Effects of troglitazone on insulin sensitivity in HIV-infected patients with protease inhibitor-associated diabetes mellitus

Antiretroviral therapy (ART) is frequently associated with metabolic alterations, including insulin resistance and diabetes mellitus. In this pilot study, we evaluated the effect of the PPARγ activator troglitazone on ART-associated insulin resistance in HIV-infected patients with ART-associated diabetes mellitus. Six patients with protease inhibitor (PI)-associated diabetes mellitus, lipodystrophy and dyslipidemia were treated with troglitazone 400 mg q.d. for 3 months. Previous oral antidiabetics were discontinued prior to the study. At baseline and after 3 months, insulin sensitivity (intravenous insulin tolerance test), body composition (multifrequence bioelectrical impedance analysis) and fat distribution (CT scan quantification) were assessed. Glycaemic control (fasting and postprandial blood glucose, fructos-amine, glycosylated haemoglobin) and serum lipid status were determined monthly. In four of the six patients, there was a clear improvement in insulin sensitivity, resulting in a reversal of insulin resistance in two of these patients. Overall, there was an increase in lean body mass and a decrease in total body fat. The volume of visceral adipose tissue decreased whilst the volume of subcutaneous adipose tissue increased. Total cholesterol, LDL and HDL cholesterol increased, and total triglycerides and VLDL-cholesterol decreased. No adverse effects such as hepatotoxicity were observed. Treatment with troglitazone 400 mg q.d. can ameliorate and in some cases even reverse ART-associated insulin resistance. Therefore, further studies including non-diabetic patients with ART-associated insulin resistance may be helpful in evaluating the long-term effects of thiazolidinediones on ART-associated insulin resistance and other metabolic complications, such as adipose maldistribution and dyslipidaemia.     

Dose-dependent loss of motor function after unilateral medial forebrain bundle rotenone lesion in rats: a cautionary note

The organic pesticide rotenone is a neurotoxin suspected to cause Parkinson's disease (PD) symptoms by selectively targeting and compromising the survival of dopaminergic neurons. Rotenone in rodent models reproduces key features of human PD by impairing the mitochondrial electron transport chain, leading to intracellular alpha-synuclein aggregates and functional impairments typical for PD. The present study characterized the dose-response relationship of standard rotenone concentrations in motor impairments in a rat model. Rats received a single medial forebrain bundle injection of 4, 8, or 12 μg of rotenone. Animals were assessed in skilled limb use, skilled and non-skilled walking and exploratory activity as well as drug-induced rotation. The results revealed rotational bias and stable impairments in skilled walking and gross motor function up to five weeks post injection. However, transient motor deficits facilitated rapid improvement of skilled reaching success. Mainly the temporal aspects of skilled and non-skilled motor performance were responsive to different rotenone concentrations. By contrast, drug-induced rotation and nigral TH+ cell loss were not influenced by different rotenone doses. Rats infused with 8 μg and 12 μg seemed to have reached a ceiling effect in motor deficits as they were not distinguishable in behavioral measures. Most strikingly, the stereological and morphological analyses revealed non-specific toxicity of vehicle and rotenone infusions that caused macroscopic lesions beyond nigral boundaries. These findings suggest that sensitivity of comprehensive motor tests to subtle modulation of dopamine function is independent of dopamine cell loss per se. Furthermore, caution is advised concerning non-specific toxicity of rotenone and vehicle substances in experimental animal models.     

Operative Therapie des Endometriumkarzinoms

In April 2018, a new German S3 guideline supported by the Leitlinienprogramm Onkologie (Guideline Program—Oncology) on diagnosis, treatment, and aftercare of endometrial cancer was published. Based on current systematic literature reviews, consensus recommendations were established by an interdisciplinary multiprofessional group. Compared to prior versions of this guideline, adaptions have been made regarding routine radical hysterectomy for stage 2 cancer, the differential indications for systematic pelvic and periaortic lymph node dissection as well as mode of peritoneal access. Further aspects are the use of sentinel lymph node dissection and the surgical approach for advanced stages and carcinosarcomas.     

