The Chemokine Receptors Ccr5 and Cxcr6 Enhance Migration of Mesenchymal Stem Cells into the Degenerating Retina.

Cell therapy approaches hold great potential for treating retinopathies, which are currently incurable. This study addresses the problem of inadequate migration and integration of transplanted cells into the host retina. To this end, we have identified the chemokines that were most upregulated during retinal degeneration and that could chemoattract mesenchymal stem cells (MSCs). The results were observed using a pharmacological model of ganglion/amacrine cell degeneration and a genetic model of retinitis pigmentosa, from both mice and human retinae. Remarkably, MSCs overexpressing Ccr5 and Cxcr6, which are receptors bound by a subset of the identified chemokines, displayed improved migration after transplantation in the degenerating retina. They also led to enhanced rescue of cell death and to preservation of electrophysiological function. Overall, we show that chemokines released from the degenerating retinae can drive migration of transplanted stem cells, and that overexpression of chemokine receptors can improve cell therapy-based regenerative approaches.

Defining priorities in the transition from paediatric to adult healthcare for rare bone disease patients: a dialogic approach.

The Italian patient association for Multiple Osteochondromas, Ollier Disease, and Maffucci Syndrome, Associazione Conto Alla Rovescia-ACAR Aps, conducted a mixed-methods study at its 2023 annual conference. The study included the Open Dialogue Approach and a feedback survey to identify the main priorities in the transitioning process from paediatric to adult healthcare for patients with Multiple Osteochondromas, Ollier Disease, and Maffucci Syndrome. The common needs identified by patients, families, caregivers, and healthcare professionals were coordination and continuity of care, patient empowerment and communication, social and practical support, and transition planning and support. This experience fostered a sense of collaboration and cooperation among stakeholders, helping to build trust and create a shared vision for improving the quality of care for these patients. Furthermore, it could be considered a starting point for other patient associations interested in using different approaches to identify the needs of their members and actively involve all stakeholders.

Alternative academic approaches for testing homologous recombination deficiency in ovarian cancer in the MITO16A/MaNGO-OV2 trial.

BACKGROUND: The detection of homologous recombination deficiency (HRD) can identify patients who are more responsive to platinum and poly ADP ribose polymerase inhibitors (PARPi). MyChoice CDx (Myriad) is the most used HRD test in ovarian cancer (OC). However, some limitations of commercial tests exist, because of the high rate of inconclusive results, costs, and the impossibility of evaluating functional resistance mechanisms. PATIENTS AND METHODS: Two academic genomic tests and a functional assay, the RAD51 foci, were evaluated to detect HRD. One hundred patients with high-grade OC enrolled in the MITO16A/MaNGO-OV2 trial and treated with first-line therapy with carboplatin, paclitaxel, and bevacizumab were analyzed. RESULTS: The failure rate of the two genomic assays was 2%. The sensitivity in detecting HRD when compared with Myriad was 98.1% and 90.6%, respectively. The agreement rate with Myriad was 0.92 and 0.87, with a Cohen's κ coefficient corresponding to 0.84 and 0.74, respectively. For the RAD51 foci assay, the failure rate was 30%. When the test was successful, discordant results for deficient and proficient tumors were observed, and additional HRD patients were identified compared to Myriad; sensitivity was 82.9%, agreement rate was 0.65, and Cohen's κ coefficient was 0.18. The HRD detected by genomic assays and residual tumor at primary surgery and stage was correlated with progression-free survival at multivariate analysis. CONCLUSIONS: Results suggest the feasibility of academic tests for assessing HRD status that show robust concordance with Myriad and correlation with clinical outcome. The contribution of the functional information related to the RAD51 foci test to the genomic data needs further investigation.

In vivo somatic cell reprogramming for tissue regeneration: the emerging role of the local microenvironment.

