Affective and anxiety disorders in patients with different rare chronic diseases: a systematic review and meta-analysis.

We aimed to identify the prevalence of affective and anxiety disorders across different rare disease and identify correlates of psychopathology. We performed a systematic review and meta-analysis. We systematically searched Medline, PSYNDEX, PsycINFO for observational studies examining clinically diagnosed affective and/or anxiety disorders in adults with rare chronic diseases. Two researchers reviewed titles and abstracts independently and, for eligible studies, independently extracted data. The prevalence rates were pooled using a random intercept logistic regression model. We published a review protocol (http://www.crd.york.ac.uk/PROSPERO/display_record.php?ID=CRD42018106614CRD42018106614). We identified and screened 34 402 records for eligibility and considered 39 studies in the qualitative and 37 studies in the quantitative analysis, including N = 5951 patients with 24 different rare diseases. Heterogeneity between studies was large. Prevalence rates ranged widely between studies, with pooled prevalence estimates of 13.1% (95% CI 9.6-17.7%; I2 = 87%, p < 0.001) for current and 39.3% (95% CI 31.7-47.4%; I2 = 84%, p < 0.001) for lifetime major depressive disorder, 21.2% (95% CI 15.4-28.6%; I2 = 90%, p < 0.001) for current and 46.1% (95% CI 35.8-56.8%; I2 = 90%, p < 0.001) for lifetime affective disorders, and 39.6% (95% CI 25.5-55.6%; I2 = 96%, p < 0.001) for current and 44.2% (95% CI 27.0-62.9%; I2 = 94%, p < 0.001) for lifetime anxiety disorders. Sensitivity analyses excluding studies of low quality revealed nearly the same results. We conducted the first systematic review examining affective and anxiety disorders in adults with different rare diseases and found high prevalence rates. Supporting patients in disease adjustment can be crucial for their overall health and well-being.

Ketogenic diets in patients with inherited metabolic disorders.

Ketogenic diets (KDs) are diets that bring on a metabolic condition comparable to fasting, usually without catabolism. Since the mid-1990s such diets have been widely used in patients with seizures/epilepsies, mostly children. This review focuses on the use of KDs in patients with various inherited metabolic disorders (IMD). In glucose transporter type 1 deficiency syndrome (GLUT1-DS) and pyruvate dehydrogenase complex (PDHc) deficiency, KDs are deemed the therapy of choice and directly target the underlying metabolic disorder. Moreover, in other IMD, mainly of intermediary metabolism such as glycogen storage diseases and disorders of mitochondrial energy supply, KDs may ameliorate clinical symptoms and laboratory parameters. KDs have also been used successfully to treat symptoms such as seizures/epilepsy in IMD, e.g. in urea cycle disorders and non-ketotic hyperglycinemia. As a note of caution, catabolism may cause the condition of patients with IMD to deteriorate and should thus be avoided during KDs. For this reason, careful monitoring (clinical, laboratory and apparatus-supported) is warranted. In some IMDs specific macronutrient supply is critical. Therefore, in cases of PDHc deficiency the carbohydrate intake tolerated without lactate increase and in urea cycle disorders the protein tolerance should be determined. Considering this, it is particularly important in patients with IMD that the use of KDs be individualized and well documented.

Successful implementation of classical ketogenic dietary therapy in a patient with Niemann-Pick disease type C.

BACKGROUND: Niemann-Pick disease type C (NP-C) is a neurodegenerative disease for which only palliative treatment exists, and only miglustat is effective in stabilizing neurological manifestations of NP-C. Ketogenic dietary therapies (KDT) are successfully used in patients with seizure disorders, including those associated with various inherited metabolic diseases (IMD), to reduce seizure frequency and medication requirement as well as to confer neuroprotection. Since patients with NP-C suffer pharmacorefractory seizures associated with ongoing neurodegeneration, KDT might be beneficial. The concomitant use of miglustat and KDT in patients with NP-C has not been reported. CASE PRESENTATION: We describe our experience in a now 17-year-old female with NP-C manifest early in childhood who has been successfully and continuously treated with miglustat and KDT in a palliative care setting for 3y. Although the neurodegeneration of NP-C progressed, she benefited from a reduction in seizure activity, fewer hospital stays related to seizure exacerbation, and increased alertness. CONCLUSION: KDT could be safely deployed in our patient with NP-C, in whom its effects have been beneficial. Generally KDT is demonstratedly efficacious in patients with epilepsy and IMD. It reduces seizure activity and medication requirements and confers neuroprotection. Intracellular cholesterol trafficking and regulation of cholesterol biosynthesis are impaired in NP-C, which may prompt caution with respect to dietary lipid intake.

