[Changing spectrum of renal disease in HIV infection]. / Veränderungen im Spektrum der Nierenerkrankungen bei HIV-Infektion.

BACKGROUND AND OBJECTIVE: Renal disease is a common complication in HIV-infected patients. The causes and spectrum of kidney disease among these patients is extensive, including HIV-related and HIV unrelated causes. Our objective was to assess the changes in distribution of renal disease under antiretroviral therapy (ART). PATIENTS AND METHODS: Retrospective analysis of all patients from the Frankfurt HIV Cohort (FHC) who underwent renal biopsy because of chronic, progressive renal disease between 1989 and 2012. Two time periods were defined: 1989-2001 (early period) and 2000-2012 (late period). RESULTS: 69 HIV-infected patients, mostly Caucasian and male, underwent renal biopsy (early period: 22 patients, late period: 47 patients). During the total observation time immuncomplex-mediated glomerulonephritis (26.1 %), hypertensive (20.3 %) and diabetic nephropathy (20.3 %) were the most frequent causes of chronic renal disease. HIV-associated renal diseases were predominant in the first period, whereas hypertensive and diabetic kidney disease accounted for almost 50 % of cases diagnosed in the late period. Other types of renal disease frequently encountered during the late period include renal AA-amyloidosis and tenofovir-related kidney disease. CONCLUSION: The underlying pathology of renal disease in HIV-infected patients is highly variable and evolving. Since the introduction of HAART, renal disease not directly related to HIV has become the predominant cause, reflecting the growing burden of co-morbidities in this aging population.

The frequency and impact of ROS1 rearrangement on clinical outcomes in never smokers with lung adenocarcinoma.

BACKGROUND: To determine the frequency and predictive impact of ROS1 rearrangements on treatment outcomes in never-smoking patients with lung adenocarcinoma. PATIENTS AND METHODS: We concurrently analyzed ROS1 and ALK rearrangements and mutations in the epidermal growth factor receptor (EGFR), and KRAS in 208 never smokers with lung adenocarcinoma. ROS1 and ALK rearrangements were identified by fluorescent in situ hybridization. RESULTS: Of 208 tumors screened, 7 (3.4%) were ROS1 rearranged, and 15 (7.2%) were ALK-rearranged. CD74-ROS1 fusions were identified in two patients using reverse transcriptase-polymerase chain reaction. The frequency of ROS1 rearrangement was 5.7% (6 of 105) among EGFR/KRAS/ALK-negative patients. Patients with ROS1 rearrangement had a higher objective response rate (ORR; 60.0% versus 8.5%; P = 0.01) and a longer median progression-free survival (PFS; not reached versus 3.3 months; P = 0.008) to pemetrexed than those without ROS1/ALK rearrangement. The PFS to EGFR-tyrosine kinase inhibitors in patients harboring ROS1 rearrangement was shorter than those without ROS1/ALK rearrangement (2.5 versus 7.8 months; P = 0.01). CONCLUSIONS: The frequency of ROS1 rearrangements in clinically selected patients is higher than that reported for unselected patients, suggesting that ROS1 rearrangement is a druggable target in East-Asian never smokers with lung adenocarcinoma. Given the different treatment outcomes to conventional therapies and availability of ROS1 inhibitors, identification of ROS1 rearrangement can lead to successful treatment in ROS1-rearranged lung adenocarcinomas.

[Intestinal pseudo-obstruction]. / Pseudoobstruktion.

Intestinal pseudo-obstruction is a rare motility disorder with symptoms and clinical signs of bowel obstruction without a mechanical cause. Symptoms might be acute or chronic. The pathogenesis of acute colonic pseudo-obstruction (Ogilvie's syndrome) is likely to result from an imbalance of the autonomic regulation of the colon. Chronic intestinal pseudo-obstruction (CIPO) may be congenital or acquired. A variety of underlying pathologies, e.g. visceral neuropathy or visceral myopathy are known. Main symptoms are abdominal pain, vomiting, constipation or diarrhoea. Mechanical obstruction, ischemia and perforation should be excluded. Supportive therapy, medical therapy or an intervention (endoscopy, surgery) might be necessary in Ogilvie's syndrome depending on ceacal diameter and duration of distension. Treatment of CIPO depends on the severity of the disease and often needs a multidisciplinary approach.