The past few years have witnessed an exponential increase of interest in the reprogramming process. This has been motivated by the enthusiasm of unravelling key aspects not only of cell identity and dedifferentiation, but also of the endogenous regenerative capacities of mammalian organs. Here, we present the most recent advances in the field of reprogramming, stressing how they are re-defining the rules of cell fate and plasticity in vivo. Specifically, we focus on the emerging role of the tissue microenvironment, with particular emphasis on tissue damage, inflammation and senescence that can facilitate in vivo reprogramming and regeneration through cell-extrinsic mechanisms.

Endogenous Mobilization of Bone-Marrow Cells Into the Murine Retina Induces Fusion-Mediated Reprogramming of Müller Glia Cells.

Müller glial cells (MGCs) represent the most plastic cell type found in the retina. Following injury, zebrafish and avian MGCs can efficiently re-enter the cell cycle, proliferate and generate new functional neurons. The regenerative potential of mammalian MGCs, however, is very limited. Here, we showed that N-methyl-d-aspartate (NMDA) damage stimulates murine MGCs to re-enter the cell cycle and de-differentiate back to a progenitor-like stage. These events are dependent on the recruitment of endogenous bone marrow cells (BMCs), which, in turn, is regulated by the stromal cell-derived factor 1 (SDF1)-C-X-C motif chemokine receptor type 4 (CXCR4) pathway. BMCs mobilized into the damaged retina can fuse with resident MGCs, and the resulting hybrids undergo reprogramming followed by re-differentiation into cells expressing markers of ganglion and amacrine neurons. Our findings constitute an important proof-of-principle that mammalian MGCs retain their regenerative potential, and that such potential can be activated via cell fusion with recruited BMCs. In this perspective, our study could contribute to the development of therapeutic strategies based on the enhancement of mammalian endogenous repair capabilities.

Age-specific incidence and duration of known diabetes. The Cremona Study.

OBJECTIVE: To estimate the overall and age-specific incidence of known diabetes and its total duration through prevalence data and to assess the consistency of the results by mortality analysis of the same cohort. RESEARCH DESIGN AND METHODS: Two different sources were used. The first was a representative sample of 2,274 prevalent known-diabetic subjects. These data provided overall and age-specific incidence estimates by fitting a logistic model to the partial incidence rates for different diagnosis cohorts and to the disease duration. The age at diagnosis structure was built from the age-specific estimates. Prevalence data also provided total duration estimates by converting the prevalent duration-to-date structure into an incident total duration structure. The second source was 145 deceased subjects who were taken from the 6-year follow-up sample of 1,132 prevalent subjects. The age at diagnosis and estimates of total disease duration were provided for these subjects, who paralleled the characteristics of the incident cohort. RESULTS: The two independent estimates of total disease duration were similar (prevalent subjects, 15.7 years; deceased subjects, 14.1 years): the average duration was 14.9 years. The ratio between prevalence and total duration yielded an independent yearly incidence estimate of 2.2 per 1,000 person-years (men, 2.0; women, 2.4), which was close to the value given by the model of 2.1 per 1,000 person-years (men, 1.9; women, 2.3). Also, the independently determined age structures overlapped, and their average was used to calculate the age-specific incidence. Incidence was negligible for individuals < 30 years of age, and it was about 6.0 per 1,000 person-years for individuals > 50 years of age. CONCLUSIONS: This study provided reliable estimates of NIDDM age-specific incidence rates and total disease duration, data that are seldom investigated in this type of disease.

Effects of personality on metabolic control in IDDM patients.

OBJECTIVE: The aim of this study was to evaluate the relationship between poor metabolic control and maladaptive personality traits (according to the Diagnostic and Statistical Manual of Mental Disorders, Third Edition-Revised) in an adult-onset insulin-dependent diabetes mellitus sample group (n = 77). RESEARCH DESIGN AND METHODS: Metabolic control was evaluated through glycosylated hemoglobin (HbA1c). Personality traits were assessed with the Personality Diagnostic Questionnaire-Revised, a self-administered questionnaire. Residual pancreatic secretion (fasting serum C-peptide) was also evaluated. RESULTS: Principal components analysis revealed three personality profiles: "withdrawn-suspicious" (P1), "dramatic-dependent" (P2), and "aggressive-irresponsible" (P3). Multiple linear regression analysis showed that C-peptide levels and P2 personality profiles were significant and independent predictors of HbA1c plasma levels: P2 predicted high HbA1c values and C-peptide predicted low HbA1c levels. CONCLUSIONS: These data suggest that a P2 personality profile is a significant predictor of poor metabolic control.

