Integrated waveguides and deterministically positioned nitrogen vacancy centers in diamond created by femtosecond laser writing.

Diamond's nitrogen vacancy (NV) center is an optically active defect with long spin coherence times, showing great potential for both efficient nanoscale magnetometry and quantum information processing schemes. Recently, both the formation of buried 3D optical waveguides and high-quality single NVs in diamond were demonstrated using the versatile femtosecond laser-writing technique. However, until now, combining these technologies has been an outstanding challenge. In this Letter, we fabricate laser-written photonic waveguides in quantum grade diamond which are aligned to within micron resolution to single laser-written NVs, enabling an integrated platform providing deterministically positioned waveguide-coupled NVs. This fabrication technology opens the way toward on-chip optical routing of single photons between NVs and optically integrated spin-based sensing.

[Multimorbidity management and the physician's daily clinical dilemma]. / Multimorbiditätsmanagement im Alltagsdilemma.

About 20-25% of all persons and about 90% of all patients who are acutely hospitalized in internal medicine departments have multiple acute or chronic diseases. They are multimorbid. The encounter with multimorbid patients has become the most common situation in the health care system. Theoretically, multimorbidity results in an innumerable potential disease constellations. In addition, the likelihood of interactions between diseases (disease-disease interactions, DDI) and the complexity increases overproportionately with each additional disease. However, multimorbidity often occurs in typical diadic, triadic, or higher characteristic combinations, in "disease clusters", e. g., vascular risk factors, heart and lung diseases, Frailty and dementia, psychiatric and somatic disorders. Such combinations lead to a worsening of the overall prognosis. In addition, DDIs are often difficult to treat or are life-threatening. Examples of DDIs include the following: anticoagulation and simultaneous severe bleeding, pain treatment and hypertension or renal insufficiency, depression and reduced medication adherence, chronic obstructive pulmonary disease and depression, Frailty and neurodepressant drugs and frequent falls, and combined psychiatric and somatic disorders. Such DDIs are common. Nevertheless, there are few studies and clinical guidelines that address these issues. The care of multimorbid patients is, therefore, heavily reliant upon guidelines developed mostly for single diseases. However, multimorbidity and serious DDIs are usually not addressed in these. Clinical guidelines can thus inadvertently jeopardize the safety of persons suffering from multiple diseases. In addition, stressful dilemmas arise for physicians encountering DDIs because of difficult treatment decisions.

Micromagnet arrays enable precise manipulation of individual biological analyte-superparamagnetic bead complexes for separation and sensing.

In this article, we review lab on a chip (LOC) devices that have been developed for processing magnetically labelled biological analytes, e.g., proteins, nucleic acids, viruses and cells, based on micromagnetic structures and a time-varying magnetic field. We describe the methods that have been developed for fabricating micromagnetic arrays and the bioprocessing operations that have been demonstrated using superparamagnetic (SPM) beads, i.e., programmed transport, switching, separation of specific analytes, and pumping and mixing of fluids in microchannels. The primary advantage of micromagnet devices is that they make it possible to develop systems that control individual SPM beads, enabling high-efficiency separation and analysis. These devices do not require hydrodynamic control and lend themselves to parallel processing of large arrays of SPM beads with modest levels of power consumption. Micromagnet devices are well suited for bioanalytical applications that require high-resolution separation, e.g., detection of rare cell types such as circulating tumour cells, or biosensor applications that require multiple magnetic bioprocessing operations on a single chip.

Micromagnet arrays for on-chip focusing, switching, and separation of superparamagnetic beads and single cells.