Isochromosome 18p results from maternal meiosis II nondisjunction.

Microsatellite analysis with 13 microsatellites spread over 18p was performed to determine the origin of the marker chromosome in 9 patients with additional metacentric marker chromosomes. Phenotypes and banding patterns suggested that the markers were isochromosomes 18p. Maternal origin was determined in all 8 cases where both parents were available for study. Six cases showed 3 alleles (one paternal, one maternal each in single and double dose) of informative markers located close to the telomere while markers close to the centromere on 18p were reduced to homozygosity (one paternal allele in single dosage and one maternal allele presumably in triple dosage). A similar result was obtained in the patient with no parents available for examination. The other 2 patients were uninformative for maternal hetero- versus homozygosity, but at some loci the maternal band was clearly stronger than the paternal one whereas the opposite was never observed. Trisomy 18 differs from trisomy 21, XXX and XXY of maternal origin through a preponderance of meiosis II versus meiosis I nondisjunction. Thus, the results of our study and the advanced mean maternal age at delivery of patients with additional i(18p) indicate that in most if not all cases the marker chromosome originates from maternal meiosis II nondisjunction immediately followed by isochromosome formation in one of the 2 maternal chromosomes 18. Possible explanations of these results include a maternally imprinted gene on 18q with a lethal effect if the paternal homologue is lost and a mechanism through which nondisjunction in some cases could be connected with isochromosome formation.

Use of the allogeneic TCR repertoire to enhance anti-tumor immunity.

It is well established that antigen-specific T lymphocytes can inhibit tumor growth in humans and in mice, leading to complete tumor elimination in some cases. However, in many cases T cell immunity is unable to successfully control tumor progression. Since tumors are derived from normal tissues, most antigens are shared with normal tissues, although expression levels are usually elevated in malignant cells. Nevertheless, low-level expression in normal cells can be sufficient to render autologous T cells tolerant and thus unable to mount effective immune responses against tumors. Here, we review how allogeneic T cells can be used to isolate T cells that effectively recognise and kill tumor cells, but not normal cells with low level of antigen expression. The TCR of allogeneic T cells can be introduced into patient T cells to equip them with anti-tumor specificity that may not be present in the autologous T cell repertoire.

[Management of diabetes in Austria 5 years after the St. Vincent Declaration]. / Diabetesbetreuung in Osterreich 5 Jahre nach der St. Vincent-Erklärung.

In 1989 representatives of all European governments agreed on the "St. Vincent Declaration". In this statement of intent and recommendations all governments, including that of Austria, pledged to implement policies on preventive measures geared to reduce morbidity and mortality of all diabetic patients in Europe. Structured patient education has been shown to improve the overall quality of care in Type 1 diabetic patients. Reduction of acute metabolic disturbances after participation in the patient education programme reduces hospitalizations and allows significant savings in health care costs, which can help to make safe and effective therapy available to all patients with Type 1 diabetes without additional costs. A teaching and treatment programme for Type 2 diabetics by general practitioners has proven to be effective, feasible and inexpensive. Nationwide implementation of such an evaluated patient education programme shifts diabetes care to "primary health care" level, and increases long-term quality of diabetes care without generating new expenses. Patient education is considered not only the basis for successful management of diabetes, but also, as laid down in the St. Vincent Declaration, a basic human right of all patients, which still needs to be put into practice.

A software package for non-invasive, real-time beat-to-beat monitoring of stroke volume, blood pressure, total peripheral resistance and for assessment of autonomic function.

The goal of the present study was to develop and evaluate algorithms for non-invasive, real-time, beat-to-beat monitoring of stroke index (SI), blood pressure (BP) and total peripheral resistance index (TPRI) which has a menu-driven interface, suitable for routine use by unskilled staff. In addition, it was our aim to include a meta-analysis for the evaluation of autonomic function derived from the above haemodynamic data. This includes spectral analysis of heart rate (HR), BP, SI and TPRI and the automatic calculation of baroreceptor reflex sensitivity. Impedance cardiography was used for beat-to-beat SI determination, Finapres corrected by an oscillometric blood pressure measurement (Dinamap) on the upper arm for beat-to-beat BP measurement. We demonstrate noise free recordings during physiological (head up tilt) and pharmacological intervention (alpha 1-, beta 2-adrenoreceptor agonists, insulin induced hypoglycemia). The newly developed software should prove valuable for physiological, pharmacological and clinical studies.