Two-step islet autoantibody screening for risk assessment of type 1 diabetes in relatives.

OBJECTIVE: To examine the performance of islet cell antibodies (ICAs) and antibodies to glutamate decarboxylase (GADA), IA-2 (IA-2 antibody [IA-2A]), and insulin (insulin autoantibody [IAA]), alone and in combination, in assessing type 1 diabetes risk within type 1 diabetic families to identify a practical and effective screening strategy for predicting type 1 diabetes in relatives. RESEARCH DESIGN AND METHODS: ICA, GADA, IA-2A, and IAA were determined in 806 first-degree relatives participating in a prospective type 1 diabetes family study (median follow-up 6.17 years, range 0.6-8.3). The conferred risk of developing type 1 diabetes within 6 years was evaluated by Kaplan-Meier for each antibody marker, used alone or in combination. RESULTS: ICAs were detected in 3%, GADA in 5.1%, IA-2A in 2.5%, and IAA in 3.7% of relatives; > or =1 antibody markers were detected in 10.7% of relatives and > or =2 were detected in 1.9% of relatives. The risk of type 1 diabetes at 6 years was 1.5% in relatives with only 1 marker and 24.8% in relatives with > or =2 markers. As a practical and effective strategy for type 1 diabetes risk assessment in relatives, this study indicates a first-step screening based on GADA and IA-2A measurement--which identified 6.5% of relatives, including all who developed the disease, with a 6-year type 1 diabetes risk of 9.0%--followed by a second step based on ICA and IAA measurement in relatives with either GADA or IA-2A, which identified a total of 1.9% of all relatives as having > or =2 markers, and a 6-year risk of 24.8%, including 6 of 7 who developed type 1 diabetes. CONCLUSIONS: A two-step antibody screening, based first on GADA and IA-2A and then on ICA and IAA measurements in identified individuals, is likely to be a practical, sensitive, and effective strategy for predicting type 1 diabetes in first-degree relatives.

Posterior Reversible Encephalopathy Syndrome in late postpartum eclampsia.

Posterior Reversible Encephalopathy Syndrome (PRES) is a neurological complication associated with several medical conditions and it has been described in clinical findings of seizures, headache, vomiting, altered mental status, and visual changes and focal neurologic deficit, in conjunction with radiological findings of primarily posterior cerebral white matter edema of both cerebral hemispheres. PRES can develop in a wide array situations including pregnancy and postpartum in patients with or without symptoms and signs of eclampsia. A prompt diagnosis of PRES by magnetic resonance imaging and an immediate antihypertensive and anticonvulsant therapy can help to prevent serious complications. The clinical case presented deals with a 35 year-old pregnant woman whose history of eclampsia was observed after a cesarean section.

Epidemiology of known diabetes in Lombardy, north Italy. Clinical characteristics and methodological aspects.

Diabetes epidemiology can benefit in Italy from the large network of outpatient diabetic clinics and patients' facilities. A large investigation was carried out in 1988, in a certain area of northern Italy, to estimate the prevalence of known diabetes. Using four information sources, 4547 distinct patients were identified. Through the capture-recapture method we assessed completeness and estimated a prevalence of 3.3%. Prevalence of type 1 diabetes was 0.8 per 1000. Italian age-standardised overall prevalence and developed-world standardised rates were 2.8% and 2.6%, respectively. A representative sample of 2358 patients was characterised through a standard questionnaire. Women were diagnosed about 6 years later than men (58.8 +/- 0.4 vs 52.9 +/- 0.4, P < 0.0001), while the duration of the disease was very similar in both sexes (9.9 +/- 0.2 vs 9.5 +/- 0.2). As regards diabetes therapy, 17.2% of the patients were on diet alone, 62.1% on oral agents and 20.6% on insulin. Among the insulin-treated subjects more than half were on adjuvant therapy with tablets, and only 6.2% were treated with 3 injections/day. Less than half of all the known diabetic subjects had had an ophthalmoscopic examination in the previous 2 years.

