Human ventral parietal cortex plays a functional role on visuospatial attention and primary consciousness. A repetitive transcranial magnetic stimulation study

In this paper, we used repetitive transcranial magnetic stimulation (rTMS) in 18 normal subjects to investigate whether the ventral posterior parietal cortex (PPC) plays a causal role on visuospatial attention and primary consciousness and whether these 2 functions are linearly correlated with each other. Two distinct experimental conditions involved a similar visual stimuli recognition paradigm. In "Consciousness" experiment, number of consciously perceived visual stimuli was lower by about 10% after rTMS (300 ms, 20 Hz, motor threshold intensity) on left or right PPC than after sham (pseudo) rTMS. In "Attentional" Posner's experiment, these stimuli were always consciously perceived. Compared with sham condition, parietal rTMS slowed of about 25 ms reaction time to go stimuli, thus disclosing effects on endogenous covert spatial attention. No linear correlation was observed between the rTMS-induced impairment on attention and conscious perception. Results suggest that PPC plays a slight but significant causal role in both visuospatial attention and primary consciousness. Furthermore, these high-level cognitive functions, as modulated by parietal rTMS, do not seem to share either linear or simple relationships.     

Long-Term Effects of Neridronate and its Discontinuation in Patients with Primary Hyperparathyroidism

In patients with primary hyperparathyroidism (PHPT) not suitable for surgical correction, a skeletal protection with bisphosphonates is considered a reasonable option, but the long-term effects after treatment discontinuation are not well known. Sixty postmenopausal women with PHPT were given 400–600 IU vitamin D₃ daily and 100 mg neridronate IV every 2 months for 2 years with 2 additional years of follow-up without antiresorptive therapies. Bone mineral density (BMD) progressively rose by 6.7 ± 7.6% (SD) and by 2.9 ± 4.5% at the spine and femoral neck, respectively. During follow-up, mean BMD progressively fell, but after 2 years it was still 3.9 ± 5.5% higher than baseline values at the spine. Bone alkaline phosphatase and serum C-telopeptide of type I collagen decreased significantly within 6 months (28 and 49% versus baseline, respectively) and rose to baseline values within 6–12 months during follow-up. Serum PTH significantly rose from baseline during treatment, but it remained significantly higher than baseline during follow-up. The PTH changes were significantly correlated with serum 25-hydroxyvitamin D (25OHD) levels. In conclusion, in this study we observed that in patients with mild PHPT treatment with bisphosphonates is associated with the expected changes in bone-turnover markers and that the significant increases of both hip and spine BMD are partially maintained for at least 2 years after treatment discontinuation at the vertebral site. The marked increases in serum PTH levels, particularly in subjects with low 25OHD levels, persist after treatment discontinuation and this raises the suspicion that this might reflect a worsening of PHPT.     

Predicting fractures in an international cohort using risk factor algorithms without BMD

Clinical risk factors are associated with increased probability of fracture in postmenopausal women. We sought to compare prediction models using self‐reported clinical risk factors, excluding BMD, to predict incident fracture among postmenopausal women. The GLOW study enrolled women aged 55 years or older from 723 primary‐care practices in 10 countries. The population comprised 19,586 women aged 60 years or older who were not receiving antiosteoporosis medication and were followed annually for 2 years. Self‐administered questionnaires were used to collect data on characteristics, fracture risk factors, previous fractures, and health status. The main outcome measure compares the C index for models using the WHO Fracture Risk (FRAX), the Garvan Fracture Risk Calculator (FRC), and a simple model using age and prior fracture. Over 2 years, 880 women reported incident fractures including 69 hip fractures, 468 “major fractures” (as defined by FRAX), and 583 “osteoporotic fractures” (as defined by FRC). Using baseline clinical risk factors, both FRAX and FRC showed a moderate ability to correctly order hip fracture times (C index for hip fracture 0.78 and 0.76, respectively). C indices for “major” and “osteoporotic” fractures showed lower values, at 0.61 and 0.64. Neither algorithm was better than the model based on age + fracture history alone (C index for hip fracture 0.78). In conclusion, estimation of fracture risk in an international primary‐care population of postmenopausal women can be made using clinical risk factors alone without BMD. However, more sophisticated models incorporating multiple clinical risk factors including falls were not superior to more parsimonious models in predicting future fracture in this population. © 2011 American Society for Bone and Mineral Research     

The challenge of basilar artery occlusion wake-up stroke: too late for intravenous thrombolysis?

