Safety and efficacy of teriparatide treatment for severe osteoporosis in patients with Duchenne muscular dystrophy.

Osteoporosis is a major concern in patients with Duchenne muscular dystrophy. In this novel study of teriparatide treatment in 6 patients with severe osteoporosis, bone health (fractures, vertebral morphometry, and DXA) remained stable, with no adverse events. These findings will help inform future osteoporosis research in this challenging population. INTRODUCTION: Despite standard therapy with vitamin D and bisphosphonates (BP), many patients with Duchenne muscular dystrophy (DMD) continue to sustain fragility fractures due to long-term glucocorticoid treatment and limited mobility. We aimed to evaluate the safety and efficacy of teriparatide for the treatment of severe osteoporosis in adolescent and young adult patients with DMD. METHODS: We prospectively treated 6 patients with DMD who had severe osteoporosis with teriparatide 20 mcg subcutaneously daily for 1-2 years. Inclusion criteria were long-term glucocorticoid therapy, and severe osteoporosis despite treatment with BP, or intolerance to BP. We examined long bone and vertebral fracture outcomes, including vertebral morphometry measures, bone mineral density and content, bone formation markers, safety indices, and adverse events. RESULTS: The mean age at teriparatide start was 17.9 years (range 13.9-22.1 years). All 6 patients were on daily glucocorticoids (mean ± SD; duration 10.9 ± 2.5 years) and 5 were non-ambulatory. Five patients had been treated with BP for 7.9 ± 4.2 years. All had vertebral and a history of long bone fragility fractures at baseline. Vertebral heights and Genant fracture grading remained stable. Long bone fracture rate appeared to decrease (from 0.84/year to 0.09/year); one patient sustained a long bone fracture at 6 months of treatment. Trajectories for change in bone mineral density and content were not different post- vs. pre-teriparatide. Procollagen type 1 amino-terminal propeptide (P1NP) increased, while laboratory safety indices remained stable and non-concerning. No adverse events were observed. CONCLUSION: In six patients with DMD treated with teriparatide for severe osteoporosis, we observed stable bone health and modest increases in P1NP, without safety concerns. Further studies are needed to better understand teriparatide efficacy for treatment of osteoporosis in patients with DMD.

Valve surgery for infective endocarditis complicated by stroke: surgical timing and perioperative neurological complications.

BACKGROUND AND PURPOSE: Ischaemic and hemorrhagic strokes are dreaded complications of infective endocarditis (IE). The timing of valve surgery for IE patients with stroke remains uncertain. The aim was to study perioperative neurological complications in relation to surgical timing. METHODS: The study cohort consisted of patients diagnosed with acute IE from January 2010 to December 2016. Early surgery was defined as valve surgery within 14 days of IE diagnosis, and late surgery as after 14 days. Neurological complications that occurred within 14 days post-surgery were considered perioperative and classified as new ischaemic stroke or hemorrhagic stroke, expansion of an existing intracranial hemorrhage and new-onset seizures. Perioperative neurological complications were compared by surgical timing and other variables, including pre-surgical imaging. RESULTS: Overall, 183 patients underwent valve surgery: 92 had early surgery at a median of 8 days (interquartile range 6-11); 91 had late surgery at a median of 28 days (interquartile range 19-50). Twenty patients (10.9%) had 24 complications: 11 ischaemic, six intraparenchymal hemorrhages, three subarachnoid hemorrhages (SAHs) and four new-onset seizures. Rates of neurological complications were similar for early and late surgery groups (10.9% vs. 11%). Enterococcal IE was more common amongst patients with perioperative neurological complications (35% vs. 12.3%, P < 0.01). An acute infarct was present on pre-surgical magnetic resonance imaging of 134 patients (74%) and was not associated with perioperative neurological complications. Thirty-five patients (19.3%) had intracranial hemorrhage on pre-surgical imaging. SAH on pre-surgical imaging was associated with developing SAH perioperatively (66.7% vs. 13.5%, P < 0.01). CONCLUSION: Early valve surgery for patients with IE complicated by stroke was not associated with perioperative neurological complications.

Cerebral microbleeds predict infectious intracranial aneurysm in infective endocarditis.