Nonlinear magnetophoresis (NLM) is a novel approach for on-chip transport and separation of superparamagnetic (SPM) beads, based on a travelling magnetic field wave generated by the combination of a micromagnet array (MMA) and an applied rotating magnetic field. Here, we present two novel MMA designs that allow SPM beads to be focused, sorted, and separated on-chip. Converging MMAs were used to rapidly collect the SPM beads from a large region of the chip and focus them into synchronised lines. We characterise the collection efficiency of the devices and demonstrate that they can facilitate on-chip analysis of populations of SPM beads using a single-point optical detector. The diverging MMAs were used to control the transport of the beads and to separate them based on their size. The separation efficiency of these devices was determined by the orientation of the magnetisation of the micromagnets relative to the external magnetic field and the size of the beads and relative to that of micromagnets. By controlling these parameters and the rotation of the external magnetic field we demonstrated the controlled transport of SPM bead-labelled single MDA-MB-231 cells. The use of these novel MMAs promises to allow magnetically-labelled cells to be efficiently isolated and then manipulated on-chip for analysis with high-resolution chemical and physical techniques.

CCTTT-repeat polymorphism of the inducible nitric oxide synthase is not associated with HIV pathogenesis.

Nitric oxide (NO) produced by the inducible form of nitric oxide synthase (iNOS) has bactericidal and virocidal effects. Although NO synthesis and iNOS expression in macrophages affect several aspects of human immunodeficiency virus (HIV) type-1 pathogenesis, their role in HIV disease remains largely unknown. In humans, the expression of iNOS is influenced by a functional CCTTT-repeat polymorphism in the promoter region of the gene. We investigated the association of this polymorphism with HIV pathogenesis in naive HIV-infected patients before the initiation of antiretroviral therapy. The allele frequencies of the iNOS CCTTT-repeat polymorphism were assessed by PCR in 857 patients from the Swiss HIV Cohort Study, including rapid progressors and long-term nonprogressors, and in 240 healthy volunteers. In HIV-infected patients, the initial viral load and the decline in total CD4 cells was calculated to estimate disease progression. Allele frequencies of the iNOS CCTTT-repeat polymorphism were similar between the HIV-infected and noninfected blood donors. In treatment-naive HIV-positive patients, there was no association of the iNOS polymorphism with viral load or with the course of CD4 cells. Regulation of iNOS expression by the functional CCTTT-polymorphism does not modify HIV pathogenesis.

Lipoprotein processing is required for virulence of Mycobacterium tuberculosis.

Lipoproteins are a subgroup of secreted bacterial proteins characterized by a lipidated N-terminus, processing of which is mediated by the consecutive activity of prolipoprotein diacylglyceryl transferase (Lgt) and lipoprotein signal peptidase (LspA). The study of LspA function has been limited mainly to non-pathogenic microorganisms. To study a potential role for LspA in the pathogenesis of bacterial infections, we have disrupted lspA by allelic replacement in Mycobacterium tuberculosis, one of the world's most devastating pathogens. Despite the presence of an impermeable lipid outer layer, it was found that LspA was dispensable for growth under in vitro culture conditions. In contrast, the mutant was markedly attenuated in virulence models of tuberculosis. Our findings establish lipoprotein metabolism as a major virulence determinant of tuberculosis and define a role for lipoprotein processing in bacterial pathogenesis. In addition, these results hint at a promising new target for therapeutic intervention, as a highly specific inhibitor of bacterial lipoprotein signal peptidases is available.

Marked changes of lipid levels during puberty in a patient with lipoprotein lipase deficiency.

UNLABELLED: Clinical and biochemical characteristics of a female patient with familial lipoprotein lipase deficiency have been followed in short intervals before and during puberty. The proband is compound heterozygote for two missense mutations in the lipoprotein lipase gene. One mutation occurs in codon 250 (Asp250-->Asn), the other is in codon 410 (Glu410-->Lys). The residual lipoprotein lipase activity in the proband is less than 10% of controls. Before puberty the proband usually presented with moderate isolated hypertriglyceridaemia. During the initial phase of puberty a dramatic increase in the plasma concentration of both cholesterol and triglycerides was observed. During the second half of puberty a reduction of cholesterol but not of triglycerides was noticed. CONCLUSION: These findings show that the phenotypic expression of familial chylomicronaemia can be modified to a large extent by hormones. Furthermore they demonstrate the need for a closer clinical observation of type I patients during puberty.