We describe the case of a patient carried to our emergency department, with the wake-up finding of dysarthria, right hemiplegia and worsening consciousness impairment (NIHSS 12). After performing a CT angiography, which showed complete basilar occlusion, we determined the MR DWI-FLAIR mismatch to estimate the stroke onset time. Because of the favorable mismatch (DWI hyperintensity in the left pons, no FLAIR hyperintensity in the same region), the patient underwent thrombolysis with sudden neurological improvement. In addition, the DWI hyperintensity first observed in the left pons totally regressed after thrombolysis. Wake-up stroke constitutes about 14 % of all strokes, while the percentage of basilar artery occlusion wake-up strokes is still unknown. Although thrombolysis in patients with unknown-onset time is still an off-label therapy, basilar artery occlusion is a potentially fatal event. In our case we used RM DWI-FLAIR mismatch to rapidly estimate the stroke onset time and to treat the patient with an off-label but potentially effective and safe therapy.     

Previous fractures at multiple sites increase the risk for subsequent fractures: the Global Longitudinal Study of Osteoporosis in Women

Previous fractures of the hip, spine, or wrist are well-recognized predictors of future fracture, but the role of other fracture sites is less clear. We sought to assess the relationship between prior fracture at 10 skeletal locations and incident fracture. The Global Longitudinal Study of Osteoporosis in Women (GLOW) is an observational cohort study being conducted in 17 physician practices in 10 countries. Women aged ≥55 years answered questionnaires at baseline and at 1 and/or 2 years (fractures in previous year). Of 60,393 women enrolled, follow-up data were available for 51,762. Of these, 17.6%, 4.0%, and 1.6% had suffered 1, 2, or ≥3 fractures, respectively, since age 45 years. During the first 2 years of follow-up, 3149 women suffered 3683 incident fractures. Compared with women with no previous fractures, women with 1, 2, or ≥3 prior fractures were 1.8-, 3.0-, and 4.8-fold more likely to have any incident fracture; those with ≥3 prior fractures were 9.1-fold more likely to sustain a new vertebral fracture. Nine of 10 prior fracture locations were associated with an incident fracture. The strongest predictors of incident spine and hip fractures were prior spine fracture (hazard ratio [HR] = 7.3) and hip (HR = 3.5). Prior rib fractures were associated with a 2.3-fold risk of subsequent vertebral fracture, and previous upper leg fracture predicted a 2.2-fold increased risk of hip fracture. Women with a history of ankle fracture were at 1.8-fold risk of future fracture of a weight-bearing bone. Our findings suggest that a broad range of prior fracture sites are associated with an increased risk of incident fractures, with important implications for clinical assessments and risk model development.     

NOD/LtSz-Rag1nullPfpnull mice: a new model system with increased levels of human peripheral leukocyte and hematopoietic stem-cell engraftment

BACKGROUND: A critical need exists for effective small-animal models that accept engraftment of human hematopoietic progenitor cells and mature lymphocytes. The purpose of this study was to determine the phenotypic effects of perforin (Pfp) deficiency on nonobese diabetic (NOD)-Rag1null mice and to evaluate the ability of NOD/LtSz-Rag1nullPfpnull recipients to support engraftment with human hematolymphoid cells. METHODS: A new genetic stock of NOD mice doubly homozygous for targeted mutations at the recombination activating gene (Rag)-1 and Pfp genes was developed. NOD/LtSz-Rag1nullPfpnull mice were studied for immunopathologic and hematologic abnormalities. The ability of these mice to support engraftment with human peripheral blood mononuclear cells (PBMC) and umbilical-cord blood hematopoietic progenitor cells was assessed. RESULTS: NOD/LtSz-Rag1nullPfpnull mice lacked mature B cells, T cells, natural killer (NK) cell cytotoxic activity and were devoid of serum immunoglobulin (Ig) throughout a 37-week lifespan. These mice supported heightened engraftment with human PBMC as compared with NOD/LtSz-Rag1null controls as evidenced by a 4- to 5-fold increase in percentages of human lymphocytes and a 7- to 13-fold increase in percentages of CD4+ T cells in the peripheral blood and spleen. Total numbers of human CD4+ T cells were increased approximately 20-fold in the spleens of NOD/LtSz-Rag1nullPfpnull mice. These mice also showed approximately 12-fold higher levels of engraftment with human umbilical-cord blood cells compared with NOD/LtSz-Rag1null mice. CONCLUSIONS: NOD/LtSz-Rag1nullPfpnull mice are devoid of mature B cell, T cell, and NK cell cytotoxic activity, engraft at high levels with human PBMC, and hematopoietic progenitor cells and provide a new NK cell-deficient model for human hematolymphoid cell engraftment.     