Integrin receptors are required for cell survival and proliferation during development of the peripheral glial lineage.

Proliferation and survival of Schwann cells are important for nerve development and for disease processes in peripheral nerves. We have analyzed embryos lacking alpha4- or alpha5-integrins and show here that these integrins contribute to the control of glial cell numbers. To overcome early embryonic lethality an explant and grafting system that allows the study of isolated glial progenitor cells both in vitro and in vivo was used. Schwann cells differentiate in the absence of alpha5 but their numbers and the proliferation rate of early progenitor cells are reduced, suggesting that alpha5 is essential for normal proliferation. Survival, rather than proliferation, is compromised in alpha4-deficient explants. Conditional immortalization allowed further characterization and revealed that alpha4 contributes to survival in a cell-density-dependent fashion. In addition, transplants into chicken embryos were used to analyze in vivo cell migration and showed that cell death occurs mainly in highly motile, individually migrating cells. The cell death patterns in vitro and in vivo argue that alpha4-integrins play a role in survival during cell migration. Neural crest migration has been suggested to require these integrins; however, no defects in migration were observed in the absence of alpha4 or alpha5. We conclude that integrins can complement growth factors in the control of glial cell numbers.

Specific and redundant functions of the paralogous Hoxa-9 and Hoxd-9 genes in forelimb and axial skeleton patterning.

Using gene targeting, we have produced mice with a disruption of Hoxa-9 or Hoxd-9, two paralogous Abdominal B-related genes. During embryogenesis, these genes are expressed in limb buds and along the vertebral axis with anterior expression boundaries at the level of prevertebra #20 for Hoxa-9 and #23 for Hoxd-9. Skeletal analysis revealed homeotic transformations corresponding to anteriorisations of vertebrae #21 to #25 (L1 to L5) in the lumbar region of Hoxa-9-/- mutants; vertebrae #23 to #25 (L3 to L5) in the lumbar region together with vertebrae #28, #30 and #31 (S2, S4 and Ca1) in the sacrum and tail were anteriorized in Hoxd-9-/- mutants. Thus, anteriorisation of vertebrae #23 to #25 were common to both phenotypes. Subtle forelimb (but not hindlimb) defects, corresponding to a reduction of the humerus length and malformation of its deltoid crest, were also observed in Hoxd-9-/-, but not in Hoxa-9-/-, mutant mice. By intercrosses between these two lines of mutant mice, we have produced Hoxa-9/Hoxd-9 double mutants which exhibit synergistic limb and axial malformations consisting of: (i) an increase of penetrance and expressivity of abnormalities present in the single mutants, and (ii) novel limb alterations at the level of the forelimb stylopod and additional axial skeleton transformations. These observations demonstrate that the two paralogous genes Hoxa-9 and Hoxd-9 have both specific and redundant functions in lumbosacral axial skeleton patterning and in limb morphogenesis at the stylopodal level. Taken all together, the present and previously reported results show that disruption of different Hox genes can produce similar vertebral transformations, thus supporting a combinatorial code model for specification of vertebral identity by Hox genes.

The establishment of murine Hox-1 expression domains during patterning of the limb.

Region-specific expression patterns have been described recently for several candidate, developmental regulatory genes in the vertebrate limb. We have identified and mapped homeobox containing genes of the 5' part of the murine Hox-1 cluster by chromosomal walking. The expression of Hox-1.8, Hox-1.9, Hox-1.10, and a paralog of the Hox-4 cluster (Hox-4.5) were analyzed during stages when the developing limb pattern was being laid down. Each of these Hox genes was expressed in a restricted domain along the proximodistal axis of the limb at stage E 12.5. Only minor asymmetries were seen along the other two axes. A detailed spatiotemporal analysis of Hox expression, including three-dimensional reconstructions, revealed that the expression domains became progressively established between stages E 9.5 and E 12.5. Expression started from a small posterior and distal region and expanded toward the anterior part of the limb for 2 days. Depending on the gene and developmental stage, expression expands either along the ventral or the dorsal periphery. The establishment of the patterns was correlated to the growth process in the limb. Hox-1.8 and Hox-1.9 were also expressed in part of the somatopleure adjacent to the forelimb. The displacement of this domain toward the tip of the limb during development suggests that Hox-1.8 and Hox-1.9 were expressed in muscle precursor cells which migrate into the limb. The importance of these findings for the proposed models of limb pattern formation is discussed.

