive episodes were higher in HIV-affected than HIV-infected participants. Psycho-social support similar to that of HIV treatment programmes around HIV-affected older people may be useful in reducing their vulnerability to depression.     

Cancer‐associated somatic DICER1 hotspot mutations cause defective miRNA processing and reverse‐strand expression bias to predominantly mature 3p strands through loss of 5p strand cleavage

Our group recently described recurrent somatic mutations of the miRNA processing gene DICER1 in non‐epithelial ovarian cancer. Mutations appeared to be clustered around each of four critical metal‐binding residues in the RNase IIIB domain of DICER1. This domain is responsible for cleavage of the 3′ end of the 5p miRNA strand of a pre‐mRNA hairpin. To investigate the effects of these cancer‐associated 'hotspot' mutations, we engineered mouse DICER1‐deficient ES cells to express wild‐type and an allelic series of the mutant DICER1 variants. Global miRNA and mRNA profiles from cells carrying the metal‐binding site mutations were compared to each other and to wild‐type DICER1. The miRNA and mRNA profiles generated through the expression of the hotspot mutations were virtually identical, and the DICER1 hotspot mutation‐carrying cells were distinct from both wild‐type and DICER1‐deficient cells. Further, miRNA profiles showed that mutant DICER1 results in a dramatic loss in processing of mature 5p miRNA strands but were still able to create 3p strand miRNAs. Messenger RNA (mRNA) profile changes were consistent with the loss of 5p strand miRNAs and showed enriched expression for predicted targets of the lost 5p‐derived miRNAs. We therefore conclude that cancer‐associated somatic hotspot mutations of DICER1, affecting any one of four metal‐binding residues in the RNase IIIB domain, are functionally equivalent with respect to miRNA processing and are hypomorphic alleles, yielding a global loss in processing of mature 5p strand miRNA. We further propose that this resulting 3p strand bias in mature miRNA expression likely underpins the oncogenic potential of these hotspot mutations. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Atypical fibroxanthoma and squamous cell carcinoma of the conjunctiva in xeroderma pigmentosum.

Patients with xeroderma pigmentosum (XP) have defective DNA repair and a high predisposition to developing abnormalities and neoplasia in the sun-exposed areas of the skin and mucous membranes. The most common tumors reported in patients with XP are squamous cell carcinomas, basal cell carcinomas, and melanomas. Atypical fibroxanthoma (AFX) is a pleomorphic tumor that arises predominantly in the sun-damaged skin of the head and neck regions of the elderly. We describe a unique case of a 6-year-old African American boy with XP who developed an atypical fibroxanthoma and 2 squamous cell carcinomas in the conjunctiva. The clinical and histopathologic findings of AFX are discussed.