BACKGROUND AND PURPOSE: Magnetic resonance imaging (MRI) features such as cerebral microbleeds and sulcal susceptibility-weighted imaging (SWI) or gradient-echo T2* lesions in infective endocarditis (IE) have been associated with the presence of infectious intracranial aneurysm (IIA). Our aim was to validate these MRI predictors for IIA in order to better assist in assessing the appropriate indications for digital subtraction angiography (DSA). METHODS: The derivation cohort comprised IE patients with neurological evaluation, MRI and DSA at a single tertiary referral center from January 2015 to July 2016. Validation was performed in a cohort of IE patients who underwent MRI and DSA at the same center from 2010 to 2014. RESULTS: Of 62 patients in the derivation cohort, 10 (16%) had IIAs. Of 129 in the validation cohort, 19 (15%) IIAs were identified. The MRI predictors for IIA consist of (i) contrast enhancement with microbleeds, (ii) cerebral microbleeds >5 mm or sulcal SWI lesions and (iii) any MRI hemorrhages. The sensitivity for the presence of IIA in each group of the derivation cohort was 90%, 80% and 100%, respectively. The sensitivity in the validation cohort was 47%, 68% and 94% respectively. The specificity in the derivation cohort was 87%, 85% and 18%. In the validation cohort, the specificity was similar at 87%, 75% and 27%. CONCLUSIONS: The absence of MRI hemorrhages may not necessitate the need for DSA.

Duration of viral shedding and factors associated with prolonged shedding among inpatients with influenza treated with oseltamivir: a prospective cohort study.

The purpose of this study was to determine the rate of decline in the diagnostic yield of influenza PCR assay after oseltamivir administration, and to identify risk factors for prolonged shedding. This was a prospective observational study. We included adult inpatients with clinical signs of influenza during the influenza seasons 2015 and 2016, who had positive influenza PCR tests and who were treated with oseltamivir. Clinical follow-up and repeat PCR testing were performed on days 2, 4 and 6 after the first positive test. We defined prolonged shedders as patients who still required hospitalization and had a positive PCR assay on day 4. Risk factors for prolonged shedding were assessed in univariate and multivariate analyses. A total of 215 patients were included in our study. The median age was 64 years and 49.3% were men. The main influenza type was H1N1 (50.1%). Rates of PCR positivity among evaluable patients on days 2, 4 and 6 were 142/215 (66%), 50/78 (64.1%) and 20/30 (66.6%), respectively. Independent risk factors for prolonged shedding (50 patients) included hypoxemia [odds ratio (OR) 2.55, 95% confidence interval (1.3-5.1)] and lower diastolic blood pressure [OR 0.94, 95% CI (0.92-0.97)] on admission. Negative PCR tests taken more than 48 h after initiation of treatment had low diagnostic yield. More severe disease, manifested by hypoxemia and lower blood pressure, is associated with prolonged shedding on oseltamivir treatment.

Photorefractive two-beam coupling joint transform correlator: modeling and performance evaluation.

The photorefractive two-beam coupling joint transform correlator combines two features. The first is embedded semi-adaptive optimality, which weighs the correlation against clutter and noise in the input, and the second is the intrinsic dynamic range compression nonlinearity, which improves several metrics simultaneously without metric trade-off. Although the two beam coupling correlator was invented many years ago, its outstanding performance was recognized on only relatively simple images. There was no study about the performance of this correlator on complicated images and using different figures of merit. In this paper, the study is extended to more complicated images. For the first time, to our knowledge, we demonstrate simultaneous improvement in metrics performance without metric trade-off. The performance was evaluated compared to the classical joint transform correlator. A typical experimental result to validate the simulation results was also shown in this work. The best performing operation parameters were identified to guide the experimental work and for future comparison with other well-known optimal correlation filters.

Prepregnancy Weight in Women with Type I Diabetes Mellitus: Effect on Pregnancy Outcomes.