Effects of the depth of anesthesia on distortion product otoacoustic emissions

To analyze the effects of the depth of anesthesia on inner ear function measured with distortion product otoacoustic emissions (DPOAEs) at 2f ₁ ? f ₂. Thirty patients who underwent tonsillectomy under general anesthesia (GA) were included. Patients were assigned randomly to one of two groups: group 1 (n = 15) received propofol, group 2 (n = 15) sevoflurane as anesthetic agent. The sedation level was assessed by the bispectral index system. DPOAE measurements were performed before premedication (T ₁), 5 min after premedication (T ₂), 3 min after induction of general anesthesia (T ₃) and every 10 min (T ₄, T ₅) thereafter until the end of surgery at about 23 min post-anesthetic induction, while sedation levels were obtained starting at the beginning until the end of anesthesia. After premedication, both blood oxygen saturation and heart rate decreased. Following induction of anesthesia systolic and diastolic blood pressure decreased, while, as expected, the level of sedation increased. Analyzing the propofol and sevoflurane group separately, both groups showed comparable overall courses of DPOAE levels at higher frequencies (2.8 kHz p = 0.310, 4 kHz p = 0.193, 6 kHz p = 0.269, 8 kHz p = 0.223) and no changes of DPOAE levels compared with baseline values were observed. At T₅ the 1 kHz DPOAE level increased in the propofol group and slightly decreased in the sevoflurane group (p < 0.001). While the 1.4 kHz DPOAE level in the propofol group did not change over time the 1.4 kHz DPOAE level decreased in the sevoflurane group (baseline to T ₄ p = 0.045; Baseline to T ₅ p = 0.004). While overall there were different courses between these two groups in the 2 kHz DPOAE level, in the post hoc analysis only a tendency in the change from baseline to T ₄ could be observed (p = 0.082). These results indicate that while the amplitudes of certain DPOAEs were influenced by GA, the depth of anesthesia had no effect on this measure of cochlear function in clinical routine. Therefore, DPOAE measurements in sedation and during GA are useful but the effect of anesthetic agents on DPOAE levels needs to be taken into account when analyzing the test.     

Follow up of children after antenatal treatment for alloimmune thrombocytopenia

OBJECTIVE: To evaluate the long-term follow-up of surviving offspring after antenatal treatment for fetal or neonatal alloimmune thrombocytopenia (FNAIT). PATIENTS: Fifty children at risk of FNAIT were antenatally treated with maternal intravenous immunoglobulins (IVIG) (n=11), IVIG with intrauterine platelet transfusions (IUPT) (n=26) or IUPT alone (n=9). In four cases (n=4), only fetal blood sampling (FBS) was performed. One child died in the neonatal period and one was lost to follow up. METHODS: The remaining 48 children, aged 1.3-11.6 years (median 5.1 years), were given both general and neurological examinations and assessed on their development and susceptibility for infections or atopic constitution. In addition, immunoglobulin levels were measured in 17 infants, aged 5 years and older. RESULTS: Intracranial hemorrhage (ICH) was not observed. The general health and neurodevelopmental outcome in the children was comparable to a normal Dutch population. Children not exposed to maternal IVIG treatment had significantly more infections and hearing problems than children exposed to IVIG treatment or the normal population. Immunoglobulin G, A and M levels were within the normal range, independent of treatment and severity of FNAIT. A high IgE level was more frequently seen in children exposed to IVIG, but did not result in clinical consequences such as allergy or atopy. CONCLUSIONS: Antenatal treatment of children for FNAIT did not affect general health or neurodevelopmental outcome. In particular, exposure to IVIG in utero showed no adverse effect on the clinical outcome of these children.     

Proliferative activity of leukaemic blasts and cytosine arabinoside pharmacodynamics are associated with cytogenetically defined prognostic subgroups in acute myeloid leukaemia

The biological mechanisms responsible for the association of specific karyotypes with prognosis in acute myeloid leukaemia (AML) remain largely unclear. A prospective study was performed to evaluate how far cytogenetically defined prognostic subgroups of AML differ in their proliferative activity as a potential mechanism for differential sensitivities to S-phase-specific induction chemotherapy comprising cytosine arabinoside (AraC). One hundred and eighty-seven patients with de novo AML were included in the study; 25 patients with a favourable [inv(16), t(8;21), t(15;17)] karyotype, 99 with a normal karyotype, 29 with an unfavourable karyotype (-5, 5q-, -7, 7q-, complex aberrations) and 34 with cytogenetic aberrations of unknown prognostic significance (all others). The favourable group demonstrated the highest ex vivo proliferative activity (PA) (3.41 pmol/105 cells), significantly (P = 0.02) exceeding the unfavourable group with the lowest PA (0.72) and the group with a normal karyotype (1.06) or with karyotype of unknown significance (1.05) that both demonstrated an intermediate PA. Samples with a high PA (> median of the whole group) were more likely to produce interleukin 3, granulocyte macrophage colony-stimulating factor (GM-CSF), granulocyte CSF (G-CSF) (56%, 43% and 50%) than cells with a low PA (33%, 36% and 36%; n.s.). The effect of priming by exogenous GM-CSF or G-CSF was significantly more pronounced in samples with a low PA than in rapidly proliferating samples (P < 0.01). For the whole group, a high PA was closely associated with an increased incorporation of AraC triphosphate (AraCTP) into the DNA (P < 0.0001). Clinically, a high PA was associated with a better complete remission (CR) rate in the normal (95% versus 62%) and the unfavourable group (75% versus 33%). The significant differences in proliferative activity between cytogenetic subgroups of AML are associated with increased cytosine arabinoside pharmacodynamics and constitute one potential mechanism for the different response of cytogenetic subgroups to AraC-based induction therapy.