Postpartum Depression-Identifying Risk and Access to Intervention.

PURPOSE OF REVIEW: As maternal mortality climbs in the USA with mental health conditions driving these preventable deaths, the field of reproductive psychiatry must shift towards identification of women and other birthing individuals at risk and facilitating access. This review brings together recent studies regarding risk of perinatal depression and highlights important comorbidities that place individuals at higher vulnerability to poor perinatal outcomes. RECENT FINDINGS: Recent research suggests that identifying risk for perinatal depression including historical diagnoses of depression, anxiety, trauma, and comorbid substance use and intimate partner violence may move the field to focus on preventive care in peripartum populations. Emerging data shows stark health inequities in racial and ethnic minority populations historically marginalized by the health system and in other vulnerable groups such as LGBTQ+ individuals and those with severe mental illness. Innovative models of care using systems-level approaches can provide opportunities for identification and risk analyses of vulnerable peripartum patients and facilitate access to therapeutic or preventive interventions. Utilizing intergenerational approaches and leveraging multidisciplinary teams that thoughtfully target high-risk women and other birthing individuals could promote significant changes to population-level care in maternal health.

Cortical abnormalities in bipolar disorder: an MRI analysis of 6503 individuals from the ENIGMA Bipolar Disorder Working Group.

Despite decades of research, the pathophysiology of bipolar disorder (BD) is still not well understood. Structural brain differences have been associated with BD, but results from neuroimaging studies have been inconsistent. To address this, we performed the largest study to date of cortical gray matter thickness and surface area measures from brain magnetic resonance imaging scans of 6503 individuals including 1837 unrelated adults with BD and 2582 unrelated healthy controls for group differences while also examining the effects of commonly prescribed medications, age of illness onset, history of psychosis, mood state, age and sex differences on cortical regions. In BD, cortical gray matter was thinner in frontal, temporal and parietal regions of both brain hemispheres. BD had the strongest effects on left pars opercularis (Cohen's d=-0.293; P=1.71 × 10-21), left fusiform gyrus (d=-0.288; P=8.25 × 10-21) and left rostral middle frontal cortex (d=-0.276; P=2.99 × 10-19). Longer duration of illness (after accounting for age at the time of scanning) was associated with reduced cortical thickness in frontal, medial parietal and occipital regions. We found that several commonly prescribed medications, including lithium, antiepileptic and antipsychotic treatment showed significant associations with cortical thickness and surface area, even after accounting for patients who received multiple medications. We found evidence of reduced cortical surface area associated with a history of psychosis but no associations with mood state at the time of scanning. Our analysis revealed previously undetected associations and provides an extensive analysis of potential confounding variables in neuroimaging studies of BD.

A Comparison of Methods for the Estimation of Body Composition in Highly Trained Wheelchair Games Players.

The purpose of this study was to assess the agreement in body composition measurements of wheelchair athletes using skinfolds, bio-impedance analysis (BIA) and air displacement plethysmography (ADP) relative to dual-energy X-ray absorptiometry (DXA). A secondary objective was to develop new skinfold prediction equations to estimate %fat for this sample. 30 wheelchair games players were recruited and the body composition outcomes of BIA, ADP, and skinfolds were compared to the DXA outcomes by a paired-samples t-test (systematic bias), intraclass correlation (ICC, relative agreement) and Bland-Altman plots (absolute agreement). Regression models to predict the %fat as measured by DXA by the sum of skinfolds or BIA were calculated. Results showed that the predictions of %fat when using BIA, ADP or skinfolds systematically underestimated the %fat mass as measured by the DXA. All ICC values, except for the measurement of fat (kg) by ADP (ICC=0.702), were below 0.7. New prediction models found the ∑7 skinfolds and calf circumference as the best model to predict %fat (R(2)=0.84). In conclusion, BIA, ADP and existing skinfolds equations should be used with caution when estimating %fat of wheelchair athletes with substantial body asymmetry, lower body muscular atrophy and upper body muscular development.

Not all glucocorticoid-induced obesity is the same: differences in adiposity among various diagnostic groups of Cushing syndrome.