Objective This study aims to evaluate the association between prepregnancy body mass index (BMI) and adverse pregnancy outcomes in women with type 1 diabetes mellitus (DM). Methods This is a secondary analysis of a cohort of 426 pregnancies in women with type 1 DM recruited before 20 weeks gestation. Women were categorized according to prepregnancy BMI: low BMI (< 20 kg/m2), normal BMI (20 to < 25 kg/m2), and high BMI (≥ 25 kg/m2). The outcomes of interest were: spontaneous abortion (delivery < 20 weeks gestation); preeclampsia; emergent delivery for maternal indications (hypertension or placental abruption); and preterm delivery (< 37 weeks gestation). Analyses included proportional hazards and multiple logistic regression models with covariates: age, age at diagnosis of type 1 DM, previous spontaneous abortion, microvascular disease (nephropathy or retinopathy), and glycohemoglobin A1 concentrations. Results Low BMI was associated with preterm delivery. High BMI was associated with emergent delivery for maternal indications. Glycemic control as measured by glycohemoglobin A1 was associated with increased risk of spontaneous abortion, attenuating the association with low prepregnancy weight. Conclusion Prepregnancy BMI is a risk factor to be considered when caring for women with type 1 DM, in particular for preterm delivery (low BMI) and emergent delivery for maternal indications (high BMI).

CASE-REPORT Case study of a patient presenting both type II bipolar affective disorder and Klinefelter syndrome.

Klinefelter syndrome (KS) is the most common sex chromosomal disorder with an estimated prevalence of 1 in 500-1000. Increased incidences of anxiety, depression, substance abuse, psychotic and behavioral disorders, and sexual disorders have been reported in patients with KS. The aim of this case study was to report a case of a man with untreated KS who was also diagnosed with type II bipolar disorder. This case report raises awareness regarding psychiatric diagnoses that may be associated with such a highly prevalent condition. A 46-year-old man who had previously been diagnosed with an untreated KS was examined in our Psychiatric Department with an acute hypomanic episode. Clinical improvement was observed within 4 days and psychiatric symptoms were resolved in 7 days without use of medication. A psychiatric history of a depressive episode and at least two hypomanic episodes, as well as a family history of two relatives diagnosed with bipolar disorder, strongly suggest that our patient has type II bipolar disorder. Bipolar disorder may be a comorbid disorder in patients with KS. Routine screening for mood disorders and appropriate referral and evaluation should be performed. Future genetic research is warranted to explore why some chromosomal abnormalities (e.g., duplications), especially those located on the X chromosome, such as Klinefelter syndrome, may be associated with a bipolar or psychotic disorder in some individuals but not in others.

A lower reduction in umbilical artery pulsatility in mid-pregnancy predicts higher infant blood pressure six months after birth.

AIM: The Norwegian-based Cardiovascular Risk Reduction Diet in Pregnancy study found that a cholesterol-lowering diet during pregnancy was associated with an accentuated reduction in the umbilical artery pulsatility index. This follow-up study assessed the possible association between the index and the infants' blood pressure at six months of age. METHODS: In the original study, pregnant women consumed an anti-atherogenic or usual diet from gestational weeks 17-20 to birth and underwent Doppler velocimetry at 24, 30 and 36 gestational weeks. In this follow-up study, blood pressure was measured in 105 mother-infant pairs in the intervention group and 106 mother-infant pairs in the control group six months after birth. RESULTS: Mean systolic and diastolic blood pressures were not significantly different between both groups. When the groups were combined, multivariate linear analyses showed that a lower versus higher reduction (≥-0.17 versus <-0.17) in the umbilical artery pulsatility index between gestational weeks 24 and 30 and maternal diastolic blood pressure at six months postpartum were significant predictors of higher infant systolic blood pressure (p = 0.03, 0.01, respectively). CONCLUSION: A lower reduction in umbilical pulsatility index in mid-pregnancy was associated with higher infant blood pressure at six months of age. This suggests that fetoplacental intrauterine factors may influence future cardiovascular risk.

Glaucoma after penetrating keratoplasty and keratoprosthesis.

