Early language measures associated with later psychosis features in 22q11.2 deletion syndrome

The 22q11.2 deletion syndrome (22q11DS) is associated with impaired cognitive functions and increased risk for schizophrenia spectrum disorders. Speech and language deficits are prominent, with evidence of decline anteceding emergence of psychosis. There is paucity of data examining language function in children with 22q11DS with follow‐up assessment of psychosis spectrum (PS) symptoms. We examined the association between early language measures, obtained clinically, and PS status, obtained on average 10.1 years later, in 166 youths with 22q11DS, with repeated language testing in 48. Participants were administered the Preschool Language Scale (receptive/expressive), and/or, for school aged children, the Clinical Evaluation of Language Fundamentals (receptive/expressive), and age appropriate IQ tests. The structured interview for prodromal syndromes (SIPS) assessed PS symptoms. We found that performance on all preschool measures showed age associated decline, and males performed more poorly on core composite (receptive/expressive) and receptive language measures. For language assessment later in childhood, poorer performance was consistently associated with subsequent PS status. Furthermore, steeper age‐related decline was seen in the PS group across language measures and marginally for full‐scale IQ. These findings suggest that while preschool language testing is useful in characterizing performance decline in individuals with 22q11DS, it does not robustly differentiate those with subsequent PS from those without. However, language testing in the school age population can help identify individuals with 22q11DS who are at risk for psychosis. Such data are needed for elucidating a lifespan trajectory for affected individuals and may help understand pathways to psychosis applicable to the general population.     

Iron and liver fibrosis: Mechanistic and clinical aspects

Liver fibrosis is characterised by excessive deposition of extracellular matrix that interrupts normal liver functionality. It is a pathological stage in several untreated chronic liver diseases such as the iron overload syndrome hereditary haemochromatosis, viral hepatitis, alcoholic liver disease, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis and diabetes. Interestingly, regardless of the aetiology, iron-loading is frequently observed in chronic liver diseases. Excess iron can feed the Fenton reaction to generate unquenchable amounts of free radicals that cause grave cellular and tissue damage and thereby contribute to fibrosis. Moreover, excess iron can induce fibrosis-promoting signals in the parenchymal and non-parenchymal cells, which accelerate disease progression and exacerbate liver pathology. Fibrosis regression is achievable following treatment, but if untreated or unsuccessful, it can progress to the irreversible cirrhotic stage leading to organ failure and hepatocellular carcinoma, where resection or transplantation remain the only curative options. Therefore,understanding the role of iron in liver fibrosis is extremely essential as it can help in formulating iron-related diagnostic, prognostic and treatment strategies. These can be implemented in isolation or in combination with the current approaches to prepone detection, and halt or decelerate fibrosis progression before it reaches the irreparable stage. Thus, this review narrates the role of iron in liver fibrosis. It examines the underlying mechanisms by which excess iron can facilitate fibrotic responses. It describes the role of iron in various clinical pathologies and lastly,highlights the significance and potential of iron-related proteins in the diagnosis and therapeutics of liver fibrosis.     

Randomized trial comparing low-dose hormone replacement therapy and HRT plus 1α-OH-vitamin D3 (alfacalcidol) for treatment of postmenopausal bone loss