HLA-antigens in Italian type 1 diabetic patients: role of DR3/DR4 antigens and breast feeding in the onset of the disease.

HLA-A, B, C, DR and DQ typing was performed in 381 Italian insulin-dependent diabetic patients and in 905 normal Italian subjects. The diabetic patients had significantly higher frequencies of HLA-Cw7, B8, B18, DR3, DR4, DQw2 and DQw3 and significantly lower frequencies of HLA-B17, Bw51, DR2, DR7 and DRw11. The frequency of heterozygosity for HLA-DR3/DR4 was significantly higher in patients who developed the disease in the first 2 years of life and DR3+/DR4-, DQw2 and DQw3 alleles were higher in those aged less than 14 years at onset. The HLA-DR4 allele was associated with onset of diabetes in autumn and HLA-B18 with onset in Autumn-winter. Diabetic children who were breast fed had a later onset of insulin-dependent diabetes mellitus than those who were bottle fed but these differences were independent of HLA typing (11.8 +/- 0.72 years vs 9.23 +/- 0.42 years; mean +/- SEM). We conclude that: (1) in general, HLA distribution in Italian insulin-dependent diabetic patients reflects previous data reported in other European and North American populations; (2) HLA-DR3 and DR4 are strongly associated with insulin-dependent diabetes in Italy as well, and these alleles seem to predispose to an earlier onset of the disease; and (3) breast feeding may delay the onset of the disease.

HLA-DQ screening for risk assessment of insulin dependent diabetes in northern Italy.

Genetic markers may be used to improve the prediction of insulin-dependent diabetes mellitus (type 1) in individuals with islet autoantibodies. In order to develop a risk assessment strategy for the Lombardy region of northern Italy based on genetic and immunological markers, we analyzed HLA DQA1 and DQB1 alleles in 60 type 1 probands and their first-degree relatives and 65 unrelated control subjects from the same area using polymerase chain reaction (PCR) and oligonucleotide probes. The major risk haplotypes were DQA1 *0501-DQB1*0201 (39.1% of diabetic vs. 8.9% of non-diabetic haplotypes) and DQA1 *0301-DQB1*0302(20% of diabetic vs 7.1% of non-diabetic haplotypes). Stratified analysis showed DQA1*0102-DQB1*0502 also to be associated with type 1 susceptibility when found together with DQA1*0501-DQB1*0201 or DQA1*0301-DQB1*0302. One type 1 patient had the type 1-protective DQA1*0102-DQB1*0602 haplotype. Overall, 88% of patients and 20% of unrelated control subjects had either DQA1*0501-DQB1*0201 or DQA1*0301-DQB1*0302 in the absence of DQA1*0102-DQB1*0602. These data suggest that typing for markers identifying these three haplotypes in the Lombardy population will achieve a sensitivity of almost 90% and exclude 80% of children from subsequent islet autoantibody testing.

Non-Hamiltonian equations of motion with a conserved energy.