Responsiveness and minimum important change of the Oswestry Disability Index in Italian subjects with symptomatic lumbar spondylolisthesis

Background

This study aims to investigate the responsiveness and the minimum important change of the Italian version of the Oswestry Disability Index (ODI-I) in subjects with symptomatic specific low back pain associated with lumbar spondylolisthesis (SPL).

Materials and methods

One hundred and fifty-one patients with symptomatic SPL completed the ODI-I, a 0–100 numerical rating scale (NRS), and performed the prone and supine bridge tests. The global perception of effectiveness was measured with a 7-point Likert scale. Responsiveness was assessed by distribution methods (minimum detectable change [MDC], effect size [ES], standardized response mean [SRM]) and anchor-based methods (ROC curves).

Results

The MDC was 4.23, the ES was 0.95 and the SRM was 1.25. ROC analysis revealed an area under the curve of 0.76 indicating moderate discriminating capacity. The best cut-off point for the dichotomous outcome was 7.5 (sensitivity 90.3%, specificity 56.7%). .

Conclusions

The ODI-I proved to be responsive in detecting changes after conservative treatment in subjects with lumbar SPL.

Level of evidence

II.

     

Idd loci synergize to prolong islet allograft survival induced by costimulation blockade in NOD mice

OBJECTIVE—NOD mice model human type 1 diabetes and are used to investigate tolerance induction protocols for islet transplantation in a setting of autoimmunity. However, costimulation blockade–based tolerance protocols have failed in prolonging islet allograft survival in NOD mice.RESEARCH DESIGN AND METHODS—To investigate the underlying mechanisms, we studied the ability of costimulation blockade to prolong islet allograft survival in congenic NOD mice bearing insulin-dependent diabetes (Idd) loci that reduce the frequency of diabetes.RESULTS—The frequency of diabetes is reduced in NOD.B6 Idd3 mice and is virtually absent in NOD.B6/B10 Idd3 Idd5 mice. Islet allograft survival in NOD.B6 Idd3 mice treated with costimulation blockade is prolonged compared with NOD mice, and in NOD.B6/B10 Idd3 Idd5, mice islet allograft survival is similar to that achieved in C57BL/6 mice. Conversely, some Idd loci were not beneficial for the induction of transplantation tolerance. Alloreactive CD8 T-cell depletion in (NOD × CBA)F1 mice treated with costimulation blockade was impaired compared with similarly treated (C57BL/6.H2^g7 × CBA)F1 mice. Injection of exogenous interleukin (IL)-2 into NOD mice treated with costimulation prolonged islet allograft survival. NOD.B6 Idd3 mice treated with costimulation blockade deleted alloreactive CD8 T-cells and exhibited prolonged islet allograft survival.CONCLUSIONS—Il2 is the Idd3 diabetes susceptibility gene and can influence the outcome of T-cell deletion and islet allograft survival in mice treated with costimulation blockade. These data suggest that Idd loci can facilitate induction of transplantation tolerance by costimulation blockade and that IL-2/Idd3 is a critical component in this process.The NOD mouse is a model of type 1–like autoimmune diabetes and is used to study costimulation blockade–based transplantation tolerance within the context of autoimmunity (1–4). However, costimulation blockade protocols fail in NOD mice. To investigate further the cellular and genetic control of costimulation blockade–induced transplantation tolerance, we used NOD Idd congenic mice that have small introgressed regions of genetic intervals derived from diabetes-resistant C57 stocks. These mice exhibit varying degrees of protection from autoantibodies, insulitis, and diabetes (5). Using Idd congenic NOD mice, we have observed that islet allograft survival is improved by the addition of the diabetes-protective Idd3 locus (6,7).Idd3 modulates infiltration of autoreactive lymphocytes into the islets (8), and there is compelling evidence that Idd3 is the interleukin (IL)-2 gene (9). In vivo stimulated NOD T-cells produce twofold less IL-2 mRNA than cells from NOD congenic mice having protective alleles at Idd3 (9,10). Neutralizing antibodies to IL-2 lead to accelerated disease in NOD mice (11), and targeted genetic disruption of IL-2 accelerates type 1–like autoimmune diabetes (9). Treatment with exogenous IL-2 inhibits diabetes development in NOD mice and improves T regulatory (Treg) function (12). IL-2 is also known to have a nonredundant role in CD8 T-cell activation–induced cell death via the CD95 (Fas) pathway (13), is required for the development of self-tolerance (14), and is essential for the induction of allograft tolerance by costimulation blockade (15). However, IL-2 is a double-edged sword, since administration of IL-2 in vivo can either enhance or depress a cytotoxic T lymphocyte (CTL) response (16).In this study, we show that costimulation blockade fails to delete alloreactive CD8 T-cells in NOD mice. Genetic replacement of IL-2 in NOD.B6 Idd3 mice enhances alloreactive CD8 T-cell deletion and improves islet allograft survival. Finally, we show that Idd3 synergizes with genes within the Idd5 interval, leading to permanent islet allograft survival in a majority of NOD.B6/B10 Idd3 Idd5 mice treated with costimulation blockade.     