[Radiological aspects of Mallory-Weiss syndrome (author's transl)]. / Aspect radiologique du syndrome de Mallory-Weiss.

A case of Mallory-Weiss syndrome was diagnosed by joint baryum study and endoscopy. A survey of publications (15 references) shows that this affection is frequent and could be responsable of 5 to 10% of upper digestive hemorrhage of which some are grave. But conventional radiology only exceptionnally reveals these superficial lesions. Without endoscopy and according the ulceration be deep, the radiologist should be able to reveal the lesion a sa niche.

Exploiting T cell receptor genes for cancer immunotherapy.

Adoptive antigen-specific immunotherapy is an attractive concept for the treatment of cancer because it does not require immunocompetence of patients, and the specificity of transferred lymphocytes can be targeted against tumour-associated antigens that are poorly immunogenic and thus fail to effectively trigger autologous T cell responses. As the isolation and in vitro expansion of antigen-specific lymphocytes is difficult, 'conventional' adoptive T cell therapy can only be carried out in specialized centres in small numbers of patients. However, T cell receptor (TCR) genes isolated from antigen-specific T cells can be exploited as generic therapeutic molecules for 'unconventional' antigen-specific immunotherapy. Retroviral TCR gene transfer into patient T cells can readily produce populations of antigen-specific lymphocytes after a single round of polyclonal T cell stimulation. TCR gene modified lymphocytes are functionally competent in vitro, and can have therapeutic efficacy in murine models in vivo. TCR gene expression is stable and modified lymphocytes can develop into memory T cells. Introduction of TCR genes into CD8(+) and CD4(+) lymphocytes provides an opportunity to use the same TCR specificity to produce antigen-specific killer and helper T lymphocytes. Thus, TCR gene therapy provides an attractive strategy to develop antigen-specific immunotherapy with autologous lymphocytes as a generic treatment option.

Occupational hazards of farriers.

A farrier is a specialist in the shoeing of horses. It has been estimated that in the United States over 8 million horses are ridden for show and pleasure. These horses need hoof and leg care. The farrier does give this care and in so doing is subject to occupational hazards. These hazards cover a wide range and include bites from horses and farmer's dogs, ergonomic problems, noise and exposure to metal and welding fumes. Many of the hazards he encounters are unique to his profession.

[Schwannoma of the trachea: discussion of a case and review of the literature]. / Schwannome de la trachée. A propos d'un cas. Revue de la littérature.

The authors report the case of a 71 years old woman admitted for severe asthmatic condition of recent origin. The chest X ray showed the opaque image of a tumour against the clearness of the trachea. Its benignity was confirmed by endoscopy. A complete surgical exerese is impossible because of the friable nature of the tumour but was attempted to relieve a worsening respiratory distress. A new intervention was necessary because of a mediastinitis; the patient died of renal insufficiency. Only one observation of schwannoma and 3 cases of tracheo-bronchial schwannoma were found in the literature. The nosological place of these tumours was debated particularly in their relation with Recklinghausen disease. Diagnosis was usually done only a few years after an endoscopic exploration. Some symptoms could nevertheless make up a "tracheal syndrome". Endoscopic exeresis of the tumour successfully tried on some cases should be attempted on a first step.

[Bone, joint, spinal and pelvic-spinal localizations of sarcoidosis (apropos of a case)]. / Les localisations osseuses, articulaires, rachidiennes et pelvi-rachidiennes de la sarcoïdose (à propos d'une observation)

Authors report on one case of particularly flourishing and evolutive sarcoidosis that conditioned numerous manifestations among which stand out lesions interesting one hip and one sacro-iliac articulation and also extensive and destructive bone lesions. This case is for them an opportunity for recalling the major facts related with bone lesions and articular manifestations of sarcoidosis and for calling attention on the spinal and pelvic-spinal involvements. The latter, when signs of bone lysis exist, are evocative of a neoplasm. More often, spondylodiscitis, coexisting sometimes with spindle-like paravertebral pictures, let think of tuberculosis. Confusion would be unavoidable if such facts, in spite of their rareness, were not better known.

Use of monoclonal antibodies in the functional characterization of the Saccharomyces cerevisiae Sep1 protein.