The cAMP signaling pathway is implicated in bilateral adrenocortical hyperplasias (BAHs), which are often associated with ACTH-independent Cushing syndrome (CS). Although CS is invariably associated with obesity and is frequently associated with PKA signaling defects, we recently reported that its different forms appear to also present with variable weight gain and adiposity. The present study was aimed at characterizing further the phenotypic and molecular differences in periadrenal adipose tissue (PAT) among patients with subtypes of CS, by anthropometric/biochemical analyses and quantification of PKA expression and activity in BAHs in comparison to a non-CS group with aldosterone producing adenomas (APAs). Glucocorticoid levels, serum parameters, and BMI were analyzed among a larger patient cohort including those with different forms of CS, APAs, and Cushing disease. Abdominal CT scans were available for a small subset of patients examined for fat distribution. PAT collected during adrenalectomy was assayed for PKA activity, cAMP, and PKA expression. BMI and BMI z-score were lower in adults with PPNAD with PRKAR1A mutations and in pediatric patients with PPNAD with and without PRKAR1A mutations, respectively. Patients with PPNAD had higher cAMP levels in PAT and different fat distribution. Thus, PKA activity in PAT differed between CS diagnostic groups. Increased cAMP and PKA activity may have contributed to phenotypic differences among subtypes of CS. In agreement with the known roles of cAMP signaling in the regulation of adiposity, patients with PPNAD were less obese than other patients with CS.

[Therapy of septic paraplegia]. / Therapie der septischen Querschnittlähmung.

The frequency of infectious diseases of the spine and associated spinal cord injury are constantly increasing. Affected are multimorbid and elderly patients, mostly after prolonged medical treatment. An acute spinal cord injury due to infection is an emergency. A rapid decision for treatment strategy and if at all possible subtle debridement of the infected tissue with decompression of the spinal cord is paramount. Additionally spinal cord injury necessitates specialized treatment and care of the infection. Spinal cord injured patients in general and these patients in particular are prone to complications and need especially trained nursing personnel. It is therefore recommended that patients with vertebral osteomyelitis associated with spinal cord injury should be transferred to dedicated centres of treatment as soon as possible.Just as in cases of spondylodiscitis without spinal cord injury inconsistent surgical or insufficient antibiotic treatment worsens the prognosis significantly. If it is possible to remit the infection, the prognosis for recovery of motor and sensory function is better than in cases with traumatic spinal cord injury. In many cases at least partial recovery can be observed.

Factors influencing the identification rate of the sentinel node in breast cancer.

Sentinel node biopsy is a widely accepted alternative to primary axillary lymph node dissection for ipsilateral nodal assessment in breast cancer. We have performed a retrospective chart review in 713 consecutive patients with primary, operable breast cancer who underwent sentinel node biopsy in order to identify factors that determine the sentinel node identification rate. Chi-squared test, univariate and multivariate analyses were used to evaluate the influence of different factors on the sentinel identification rate. Among the factors investigated, tumour size was correlated with sentinel lymph nodes detection rates (multiple logistic regression, P= 0.002). In addition, the patient's age showed to be a significant influencing factor (multiple logistic regression, P= 0.006). Body mass index and grade only exhibited a significant correlation with the identification rate in the univariate (P= 0.041, P= 0.025), but not in the multivariate analysis (P= not significant). All associations were found to be independent of the site of injection. Interestingly, surgeons with intermediate expertise (11-20 prior dissections) had the highest detection rates (P= 0.004). We conclude that sentinel identification rates are higher in larger tumours and in younger patients, independent of the injection site. Surgical experience in sentinel node dissection is not linearly correlated with higher identification rates.

The role of germline AIP, MEN1, PRKAR1A, CDKN1B and CDKN2C mutations in causing pituitary adenomas in a large cohort of children, adolescents, and patients with genetic syndromes.