[Mucopolysaccharidosis 6-A (Maroteaux-Lamy disease): comparison of clinical and pathologico-anatomic findings in a 27-year-old patient]. / Mukopolysaccharidose Typ VI-A (Morbus Maroteaux-Lamy): Korrelation der klinischen und pathologisch-anatomischen Befunde bei einem 27jährigen Patienten.

The autopsy of the 27-year-old patient suffering from a severe form of mucopolysaccharidosis type VI-A (Maroteaux-Lamy) described in the article by Rampini et al. revealed the compressive cervical myelopathy (C1) to be due to a severe, slit-like deformity of the vertebral canal which was due to a massive thickening of the ligaments, dislocation of the posterior arch of the atlas and broadening of the dura. The massive, generalized disorder of the enchondral ossification involving mainly tubular bones and spine, led to short stature, arthrosis of large joints, and to an angular thoraco-lumbar kyphoscoliosis. Our patient had a massive V-shaped stenosis of the upper third of the trachea. The atrio-ventricular valves of the heart were thickened, and there was fibrosis of the endocardium. The cardiac conduction system displayed fibrosis and foam cell transformation of the fibroblasts in the bundle of His, a lesion not previously reported. Light and electron microscopic investigation showed a massive increase of mucopolysaccharides mainly in the matrix of the fibrous tissue and of the cartilage. Furthermore, the fibroblasts and chondrocytes as well as the hepatocytes and the ganglion cells of the central nervous system contained increased amounts of glycosaminoglycans.

[Infantile cataract, hypertrophic cardiomyopathy and lactic acidosis following minor muscular exertion--a little known metabolic disease]. / Infantile Katarakt, hypertrophe Kardiomyopathie und Laktatazidose nach geringer Muskelarbeit--eine noch wenig bekannte metabolische Krankheit.

Three children from two unrelated families were found to be suffering from a hitherto little-known disorder. Infantile cataract was the primary symptom at the age of 3 months, progressed quickly and necessitated surgery. At the same age, muscular hypotonia was prominent and delayed gross motor development. At preschool and school ages muscle strength and exercise tolerance were reduced, and slight muscular exercise caused marked lactic acidemia. Subsequently, hypertrophic cardiomyopathy was discovered by echocardiography, though with no signs of cardiac obstruction at that time. There were no neurological symptoms. Intellectual development was normal. The disorder is inherited as an autosomal recessive. It can be recognized from the combination of infantile cataract, muscular hypotonia, cardiomyopathy, and lactic acidosis, which, however, must be looked for carefully. Early diagnosis is mandatory for genetic counseling. The ophthalmologist holds the key to diagnosis.

[Mucopolysaccharidosis IV-A (Maroteaux-Lamy disease, severe form): incipient compressive myelopathy, cerebrospinal fluid fistula and tracheal stenosis in an adult patient]. / Mukopolysaccharidose VI-A (Morbus Maroteaux-Lamy, schwere Form): beginnende kompressive Myelopathie, Liquorfistel und Trachealstenose bei einem erwachsenen Patienten.

A 25-year-old male with the severe form of Maroteaux-Lamy disease (mucopolysaccharidosis VI-A) developed rhinoliquorrhea of undetermined origin. The head was held permanently in extension, and there was both inspiratory and expiratory stridor. Flexion of the head worsened the stridor and caused dyspnea. Radiological examination showed a massive narrowing of the trachea and a marked retropharyngeal and retrotracheal swelling. Hyperreflexia and slight impairment of the sensation of the lower limbs were found on neurological examination. Computed tomography revealed hydrocephalus and extreme narrowing of the subarachnoid space in the region of the occipito-cervical junction, caused by marked epidural soft tissue thickening and a dysplastic arch of the atlas protruding dorsally into the foramen magnum, and displacement of the cervical spinal cord. At the age of 26 years rhinoliquorrhea suddenly stopped and the patient developed acute signs of occlusive hydrocephalus. Emergency ventriculo-peritoneal shunting was performed.