We conducted a prospective, randomized, multicenter, open-label 2-year trial with 76 postmenopausal women aged ≥60 years with low (T-score less than −1) lumbar bone mineral density (BMD). The hormone replacement therapy (HRT) group received a low dose of conjugated estrogen (CEE) at a dose of 0.31 mg/day ± medroxyprogesterone acetate (MPA) 2.5 mg/day. Group HRT/D received the same dose of HRT together with alfacalcidol in a daily dose of 1.0 μg/day. Changes in lumbar BMD measured by dual energy X-ray absorptiometry (DXA) were followed every 6 months for 2 years. The lumbar BMD of group HRT increased 3.37% [95% confidence interval (CI) 1.6%–5.2%], 4.00% (95%CI 1.6%–6.4%), and 2.32% (95%CI −0.7% to 5.3%) at 12, 18, and 24 months, respectively, when the baseline value was taken as 0%. Lumbar BMD of group HRT/D showed a significant increase beyond 6 months. The percent increases for this group at 6, 12, 18, and 24 months were 6.18 (95%CI 1.3%–6.6%), 6.18% (95%CI 3.9%–8.5%), 7.17% (95%CI 4.3%–10.0%), and 8.75% (95%CI 6.0%–11.5%), respectively. In addition, there was a significant difference in the changes of the lumbar BMD between the two groups at 24 months, suggesting that the combination of HRT and alfacalcidol is more effective than HRT alone in terms of the BMD effect. This study is the first prospective trial demonstrating an additive effect of alfacalcidol on lumbar BMD in postmenopausal women receiving low-dose HRT. It suggests that the combination therapy can be considered to be a promising mode of treatment for bone loss after menopause.     

Relationships between serum leptin level and regional bone mineral density, bone metabolic markers in healthy women

BACKGROUND: Leptin might affect bone metabolism. This study was performed to investigate the relationship of leptin to bone metabolism in detail in premenopausal and postmenopausal healthy women. METHODS: The relationships between serum leptin level and bone mineral density of several regional sites of the body as well as whole body, along with bone metabolic markers, were examined in 47 premenopausal and 29 postmenopausal healthy women. RESULTS: Serum leptin level was weakly correlated with bone mineral density of pelvis (Pearson's correlation coefficient r=0.39, p<0.05) and left leg (r=0.41, p<0.01) in the premenopausal women, although the correlation decreased after adjustment for BMI. There was no significant relationship between serum leptin level and whole body bone mineral density both in the premenopausal and postmenopausal women. Serum leptin level was correlated with serum alkaline phosphatase (r=0.56, p<0.001) and urinary deoxypyridinoline/cr (r=-0.32, p<0.05) by Pearson's correlation test in the premenopausal women; the relationships were maintained even after adjustment for BMI (r=0.50 and -0.48, respectively). CONCLUSIONS: Leptin is not a key regulator of bone metabolism, although it may have some effects on bone metabolic markers and BMD regionally in premenopausal women.     

Effects of vitamin K(2) on bone of ovariectomized rats and on a rat osteoblastic cell line

The effects of vitamin K(2) on bone mineral density (BMD) and bone metabolic markers of ovariectomized rats, and those on mRNA expression of osteocalcin and IL-6 on a rat osteoblastic cell line, were investigated. BMD and bone metabolic markers were examined in ovariectomized rats after 2 months' treatment with vitamin K(2), and mRNA expression of osteocalcin and IL-6 were measured in the cell line after 24-hour treatment with vitamin K(2). Vitamin K(2) attenuated the decline in BMD after ovariectomy in the rats, and suppressed serum deoxypyridinoline levels of the ovariectomized rats. No effect on osteocalcin and IL-6 mRNA expression on the cell line was observed. In conclusion, vitamin K(2) has a bone-protective effect on ovariectomized rats.     

Validity evidence for the Fundamentals of Laparoscopic Surgery (FLS) program as an assessment tool: a systematic review

Background

The Fundamentals of Laparoscopic Surgery (FLS) program uses five simulation stations (peg transfer, precision cutting, loop ligation, and suturing with extracorporeal and intracorporeal knot tying) to teach and assess laparoscopic surgery skills. We sought to summarize evidence regarding the validity of scores from the FLS assessment.

Methods

We systematically searched for studies evaluating the FLS as an assessment tool (last search update February 26, 2013). We classified validity evidence using the currently standard validity framework (content, response process, internal structure, relations with other variables, and consequences).