The prevalence of germline mutations in MEN1, AIP, PRKAR1A, CDKN1B and CDKN2CI is unknown among pediatric patients with pituitary adenomas (PA). In this study, we screened children with PA for mutations in these genes; somatic GNAS mutations were also studied in a limited number of growth hormone (GH) or prolactin (PRL)-secreting PA. We studied 74 and 6 patients with either isolated Cushing disease (CD) or GH- or PRL-secreting PA, respectively. We also screened four pediatric patients with CD, and four with GH/PRL-secreting tumors who had some syndromic features. There was one AIP mutation (p.Lys103Arg) among 74 CD patients. Two MEN1 mutations that occurred in patients with recurrent or difficult-to-treat disease were found among patients with CD. There was one MEN1 and three AIP mutations (p.Gln307ProfsX104, p.Pro114fsX, p.Lys241X) among pediatric patients with isolated GH- or PRL-secreting PA and one additional MEN1 mutation in a patient with positive family history. There were no mutations in the PRKAR1A, CDKN1B, CDKN2C or GNAS genes. Thus, germline AIP or MEN1 gene mutations are frequent among pediatric patients with GH- or PRL-secreting PA but are significantly rarer in pediatric CD; PRKAR1A mutations are not present in PA outside of Carney complex.

The growth hormone receptor (GHR) polymorphism in growth-retarded children with Cushing disease: lack of association with growth and measures of the somatotropic axis.

Pediatric Cushing disease (CD) often presents with short stature, but we have observed significant inter-individual variability in the growth delay caused by endogenous hypercortisolism. Glucocorticoids cause growth retardation by affecting the growth hormone (GH) - insulin-like growth factor-1 (IGF 1) somatotropic axis, but also other, GH-independent sites. Recently, the GH receptor (GHR) gene was found to have a common polymorphism (P) that leads to a deletion (d3) or retention of exon 3. In this study, we tested the hypothesis that the GH receptor polymorphism (GHR-P) maybe one of the significant variants that determines the degree of growth delay among patients with CD. GHR genotyping was performed on 56 children with newly diagnosed CD (24 females, 32 males, mean age of 12.9+/-3.3 years) who were followed at our institution between the years 1997-2007. Correlation analysis included genotype, measures of growth and the somatotropic axis, and anthropometrics. Within the group, 31 (12 girls, 19 boys) expressed the full length GHR allele, 10 (4 girls, 6 boys) were d3-GHR homozygotes and 15 (7 girls, 8 boys) were d3-GHR heterozygotes. No significant differences were found between the GHR genotypes and patient's height and/or growth velocity, or any other measures that we evaluated. The presence of a well-studied and common GHR polymorphism does not appear to be responsible for the variability of growth delay observed in patients with Cushing disease.

Localization of Elements Important for the Wound-Inducible Expression of a Chimeric Potato Proteinase Inhibitor II-CAT Gene in Transgenic Tobacco Plants.

The effect of progressive 5[prime] deletions within a potato proteinase inhibitor II promoter on wound-inducible expression of the chloramphenicol acetyltransferase (CAT) gene in leaves of transgenic tobacco plants was analyzed. After deletion of a region ranging from position -1300 to -700 with respect to the transcription start site, promoter activity was markedly reduced but still wound-inducible. Further deletion of approximately 200 base pairs resulted in a promoter activity that was below the detection limit, proving that the activity of the proteinase inhibitor II promoter is controlled by sequences upstream of position -514. Addition of the enhancer of the 35S promoter of the cauliflower mosaic virus (CaMV) either 5[prime] upstream or 3[prime] downstream of chimeric genes consisting of different proteinase inhibitor II promoter deletions (-700, -514, -210) fused to the CAT gene led to wound-inducible CAT gene expression in a fraction of transgenic plants containing either the "-700" or "-514" promoters, indicating the presence of wound-responsive elements in the promoter-proximal region. A fragment of the proteinase inhibitor II promoter comprising sequences between positions -1300 and -195 is able to confer wound-inducible expression to an inactive CaMV 35S promoter truncated at position -90 in either orientation, proving that this fragment displays wound-specific, enhancer-like properties. In addition, data are presented excluding that the proteinase inhibitor II 3[prime] end is of importance for wound-inducible gene expression.

Enhanced uptake and siRNA-mediated knockdown of a biologically relevant gene using cyclodextrin polyrotaxane.