PURPOSE: To compare visual and glaucoma outcomes in patients with known glaucoma after a penetrating keratoplasty (PKP) or a Boston Keratoprosthesis Type 1 (KPro) as a second corneal replacement procedure. DESIGN: Retrospective interventional case series. PARTICIPANTS: Charts of 141 eyes that underwent either a PKP or KPro at the Centre hospitalier de l'Université de Montréal after one failed PKP from 2008 to 2020 were reviewed. Forty-six eyes with preoperative glaucoma were included. METHODS: Data collected included demographics, indication for the initial surgery, best corrected visual acuity (BCVA), concurrent ocular disorders, number of glaucoma medications, need for glaucoma surgery, cup-to-disc ratios (CDRs), mean RNFL thickness, and visual field (VF) characteristics. Primary outcomes were glaucoma progression trends. Secondary outcomes were visual outcomes and need for additional procedures. RESULTS: Mean follow-up was 4.7 years for the PKP and 7.3 for the KPro group (P<0.007). 30.6% of PKP compared to 70.5% of KPro patients were diagnosed with glaucoma preoperatively. Glaucoma worsened similarly in both groups; this is based on an analysis of the number of glaucoma medications, CDR, need for glaucoma surgery, and characteristic VF changes. Patients in the PKP group required significantly more regrafts than patients in the KPro group (31.8 vs. 8.3%; P=0.045). CONCLUSIONS: A preoperative diagnosis of glaucoma does not preclude KPro implantation. In glaucomatous eyes, the disease progressed similarly in both groups. Since both procedures increase the risk of worsening glaucoma, close follow-up is recommended. KPro may decrease the need for further corneal transplantation surgery.

Clinical relevance of cancer stem cells in bone marrow of early breast cancer patients.

BACKGROUND: Cancer stem cells (CSCs) are epithelial tumor cells that express CD44(+)CD24(-/lo). CSCs can be further divided into those that have aldehyde dehydrogenase (ALDH) activity (Aldefluor(+)) and those that do not. We hypothesized that if CSCs are responsible for tumor dissemination, their presence in bone marrow (BM) would be prognostic in early stages of breast cancer (EBC) patients. PATIENTS AND METHODS: BM aspirates were collected at the time of surgery from 108 patients with EBC. BM was analyzed for CSCs and ALDH activity by flow cytometry. Overall survival and disease-free survival (DFS) were calculated from the date of diagnosis and analyzed with Kaplan-Meier survival plots. Cox multivariate proportional hazards model was also carried out. RESULTS: Patients with CSCs in BM had a hazard ratio (HR) of 8.8 for DFS (P = 0.002); patients with Aldefluor(+) CSCs had a HR of 5.9 (P = 0.052) for DFS. All deceased patients (n = 7) had CSCs in BM. In multivariate analysis, the presence of CSCs in BM was a prognostic factor of DFS (HR = 15.8, P = 0.017). CONCLUSIONS: The presence of BM metastasis is correlated with CSCs and these CSCs irrespective of ALDH activity are an independent adverse prognostic factor in EBC patients.

[Toxicity of metformin, pro- or con- a future restriction to its contraindications?]. / Toxicité de la metformine: pour ou contre une restriction de ses contre-indications?

Type 2 diabetes, a world-wide epidemic, is a major concern of health systems around the world. The recommandation of its early management with metformin by the majority of guidelines has made metformin the object of multiple studies to demonstrate its benefits, but more importantly its side effects among whom the most serious is lactic acidosis. The latter is rare, but responsible for high mortality rates and is strongly associated with acute and chronic conditions for which diabetics are prone. These conditions reduce tissue perfusion and activate anaerobic metabolism producing lactate. Despite the beneficial effects of metformin and the debate about its causal role, we should remain vigilant about this serious complication by respecting its usage's contraindications, for the time being unchanged.

Mac-1 (CD11b/CD18) is an oligodeoxynucleotide-binding protein.

We have studied the interactions of phosphodiester and phosphorothioate oligodeoxynucleotides with Mac-1 (CD11b/CD18; alpha M beta 2), a heparin-binding integrin found predominantly on the surface of polymorphonuclear leukocytes (PMNs), macrophages and natural killer cells. Binding of a homopolymer of thymidine occurred on both the alpha M and beta 2 subunits. Soluble fibrinogen, a natural ligand for Mac-1, was an excellent competitor of the binding of a phosphorothioate oligodeoxynucleotide to both TNF-alpha-activated and nonactivated PMNs. Upregulation of cell-surface Mac-1 expression increased cell-surface binding of oligodeoxynucleotides. Binding was inhibited by anti-Mac-1 monoclonal antibodies, and the increase in cell-surface binding was correlated with a three- to fourfold increase in internalization by PMNs. An oligodeoxynucleotide inhibited beta 2-dependent migration through Matrigel, but the production of reactive oxygen species in PMNs adherent to fibrinogen dramatically increased. Thus, our data demonstrate that Mac-1 is a cell-surface receptor for oligodeoxynucleotides that can mediate their internalization and that this binding may have important functional consequences.