Results

From a pool of 11,628 studies, we identified 23 studies reporting validity evidence for FLS scores. Studies involved residents (n = 19), practicing physicians (n = 17), and medical students (n = 8), in specialties of general (n = 17), gynecologic (n = 4), urologic (n = 1), and veterinary (n = 1) surgery. Evidence was most common in the form of relations with other variables (n = 22, most often expert–novice differences). Only three studies reported internal structure evidence (inter-rater or inter-station reliability), two studies reported content evidence (i.e., derivation of assessment elements), and three studies reported consequences evidence (definition of pass/fail thresholds). Evidence nearly always supported the validity of FLS total scores. However, the loop ligation task lacks discriminatory ability.

Conclusion

Validity evidence confirms expected relations with other variables and acceptable inter-rater reliability, but other validity evidence is sparse. Given the high-stakes use of this assessment (required for board eligibility), we suggest that more validity evidence is required, especially to support its content (selection of tasks and scoring rubric) and the consequences (favorable and unfavorable impact) of assessment.

     

Direct comparison of the BD ProbeTec ET system with in-house LightCycler PCR assays for detection of Chlamydia trachomatis and Neisseria gonorrhoeae from clinical specimens

The commercial BD ProbeTec ET (BDPT) system for the detection of Neisseria gonorrhoeae and Chlamydia trachomatis from clinical specimens was compared with our in-house LightCycler real-time PCR (LC-PCR) assays. Specimens initially positive by the BDPT system were retested by our LC-PCR assays. Our results for C. trachomatis testing indicate a 91.2% agreement when the results of 114 clinical specimens, initially positive by BDPT over a wide range of method-other-than-acceleration (MOTA) scores, were retested by our LC-PCR assay. The agreement between the two systems improved to 96% when only MOTA scores of >30,000 were retested by the LC-PCR assay. The overall agreement between the two systems for Neisseria gonorrhoeae detection from 155 clinical specimens was only 77.4%, with agreement particularly low (24.1%) for MOTA scores ranging from 2,000 to 19,999. Repeat testing of specimens with the BDPT only closely correlated with that seen by others demonstrating that reproducibility of the BDPT system for specimens initially within the MOTA score range from 2,000 to 9,999 is problematic, especially for Neisseria gonorrhoeae testing. With our study, we proposed an algorithm for C. trachomatis and N. gonorrhoeae testing which involves screening with the BDPT system followed by selective use of our in-house LC-PCR assays.     

A-kinase anchoring protein 150 controls protein kinase C-mediated phosphorylation and sensitization of TRPV1

Post-translational modifications on various receptor proteins have significant effects on receptor activation. For the Transient Receptor Potential family V type 1 (TRPV1) receptor, phosphorylation of certain serine/threonine amino acid residues sensitizes the receptor to activation by capsaicin and heat. Although Protein Kinase C (PKC) phosphorylates TRPV1 on certain serine/threonine residues, it is not completely understood how PKC functionally associates with TRPV1. Recent studies have reported that the A-kinase Anchoring Protein 150 (AKAP150) mediates PKA phosphorylation of TRPV1 in several nociceptive models. Here, we demonstrate that AKAP150 also mediates PKC-directed phosphorylation and sensitization of TRPV1. In cultured rat trigeminal ganglia, immunocytochemical analyses demonstrate co-localization of AKAP150 and PKC isoforms α, δ, ε, and γ in TRPV1-positive neurons. Additional biochemical evidence supports immunocytochemical results, indicating that AKAP150 preferentially associates with certain PKC isoforms in rat trigeminal ganglia neurons. Employing siRNA-mediated knock-down of AKAP150 expression, we demonstrate that PKC-mediated phosphorylation of TRPV1 and sensitization to a capsaicin response is dependent upon functional expression of the AKAP150 scaffolding protein. Furthermore, PKC-induced sensitization to a thermal stimulus is abrogated in AKAP150 knock-out animals relative to wild-type. Collectively, the results from these studies indicate that the AKAP150 scaffolding protein functionally modulates PKC-mediated phosphorylation and sensitization of the TRPV1 receptor in rat sensory neurons, suggesting the scaffolding protein to be an integral regulator of peripheral inflammatory hyperalgesia.     