Ideal cationic polymers for siRNA delivery could result in its enhanced cellular internalization, escape from endosomal degradation, and rapid release in cell cytoplasm, to facilitate knockdown of the target gene. In this study, we have investigated the ability of an in-house synthesized cationic polyrotaxane to bind siRNA into nanometric complexes. This polymer, which had earlier shown improved transfection of model siRNA (luciferase), was used to improve the cellular internalization of the siRNA molecule with therapeutic implications. In cellular assays, the polymer enhanced the knockdown of a gene involved in the pathogenesis of tuberculosis, when the nanocomplexes were compared with free siRNA. The efficacy and cellular non-toxicity of this polymer encourage its further exploitation in animal models of tuberculosis and other intracellular bacterial infections.

Lipoprotein Particles in Adolescents and Young Women With PCOS Provide Insights Into Their Cardiovascular Risk.

CONTEXT: Adult women with polycystic ovarian syndrome (PCOS) have an increased risk for cardiovascular disease, but the evidence for this is controversial in adolescents and young women with PCOS. Measurement of low-density lipoprotein (LDL) particle number, measured by nuclear magnetic resonance spectroscopy is a novel technology to assess cardiovascular risk. OBJECTIVE: The objective of the study was to evaluate lipoprotein particle number and size in young women with PCOS and its relationship with insulin resistance and hyperandrogenism. DESIGN: This was a cross-sectional case control study. SETTING: The study was conducted at a clinical research center. PARTICIPANTS: Women with PCOS (n = 35) and normal controls (n = 20) participated in the study. INTERVENTIONS: Blood samples and anthropometric measures were obtained. MAIN OUTCOME MEASURES: LDL particle size and number were measured using nuclear magnetic resonance spectroscopy. A secondary outcome was to investigate the correlation of LDL particle number with high-sensitivity C-reactive protein, waist to hip ratio, hyperandrogenism, insulin resistance, and adiponectin. RESULTS: Women with PCOS had higher LDL particle number when compared with healthy controls (935 ± 412 vs 735 ± 264, P = .032); LDL particle number correlated strongly with high-sensitivity C-reactive protein (r = 0.37, P = .006) and waist-to-hip (r = 0.57, P = .0003). The higher LDL particle number was driven mainly due to differences in the small LDL particle number (sLDLp), with PCOS patients having more sLDLp (348 ± 305 vs 178 ± 195, P = .015). The sLDLp correlated with the Matsuda index (r = -0.51, P = .0001), homeostasis model assessment index of insulin resistance (r = 0.41, P = .002), and adiponectin (r = -0.46, P = .0004) but not with T. CONCLUSION: Adolescent and young women with PCOS have an atherogenic lipoprotein profile suggestive of increased cardiovascular risk that appears to be driven by the degree of visceral adiposity and insulin resistance.

Comparison of insulin sensitivity, clearance, and secretion estimates using euglycemic and hyperglycemic clamps in children.

The euglycemic clamp is the gold standard for estimating insulin sensitivity. The hyperglycemic clamp is easier to perform and is the gold standard for estimating beta-cell secretion. Reports in adults suggest that hyperglycemic clamps can estimate insulin sensitivity with results equivalent to euglycemic clamps. We investigated whether insulin sensitivity measures from both clamps are equivalent in children. Thirty-one lean and obese children (mean body mass index, 25.1 +/- 4.9 kg/m(2); mean age, 8.7 +/- 1.4 yr; 15 girls and 16 boys; 12 black and 19 white) were studied. All subjects underwent hyperglycemic clamps, then euglycemic clamps 2-6 wk later. Body composition was estimated by dual energy x-ray absorptiometry. Visceral and sc abdominal fat was estimated by abdominal magnetic resonance imaging. Whole-body glucose disposal and insulin sensitivity (SI clamp) derived from both clamps and normalized for total or visceral fat and lean mass were significantly correlated (r, 0.45-0.65; P < 0.05). However, absolute SI clamp values were not equivalent. Bland-Altman comparisons found that SI clamp estimates from hyperglycemic clamps became less precise as SI clamp increased. There were significant correlations between indices of beta-cell secretion from the hyperglycemic clamp and mean C-peptide values from the euglycemic clamp (P < 0.05). However, no correlation was found between measures of total insulin clearance (derived from the euglycemic clamp) and surrogates of hepatic insulin clearance (derived from the hyperglycemic clamp). In this cohort of diverse children, SI clamp values from euglycemic and hyperglycemic clamps were significantly correlated but were not equivalent, whereas the insulin clearance measures were not correlated. It cannot be assumed that the hyperglycemic clamp obviates the need for euglycemic clamp studies to accurately estimate insulin sensitivity in children.