Protection from lethal gram-positive infection by macrophage scavenger receptor-dependent phagocytosis.

Infections with gram-positive bacteria are a major cause of morbidity and mortality in humans. Opsonin-dependent phagocytosis plays a major role in protection against and recovery from gram-positive infections. Inborn and acquired defects in opsonin generation and/or recognition by phagocytes are associated with an increased susceptibility to bacterial infections. In contrast, the physiological significance of opsonin-independent phagocytosis is unknown. Type I and II class A scavenger receptors (SR-AI/II) recognize a variety of polyanions including bacterial cell wall products such as lipopolysaccharide (LPS) and lipoteichoic acid (LTA), suggesting a role for SR-AI/II in innate immunity to bacterial infections. Here, we show that SR-AI/II-deficient mice (MSR-A(-/-)) are more susceptible to intraperitoneal infection with a prototypic gram-positive pathogen, Staphylococcus aureus, than MSR-A(+/+) control mice. MSR-A(-/-) mice display an impaired ability to clear bacteria from the site of infection despite normal killing of S. aureus by neutrophils and die as a result of disseminated infection. Opsonin-independent phagocytosis of gram-positive bacteria by MSR-A(-/-) macrophages is significantly decreased although their phagocytic machinery is intact. Peritoneal macrophages from control mice phagocytose a variety of gram-positive bacteria in an SR-AI/II-dependent manner. Our findings demonstrate that SR-AI/II mediate opsonin-independent phagocytosis of gram-positive bacteria, and provide the first evidence that opsonin-independent phagocytosis plays a critical role in host defense against bacterial infections in vivo.

Complementary roles for scavenger receptor A and CD36 of human monocyte-derived macrophages in adhesion to surfaces coated with oxidized low-density lipoproteins and in secretion of H2O2.

Oxidized low-density lipoprotein (oxLDL) is considered one of the principal effectors of atherogenesis. To explore mechanisms by which oxLDL affects human mononuclear phagocytes, we incubated these cells in medium containing oxLDL, acetylated LDL (acLDL), or native LDL, or on surfaces coated with these native and modified lipoproteins. The presence of soluble oxLDL, acLDL, or native LDL in the medium did not stimulate H2O2 secretion by macrophages. In contrast, macrophages adherent to surfaces coated with oxLDL secreted three- to fourfold more H2O2 than macrophages adherent to surfaces coated with acLDL or native LDL. Freshly isolated blood monocytes secreted little H2O2 regardless of the substrate on which they were plated. H2O2 secretion was maximal in cells maintained for 4-6 d in culture before plating on oxLDL-coated surfaces. Fucoidan, a known ligand of class A macrophage scavenger receptors (MSR-A), significantly reduced macrophage adhesion to surfaces coated with oxLDL or acLDL. Monoclonal antibody SMO, which blocks oxLDL binding to CD36, did not inhibit adhesion of macrophages to oxLDL-coated surfaces but markedly reduced H2O2 secretion by these cells. These studies show that MSR-A is primarily responsible for adhesion of macrophages to oxLDL-coated surfaces, that CD36 signals H2O2 secretion by macrophages adherent to these surfaces, and that substrate-bound, but not soluble, oxLDL stimulates H2O2 secretion by macrophages.

Fibrin regulates neutrophil migration in response to interleukin 8, leukotriene B4, tumor necrosis factor, and formyl-methionyl-leucyl-phenylalanine.