The Saccharomyces cerevisiae strand-exchange protein 1 (Sep1 also known as Xrn1, Kem1, Rar5, Stp beta/DST2) has been demonstrated to mediate the formation of hybrid DNA from model substrates of linear double-stranded and circular single-stranded DNA in vitro. To delineate the mechanism by which Sep1 acts in the strand-exchange reaction, we analyzed mouse anti-Sep1 monoclonal antibodies for inhibition of the Sep1 in vitro activity. Of 12 class-G immunoglobulins tested, four were found to consistently inhibit the Sep1-mediated strand-exchange reaction. The inhibiting antibodies were tested for inhibition of a variety of Sep1-catalyzed DNA reactions including exonuclease activity on double-stranded and single-stranded DNA, renaturation of complementary single-stranded DNA and condensation of DNA into large aggregates. All four inhibiting antibodies had no effect on the exonuclease activity of Sep1. Three antibodies specifically blocked DNA aggregation. In addition, one antibody inhibited renaturation of complementary single-stranded DNA. This inhibition pattern underlines the importance of condensation of DNA into large aggregates in conjunction with double-stranded DNA exonuclease activity for the in vitro homologous pairing activity of Sep1. The implications of these data for the interpretation of proteins which promote homologous pairing of DNA are discussed, in particular in light of the reannealing activity of the p53 human tumor-suppressor protein.

Catalytic activity concentrations of diadenosine tetraphosphate hydrolase in normal and pathological sera.

The levels of diadenosine tetraphosphate hydrolase, a nucleotide pyrophosphatase (EC 3.6.1.9), were measured in human sera with a bioluminescence method. 40 sera of healthy donors and 207 samples obtained from inpatients of a medical clinic were analysed. About two thirds of the patients showed increased hydrolase levels, as compared to the normal donors. Elevated levels were not specific for a certain disease, and they were found in quite different disorders. There was no indication for a dependency of enzyme activity on age or sex of the patients. The comparison of diadenosine tetraphosphate hydrolase with seven other laboratory parameters revealed a highly significant correlation with gamma-glutamyl transferase, suggesting that the liver may be a source of elevated serum activities. There was evidence that the gastrointestinal tract and the pancreas may also be regarded as possible organ sources of the hydrolase.

Evaluation of a structured teaching and treatment programme for type 2 diabetes in general practice in a rural area of Austria.

The efficacy of a treatment and teaching programme for non-insulin-treated Type 2 diabetic patients in general practice was evaluated in a prospective, controlled study. In a rural area in southern Austria, 53 patients from seven general practices participated in a structured programme (intervention group) and 55 patients from seven general practices without the programme served as the control group. After 6 months the weight reduction in the intervention group was 2.6 kg (1.6-3.7 kg, p < 0.001) and the difference in HbA1c between the groups was 0.92% (0.23-1.61%, p < 0.01) at follow-up. Systolic (-16.6 mmHg) and diastolic (-11.1 mmHg) blood pressure, serum triglycerides (-0.63 mmol I-1), and serum cholesterol (-0.40 mmol I-1) were reduced significantly in the intervention group (p < 0.006). The number of patients with callus formation and poor nail care decreased significantly after participating in the teaching programme (p < 0.001). In the control group no reduction in body weight, metabolic control or in risk factors for diabetic foot complications were observed. Calculated health care costs per patient and year decreased in the intervention group (-33 pounds) and increased in the control group (+ 30 pounds) mainly due to changes in prescription of oral hypoglycaemic agents in both groups. This programme may be an efficient and helpful model to increase overall quality of diabetes care according to the St Vincent Declaration.

WT1-targeted immunotherapy of leukaemia.

Since malignant cells are derived from normal cells, many tumour-associated antigens are also expressed in normal tissues. For examples, WT1 is expressed at elevated levels in most leukaemias, but it is also expressed at reduced levels in normal CD34+ haematopoietic stem cells and in progenitor cells of other tissues. Antigen expression in normal tissues is likely to trigger immunological tolerance and thus blunt T cell responses. This could explain the observation that WT1 vaccination in mice frequently fails to stimulate high avidity cytotoxic T cell responses. In order to circumvent tolerance, we have isolated from HLA-A2-negative donors high avidity CTL specific for HLA-A2-presented peptide epitopes of WT1. These allorestricted CTL efficiently kill HLA-A2-positive leukaemia cells but not normal CD34+ haematopoietic stem cells. However, adoptive cellular therapy with allorestricted CTL could only be performed in leukaemia patients rendered tolerant to the infused CTL by prior allogeneic stem cell transplantation. In order to circumvent this limitation, we propose to exploit the TCR of allorestricted CTL as therapeutic tool. TCR gene transfer can be used to take advantage of the specificity of allorestricted CTL and transfer it to patient CTL, while avoiding the transfer of immunogenic alloantigens from the donor CTL to the patient.