Hydrocortisone suspension and hydrocortisone tablets are not bioequivalent in the treatment of children with congenital adrenal hyperplasia.

In July 1998, Cortef oral suspension (Pharmacia & Upjohn) was reformulated changing the suspending agent tragacanth to xanthan gum. We subsequently observed suboptimal control of hormone levels in a group of children with classic congenital adrenal hyperplasia, despite increasing doses of Cortef suspension and stringent instructions to parents regarding shaking of the bottles of medication. Nineteen children receiving Cortef and fludrocortisone therapy were changed to hydrocortisone tablets and fludrocortisone, with a 10 percent reduction in hydrocortisone dose. A significant decrease in 17-hydroxyprogesterone (235 +/- 120 vs. 27 +/- 7 nmol/L; p

Flutamide, testolactone, and reduced hydrocortisone dose maintain normal growth velocity and bone maturation despite elevated androgen levels in children with congenital adrenal hyperplasia.

Treatment outcome in congenital adrenal hyperplasia is often sub-optimal due to hyperandrogenism, treatment-induced hypercortisolism, or both. We previously reported better control of linear growth, weight gain, and bone maturation in a short term cross-over study of a new four-drug treatment regimen containing an antiandrogen (flutamide), an inhibitor of androgen to estrogen conversion (testolactone), reduced hydrocortisone dose, and fludrocortisone, compared to the effects of a control regimen of hydrocortisone and fludrocortisone. Twenty-eight children have completed 2 yr of follow-up in a subsequent long term randomized parallel study comparing these two treatment regimens. During 2 yr of therapy, compared to children receiving hydrocortisone, and fludrocortisone treatment, children receiving flutamide, testolactone, reduced hydrocortisone dose (average of 8.7 +/- 0.6 mg/m2 x day), and fludrocortisone had significantly (P < or = 0.05) higher plasma 17-hydroxyprogesterone, androstenedione, dehydroepiandrosterone, dehydroepiandrosterone sulfate, and testosterone levels. Despite elevated androgen levels, children receiving the new treatment regimen had normal linear growth rate (at 2 yr, 0.1 +/- 0.5 SD units), and bone maturation (at 2 yr, 0.7 +/- 0.3 yr bone age/yr chronological age). No significant adverse effects were observed after 2 yr. We conclude that the regimen of flutamide, testolactone, reduced hydrocortisone dose, and fludrocortisone provides effective control of congenital adrenal hyperplasia with reduced risk of glucocorticoid excess. A long term study of this new regimen is ongoing.

Pituitary macroadenoma in a 5-year-old: an early expression of multiple endocrine neoplasia type 1.

Multiple endocrine neoplasia type 1 (MEN 1) is associated with parathyroid, enteropancreatic, pituitary, and other tumors. The MEN1 gene, a tumor suppressor, is located on chromosome 11. Affected individuals inherit a mutated MEN1 allele, and tumorigenesis in specific tissues follows inactivation of the remaining MEN1 allele. MEN 1-associated endocrine tumors usually become clinically evident in late adolescence or young adulthood, as high levels of PTH, gastrin, or PRL. Because each of these tumors can usually be controlled with medications and/or surgery, MEN 1 has been regarded mainly as a treatable endocrinopathy of adults. Unlike in MEN 2, early testing of children in MEN 1 families is not recommended. We report a 2.3-cm pituitary macroadenoma in a 5-yr-old boy with familial MEN 1. He presented with growth acceleration, acromegaloid features, and hyperprolactinemia. We tested systematically to see whether his pituitary tumor had causes similar to or different from a typical MEN 1 tumor. Germ line DNA of the propositus and his affected relatives revealed a heterozygous point mutation in the MEN1 gene, which leads to a His139Asp (H139D) amino acid substitution. The patient had no other detectable germ-line mutations on either MEN1 allele. DNA sequencing and fluorescent in situ hybridization with a MEN1 genomic DNA sequence probe each demonstrated one copy of the MEN1 gene to be deleted in the pituitary tumor and not in normal DNA, proving MEN1 "second hit" as a tumor cause. Gsalpha mutation, common in nonhereditary GH-producing tumors, was not detected in this tumor. We conclude that this pituitary macroadenoma showed molecular genetic features of a typical MEN 1-associated tumor. This patient represents the earliest presentation of any morbid endocrine tumor in MEN 1. A better understanding of early onset MEN 1 disease is needed to formulate recommendations for early MEN 1 genetic testing.