We have examined the capacity of four different chemoattractants/cytokines to promote directed migration of polymorphonuclear leukocytes (PMN) through three-dimensional gels composed of extracellular matrix proteins. About 20% of PMN migrated through fibrin gels and plasma clots in response to a gradient of interleukin 8 (IL-8) or leukotriene B4 (LTB4). In contrast, < 0.3% of PMN migrated through fibrin gels in response to a gradient of tumor necrosis factor alpha (TNF) or formyl-methionyl-leucyl-phenylalanine (FMLP). All four chemoattractants stimulated PMN to migrate through gels composed of collagen IV or of basement membrane proteins (Matrigel), or through filters to which fibronectin or fibrinogen had been adsorbed. PMN stimulated with TNF or FMLP adhered and formed zones of close apposition to fibrin, as measured by the exclusion of a 10-kD rhodamine-polyethylene glycol probe from the contact zones between PMN and the underlying fibrin gel. By this measure, IL-8- or LTB4-treated PMN adhered loosely to fibrin, since 10 kD rhodamine-polyethylene glycol permeated into the contact zones between these cells and the underlying fibrin gel. PMN stimulated with FMLP and IL-8, or FMLP and LTB4, exhibited very little migration through fibrin gels, and three times as many of these cells excluded 10 kD rhodamine-polyethylene glycol from their zones of contact with fibrin as PMN stimulated with IL-8 or LTB4 alone. These results show that PMN chemotaxis is regulated by both the nature of the chemoattractant and the composition of the extracellular matrix; they suggest that certain combinations of chemoattractants and matrix proteins may limit leukocyte movements and promote their localization in specific tissues in vivo.

Ca(2+)-independent F-actin assembly and disassembly during Fc receptor-mediated phagocytosis in mouse macrophages.

Phagocytosis of IgG-coated particles by macrophages is presumed to involve the actin-based cytoskeleton since F-actin accumulates beneath forming phagosomes, and particle engulfment is blocked by cytochalasins, drugs that inhibit actin filament assembly. However, it is unknown whether Fc receptor ligation affects the rate or extent of F-actin assembly during phagocytosis of IgG-coated particles. To examine this question we have used a quantitative spectrofluorometric method to examine F-actin dynamics during a synchronous wave of phagocytosis of IgG-coated red blood cells by inflammatory mouse macrophages. We observed a biphasic rise in macrophage F-actin content during particle engulfment, with maxima at 1 and 5 min after the initiation of phagocytosis. F-actin declined to resting levels by 30 min, by which time particle engulfment was completed. These quantitative increases in macrophage F-actin were reflected in localized changes in F-actin distribution. Previous work showed that the number of IgG-coated particles engulfed by macrophages is unaffected by buffering extracellular calcium or by clamping cytosolic free calcium concentration ([Ca2+]i) to very low levels (Di Virgilio, F., B. C. Meyer, S. Greenberg, and S. C. Silverstein. 1988. J. Cell Biol. 106: 657-666). To determine whether clamping [Ca2+]i in macrophages affects the rate of particle engulfment, or the assembly or disassembly of F-actin during phagocytosis, we examined these parameters in macrophages whose [Ca2+]i had been clamped to approximately less than 3 nM with fura 2/AM and acetoxymethyl ester of EGTA. We found that the initial rate of phagocytosis, and the quantities of F-actin assembled and disassembled were similar in Ca(2+)-replete and Ca(2+)-depleted macrophages. We conclude that Fc receptor-mediated phagocytosis in mouse macrophages is accompanied by an ordered sequence of assembly and disassembly of F-actin that is insensitive to [Ca2+]i.

Differential regulation of beta1 integrins by chemoattractants regulates neutrophil migration through fibrin.

Chemoattractants differ in their capacity to stimulate neutrophils to adhere to and to migrate through matrices containing fibrin. Formyl methionyl leucyl phenylalanine (fMLP) stimulates neutrophils to adhere closely to, but not to migrate into, fibrin gels. Leukotriene B4 (LTB4) stimulates neutrophils to adhere loosely to and to migrate through fibrin gels. We report that alpha5beta1 integrins regulate the different migratory behaviors on fibrin gels of neutrophils in response to these chemoattractants. fMLP, but not LTB4, activated neutrophil beta1 integrins, as measured by binding of mAb 15/7 to an activation epitope on the beta1 integrins. Antibodies or peptides that block alpha5beta1 integrins prevented fMLP-stimulated neutrophils from forming zones of close apposition on fibrin and reversed fMLP's inhibitory effect on neutrophil chemotaxis through fibrin. In contrast, neither peptides nor antibodies that block beta1 integrins affected the capacity of LTB4-stimulated neutrophils to form zones of loose apposition or to migrate through fibrin gels. These results suggest that chemoattractants generate at least two different messages that direct neutrophils, and perhaps other leukocytes, to accumulate at specific anatomic sites: a general message that induces neutrophils to crawl and a specific message that prepares neutrophils to stop when they contact appropriate matrix proteins for activated beta1 integrins.