In Vivo Capillary Structure and Blood Cell Flux in the Normal and Diabetic Mouse Eye

PurposeTo characterize the early structural and functional changes in the retinal microvasculature in response to hyperglycemia in the Ins2^Akita mouse.MethodsA custom phase-contrast adaptive optics scanning light ophthalmoscope was used to image retinal capillaries of 9 Ins2^Akita positive (hyperglycemic) and 9 Ins2^Akita negative (euglycemic) mice from postnatal weeks 5 to 18. A 15 kHz point scan was used to image capillaries and measure red blood cell flux at biweekly intervals; measurements were performed manually. Retinal thickness and fundus photos were captured monthly using a commercial scanning laser ophthalmoscope/optical coherence tomography. Retinal thickness was calculated using a custom algorithm. Blood glucose and weight were tracked throughout the duration of the study.ResultsElevated blood glucose (>250 mg/dL) was observed at 4 to 5 weeks of age in Ins2^Akita mice and remained elevated throughout the study, whereas euglycemic littermates maintained normal glucose levels. There was no significant difference in red blood cell flux, capillary anatomy, lumen diameter, or occurrence of stalled capillaries between hyperglycemic and euglycemic mice between postnatal weeks 5 and 18. Hyperglycemic mice had a thinner retina than euglycemic littermates (p < 0.001), but retinal thickness did not change with duration of hyperglycemia despite glucose levels that were more than twice times normal.ConclusionsIn early stages of hyperglycemia, retinal microvasculature structure (lumen diameter, capillary anatomy) and function (red blood cell flux, capillary perfusion) were not impaired despite 3 months of chronically elevated blood glucose. These findings suggest that hyperglycemia alone for 3 months does not alter capillary structure or function in profoundly hyperglycemic mice.     

Immunohistochemical Evidence of Loss of PTEN Expression in Primary Ductal Adenocarcinomas of the Breast

Germline mutations in PTEN, encoding a dual-specificity phosphatase on 10q23.3, cause Cowden syndrome (CS), which is characterized by a high risk of breast and thyroid cancers. Loss of heterozygosity of 10q22-24 markers and somatic PTEN mutations have been found to a greater or lesser extent in a variety of sporadic component and noncomponent cancers of CS. Among several series of sporadic breast carcinomas, the frequency of loss of flanking markers around PTEN is approximately 30 to 40%, and the somatic intragenic PTEN mutation frequency is <5%. In this study, we analyzed PTEN expression in 33 sporadic primary breast carcinoma samples using immunohistochemistry and correlated this to structural studies at the molecular level. Normal mammary tissue had a distinctive pattern of expression: myoepithelial cells uniformly showed strong PTEN expression. The PTEN protein level in mammary epithelial cells was variable. Ductal hyperplasia with and without atypia exhibited higher PTEN protein levels than normal mammary epithelial cells. Among the 33 carcinoma samples, 5 (15%) were immunohistochemically PTEN-negative; 6 (18%) had reduced staining, and the rest were PTEN-positive. In the PTEN-positive tumors as well as in normal epithelium, the protein was localized in the cytoplasm and in the nucleus (or nuclear membrane). Among the immunostain negative group, all had hemizygous PTEN deletion but no structural alteration of the remaining allele. Thus, in these cases, an epigenetic phenomenon such as hypermethylation, -ecreased protein synthesis or increased protein degradation may be involved. In the cases with reduced staining, 5 of 6 had hemizygous PTEN deletion and 1 did not have any structural abnormality. Finally, clinicopathological features were analyzed against PTEN protein expression. Three of the 5 PTEN immunostain-negative carcinomas were also both estrogen and progesterone receptor-negative, whereas only 5 of 22 of the PTEN-positive group were double receptor-negative. The significance of this last observation requires further study.