Bilateral tumors of the testis in 21-alpha hydroxylase deficiency without adrenal hyperplasia

Congenital 21-alpha hydroxylase deficiency is a syndrome characterized by a cortisol synthesis deficiency and, rarely, by testicular masses. We present a case of bilateral nodular hyperplasia of the testis without adrenal hyperplasia in a patient affected by 21-alpha hydroxylase deficiency. This mass mimicked a testicular tumor and made differential diagnosis with a Leydig cell tumor extremely difficult. Multiple hard nodules (1 cm in diameter) could be palpated in both testes but were more prominent on the right. After an unsuccessful 30-day trial of an adrenocorticotropic hormone suppression regimen with dexamethasone (0.5 mg/qid), a right total orchifunicolectomy was performed. The final histological diagnosis was that of multiple, well-circumscribed nodules consisting of cord-like and microalveolar-like gonadal stroma, typical of an adrenogenital syndrome, and fibrosis. Differential diagnosis between testicular nodules in patients with congenital adrenal hyperplasia and Leydig cell tumors is a major clinical challenge. In cases of cortisol suppression resistant testicular masses, a serum adrenal hormone profile obtained from the gonadal vein and histology of the testicular nodule (with parenchyma sparing surgery) are recommended to obtain a correct diagnosis.     

Recurrent proximal white subungual onychomycosis associated with a defect of the polymorphonuclear chemotaxis.

Proximal white subungual onychomycosis (PWSO) is a rare form of nail infection that occurs almost exclusively in immunocompromised patients. Initially, in several reports, PWSO was described in ARC and AIDS patients. Later this pattern of onychomycosis was observed in patients with renal transplants, who received immunosuppressive therapy, and recently in a woman with active systemic lupus erythematosus (SLE) treated with systemic steroid therapy. We report a case of recurrent PWSO in a woman affected by a defect of polymorphonuclear chemotaxis. The association between PWSO and a defect of neutrophil chemotaxis, not yet described in the literature, suggests a point of discussion about the role of polymorphonuclear leucocyte functions in the defense mechanisms of the host affected by dermatophytosis. In this report the close association between PWSO and an immunocompromised condition is once again described. For this reason the authors emphasize the importance of investigating the common and uncommon causes of immunodeficiency in all patients affected by PWSO.