In 1980 Andersen introduced the use of "extended system" as a means of exploring by molecular dynamics simulation the phase space of a physical model according to a desired ensemble distribution different from the standard microcanonical function. Following his original work on constant pressure-constant enthalpy a large number of different equations of motion, not directly derivable from a Hamiltonian, have been proposed in recent years, the most notable of which is the so-called Nosé-Hoover formulation for "canonical" molecular dynamics simulation. Using a generalization of the symplectic form of the Hamilton equations of motion we show here that there is a unique general structure that underlies most, if not all the equations of motion for "extended systems." We establish a unifying formalism that allows one to identify and separately control the conserved quantity, usually known as the "total energy" of the system, and the phase-space compressibility. Moreover, we define a standard procedure to construct conservative non-Hamiltonian flows that sample the phase space according to a chosen distribution function [Tuckerman et al., Europhys. Lett. 45, 149 (1999)]. To illustrate the formalism we derive new equations of motion for two example cases. First we modify the equations of motion of the Nosé-Hoover thermostat applied to a one-dimensional harmonic oscillator, and we show how to overcome the ergodicity problem and obtain a canonical sampling of phase space without making recourse to additional degrees of freedom. Finally we recast an idea recently put forward by Marchi and Ballone [J. Chem. Phys. 110, 3697 (1999)] and derive a dynamical scheme for sampling phase space with arbitrary statistical biases, showing as an explicit application a demixing transition in a simple Lennard-Jones binary mixture.

Gunshot wounds to the foot and ankle.

Gunshot wounds to the foot and ankle can be a devastating injury. This article discusses the basic physics of ballistics and its unique role in open fracture treatment. Classification and treatment protocol are also discussed.

Experimental and simulative dissociation of dimeric Cu,Zn superoxide dismutase doubly mutated at the intersubunit surface.

The equilibrium properties of dimeric Photobacterium leiognathi Cu,Zn superoxide dismutase mutant bearing two negative charges in the amino acid clusters at the association interface has been studied, experimentally and computationally, and compared to those of the native enzyme. Pressure-dependent dissociation is observed for the mutant, as observed by the fluorescence shift of the unique tryptophan residue located at the intersubunit surface. The spectral shift occurs slowly, reaching a plateau after 15-20 min, and is fully reversible. Measurement of the degree of dissociation allows us to calculate the standard volume variation upon association and the dissociation constant at atmospheric pressure. On the other hand the native protein is undissociable at any pressure. In the simulative approach, the dissociation free energy has been calculated through the blue moon calculation method for the case of a multidimensional reaction coordinate, corrected for the rotational contribution within the semiclassical approximation for a free rigid-body rotor. The scheme permits to define a definite path for the rupture of the dimer and to calculate the effective force involved in the process. The calculated free energy difference is close to the experimental one, and the value obtained for the mutant is well below that obtained for the native protein, indicating that the theoretical reaction scheme is able to reproduce the experimental trend. Moreover, we find that, when the separation distance increases, the protein structure of the monomer is stable in line with the fast recovery of the original fluorescence properties after decompression, which excludes the presence of partly unfolded intermediates during the dimer-monomer transition.

Deep venous thrombosis and pulmonary embolism following cast immobilization of the lower extremity.

It is generally accepted that venous thrombosis in the lower extremity predisposes to pulmonary embolism. A case of pulmonary embolism after cast immobilization of the lower extremity, as well as a review of thromboembolic disease is presented. A high level of vigilance and close follow-up of even simple cast treatment is necessary to avoid this complication.

Acute radiculomyelitis after antitetanus vaccination.

Active or passive immunisation with vaccines or sera can cause lesions of immunomediated pathogenesis involving both the central (CNS) and the peripheral nervous system (PNS). Although very rare, the neurological complications described during antitetanus vaccinations almost exclusively affect the PNS, those affecting the CNS being even more rare. The authors report a case of transverse myelitis with a radicular component, which arose acutely following the administration of tetanus toxoid and had a partially favourable course.

Opening base wedge osteotomy with first metatarsophalangeal joint implantation arthroplasty--a retrospective study.

The authors present a retrospective study of the opening base wedge osteotomy with first metatarsophalangeal joint implant arthroplasty, for the correction of long-standing hallux abducto valgus deformity. Twenty cases involving 23 feet were performed, and the results are discussed. The indications and procedure are described, as well as an in-depth discussion.