[Acquired immunodeficiency syndrome in a child of Swiss origin whose mother died from AIDS]. / Erworbenes Immunmangelsyndrom bei einem Kind schweizerischer Abstammung, dessen Mutter an AIDS verstorben ist.

Report of a now 2 8/12-year-old girl, who presented at the age of 8 months with chronic progressive pneumonia, mucocutaneous candidiasis, diarrhea, failure to thrive and a non-progressive paraplegia. The child's mother presented AIDS with pneumocystis carinii pneumonia and progressive general paralysis one year after the beginning of the child's disease and died within a few months. Additional findings in the child include lymphopenia, hyperimmunoglobulinemia, cutaneous anergy and an abnormal T helper/T suppressor cell ratio. HTLV-III antibodies were positive (ELISA and Western blot virus strip RIA). Prophylactic treatment with Co-trimoxazole relieved pulmonary infections but failure to thrive remained unchanged in spite of a continuous nutritional support. A vertical mode of transmission of AIDS from mother to child seems very probable.

Multiple acyl-Co A dehydrogenation deficiency (MADD) in a boy with nonketotic hypoglycemia, hepatomegaly, muscle hypotonia and cardiomyopathy. Detection of N-isovalerylglutamic acid and its monoamide.

A boy, aged 7 months, of consanguineous parents presented with an acute onset of vomiting, fever, nonketotic hypoglycemia and acidosis and died from cardiac arrest after ventricular fibrillation. He had hepatomegaly and echocardiographically a non-obstructive cardiomyopathy. Autopsy was not allowed. After birth the child had suffered from a severe respiratory distress syndrome, transient metabolic acidosis and had a sweaty feet odour. Later on, development was retarded with a severe muscular hypotonia. Post mortem, numerous unusual organic acids were found in high concentrations in urine, e.g. dicarbonic acids, 2-hydroxyisobutyric, isovaleric, 3-hydroxyisovaleric acid, N-acyl glycines, isovalerylglutamic acid and sarcosine. This pattern indicated deficiencies of several acyl-Co A dehydrogenases in the metabolism of leucine, isoleucine, valine, lysine, short-chain fatty acids and sarcosine. This could be confirmed using cultured skin fibroblasts which were shown to degrade the corresponding labeled substrates insufficiently to 14CO2. It is assumed that the functional multiple acyl-Co A dehydrogenation deficiency is caused by a deficiency of a common link in the electron transfer system of these dehydrogenases which is inherited autosomal recessively in this family. Among the 12 patients reported, 7 died within the first 5 days of age.

[Dyggve-Melchior-Clausen syndrome. Case report and review of the literature]. / Das Dyggve-Melchior-Clausen-Syndrom. Fallbeschreibung und Literaturübersicht.

The Dyggve-Melchior-Clausen syndrome is inherited in an autosomal recessive mode and is clinically characterized by mental retardation, small stature mainly due to a short vertebral column with thoracal kyphosis, protruding sternum, reduced articular mobility, and in most cases also by microcephaly. Specific radiologic findings concern the vertebral column, the pelvis, and the hands. A patient suffering from this syndrome is presented, the literature is summarized, and the clinical and radiologic manifestations are reviewed. As in two cases studied by others [27], the incorporation of radioactive sulphate into the mucopolysaccharides of the fibroblasts was normal in our patient. The activity of arylsulphatase B in the fibroblasts, however, was reduced as in the leucocytes of three reported cases [21]. These observations suggest that an as yet undefined specific sulphatase could be of importance for the pathogenesis of this condition.