Retinal dystrophy: development retarded by galactose feeding in spontaneously hypertensive rats.

Retinal photoreceptor cell dystrophies have been widely observed in humans and in animals, but pathogenetic mechanisms are known in only a few such disorders, and successful therapeutic intervention has been reported in fewer still. Spontaneously hypertensive albino rats develop a retinal photoreceptor cell dystrophy with onset late in the first year or early in the second year of life. Between 60 and 70 percent of the animals are affected. A substantial reduction in the prevalence and severity of the dystrophy occurred in such animals whose diet contained 30 percent (by weight) D-galactose. Neither an inhibitor of the enzyme aldose reductase, present in the diet, nor diabetes mellitus, induced by streptozotocin, had any statistically significant influence on the dystrophy. Ambient light and systolic blood pressure levels also did not seem to influence the course of the disorder. The mechanism by which galactose exerts its effect is unknown, but a mutant enzyme with an elevated Michaelis constant (Km) for galactose is plausible.

Validation of a HOME Injury Survey.

BACKGROUND: There are no validated observational surveys to assess injury hazards in the home environment. OBJECTIVE: To evaluate the reproducibility and reliability of a survey quantifying home injury hazards for children. METHODS: A nested cohort of children in the intervention arm of the Home Observations and Measures of the Environment (HOME) Study trial were analysed. The number and density of hazards were quantified by research assistants in the homes of participants at a baseline visit (BHV) for four high-risk rooms (kitchen, main activity room, child's bathroom and child's bedroom) and stairways and later at an intervention planning visit (IPV) for the four high-risk rooms and entire household. Statistical analysis included Pearson correlation, Bland-Altman analysis of agreement, analysis of variance and kappa statistics. RESULTS: There were 163 households with measurements at BHV and IPV. The number and density of hazards for the four high-risk rooms correlated significantly between BHV and IPV (r = 0.50 and 0.75, respectively). The number and density of hazards for the four high-risk rooms correlated significantly with that for the whole household at the IPV (r = 0.17 and 0.52, respectively). The number of injury hazards was significantly higher in the kitchen than in the other high-risk rooms, whereas density was highest in the child's bathroom. Inter-rater reliability between research assistants, as measured by the kappa statistic, was excellent with a mean of 0.81. CONCLUSIONS: The HOME Injury Survey was a reliable and replicable tool for quantifying residential injury hazards. The density of injury hazards was a more stable and valid measure than the number of injury hazards.

Relations among maternal withdrawal in infancy, borderline features, suicidality/self-injury, and adult hippocampal volume: A 30-year longitudinal study.

The hippocampus plays an important role in stress regulation and has been the focus of research regarding the effects of early life stress on brain development. Much of this research has focused on severe forms of early adversity, particularly maltreatment. However, a handful of studies are now examining the effects of more subtle variations in quality of early caregiving on hippocampal development. In addition, both early caregiving and hippocampal volumes have been linked to psychopathology, particularly borderline personality disorder (BPD) and its associated features, such as suicidality. In the context of a 30-year longitudinal study, we assessed associations between maternal withdrawal in infancy, hippocampal volume, and BPD features in adulthood. Hippocampal volume was assessed among 18 adults (29.33 ±â€¯0.49 years) assessed for caregiving quality at 18 months (M =18.55 months, SD = 1.21 months) and followed longitudinally to age 29. Left hippocampal volume in adulthood was associated with maternal withdrawal in infancy, but not by other components of disrupted parenting. Other risk factors, including maternal psychosocial risk and severity of maltreatment in childhood, were not significantly related to left hippocampal volume. Left hippocampal volume was further associated with increased BPD features and suicidality/self-injury. In addition, left hippocampal volume partially mediated the association between early maternal withdrawal and later suicidality/self-injury. Results point to the importance of quality of early care for hippocampal development and suggest that the first two years of life may be an early sensitive period during which intervention could have important consequences for long-term psychological functioning into adulthood.