Effect of theophylline on ischemically induced hippocampal damage in Mongolian gerbils: a behavioral and histopathological study.

We investigated the influence of the adenosine antagonist theophylline on the degree of hippocampal cell damage in the Mongolian gerbil following brief periods of forebrain ischemia. Male gerbils were randomly divided into nine groups. Ten minutes before surgery, four groups, which were later subjected to 1, 2, 3, or 5 min of bilateral carotid occlusion under halothane anesthesia, received theophylline (30 mg/kg, p.o.). Four groups served as nontreated ischemic controls; the ninth group was used to measure theophylline serum concentration. Neurological symptoms were classified by using a behavioral score. Fourteen days after ischemia, the brains were removed, and the hippocampus was histologically examined "blind" for the degree of cell damage in the CA1 sector, which was expressed as a semiquantitative histopathological score. There were no behavioral or histological abnormalities in either the control or theophylline group with 1 min of ischemia. With increasing duration of ischemia, the neurological symptoms worsened and the number of necrotic pyramidal cells increased significantly. The pretreatment with theophylline only moderately aggravated the neurological symptoms, whereas it enhanced the ischemic cell damage significantly. The results are discussed with respect to recent findings that theophylline may block putatively protective effects of endogenous adenosine, whose concentration in the brain is known to rise significantly during ischemia.

A leucine-rich repeat protein of carrot that exhibits antifreeze activity.

A gene encoding an antifreeze protein (AFP) was isolated from carrot (Daucus carota) using sequence information derived from the purified protein. The carrot AFP is highly similar to the polygalacturonase inhibitor protein (PGIP) family of apoplastic plant leucine-rich repeat (LRR) proteins. Expression of the AFP gene is rapidly induced by low temperatures. Furthermore, expression of the AFP gene in transgenic Arabidopsis thaliana plants leads to an accumulation of antifreeze activity. Our findings suggest that a new type of plant antifreeze protein has recently evolved from PGIPs.

Gene expression during tuber development in potato plants.

Potato tubers are modified stems that have differentiated into storage organs. Factors such as day-length, nitrogen supply, and levels of the phytohormones cytokinin and gibberellic acid, are known to control tuberization. Morphological changes during tuber initiation are accompanied by the accumulation of a characteristic set of proteins, thought to be involved in N-storage (i.e. patatin) or defense against microbial or insect attack (i.e. proteinase inhibitor II). Additionally, deposition of large amounts of starch occurs during tuber formation, which is paralleled by an increase in sucrose synthase and other enzymes involved in starch biosynthesis (i.e. ADP-glucose pyrophosphorylase, starch synthases, and branching enzyme). Potential controlling mechanisms for genes expressed during tuberization are discussed.

Ischaemic damage in gerbil hippocampus is reduced following upregulation of adenosine (A1) receptors by caffeine treatment.

We have used the fact that long-term caffeine treatment upregulates the adenosine receptors, to examine the role of adenosine in ischaemia. Four-week oral treatment with caffeine (0.2% in drinking water) caused a significant (10-17%) increase in the binding of the adenosine A1-receptor ligand [3H]cyclohexyl-adenosine (CHA) to several brain regions, including the hippocampal CA1 area, in Mongolian gerbils. Animals subjected to such treatment exhibited significantly less neuronal damage in the CA1 region following 5 min bilateral carotid occlusion than did control animals (50% of the caffeine-treated animals showed no damage at all compared to 11% in the control group). Our findings provide further evidence for a protective role of endogenous adenosine during ischaemia.