The role of protein C as an inhibitor of blood clotting during extracorporeal circulation.

The plasma levels of protein C, AT III, the perioperative administration of fresh frozen plasma (FFP) and AT III concentrate were compared under the use of various drugs in a randomized, prospective double-blind study in 40 patients in whom an aortocoronary bypass operation was carried out. We formed four groups of ten patients: group A served as a control group, group B received a prostacyclin (PGI2) infusion of 10 or 20 ng/kg/min, group C high-dose aprotinin substitution, and group D was treated with a combination of prostacyclin and aprotinin. After an initial short-term rise in the inhibitors protein C and AT III, there was a fall in all groups in the further course of extracorporeal circulation. The initial preoperative values were reached again on the morning of the first postoperative day. This indicates a raised turnover and in association with this a raised rate of elimination of these factors caused by an increased thrombin activation during the extracorporeal circulation which cannot be prevented by the usual heparinization. Whereas prostacyclin had no effect on our results mediated by thrombocytic mechanisms, use of aprotinin led to a significant saving in the requirement for perioperative fresh frozen plasma and AT III substitution therapy. A clinical advantage of prostacyclin and aprotinin combination was not observed. In view of our results (individual analyses were mainly in the normal range), we consider that AT III and fresh frozen plasma should not be substituted routinely during or after extracorporeal circulation.

Tests for parental imprinting in the nematode Caenorhabditis elegans.

The mutation him-6 (e1423) leads to generalized chromosomal nondisjunction during meiosis in oogenesis and spermatogenesis of C. elegans. As a result, gametes nullisomic or disomic for each of the six chromosomes occur at appreciable frequency. Crosses utilizing marked him-6 strains were used to generate and identify exceptional euploid progeny which had received both homologues of a marked autosome either from the male parent or from the female parent. Examples of all ten possible exceptions were identified and found to be viable and fertile. These results (together with previous data for the X chromosome) indicate that major chromosomal imprinting effects do not occur during gametogenesis in this organism.

[Potential filaricides. Suramin analogs]. / Potentielle Filarizide. Suramin-Analoge.

A series of suramin analogues has been synthesized in which the methyl groups of suramin have been replaced by hydrogen, alkyl, phenyl, and fluoro substituents, or which contain more than two methyl groups. The substances have been screened against Dipetalonema viteae in Meriones unguiculatus, Litomosoides carinii in Sigmodon hispidus and L. carinii in Mastomys natalensis, respectively. Small structural modifications have a marked influence on the antifilarial activity. There are marked differences between antifilarial and trypanocidal activities. A symmetrical molecule structure seems not to be essential for the antifilarial activity.

[How frequently is a headache the expression of endogenous depression?]. / Wie häufig sind Kopfschmerzen Ausdruck einer endogenen Depression?

In a period of nine months, all patients referred for purely neurological assessment of headache were fully examined both neurologically and psychiatrically. In 68 of 148 patients the cardinal symptom of headache was found to be the expression of an endogenous depression (46%). This diagnosis was based on the presence of an endogenomorphic-depressive axis syndrome (as classified by Berger), follow-up observations, and the efficacy of antidepressive drug treatment. Neurological and other physical underlying illness was excluded.

[Stereotyped movements and autonomous rhythms]. / Bewegungsstereotypien und autonome Rhythmen

The present study is concerned with the pathogenesis of jactatio capitis, of the stereotyped movements of oligophrenics, of dements, and of long-stay hospitalized defect schizophrenics, as well as with stereotyped movements in domestic animals. This leads to a discussion of the significance of rhythmically alternating innervation for pathological and normal movements. The relevance of rhythmic events for movements in inanimate systems is emphasized and the analogies which exist between movement in the organic and in the inorganic sphere are pointed out.