The Global Task Force for Chronic Pain in People with HIV (PWH): Developing a research agenda in an emerging field.

Chronic pain is a common comorbidity in people with HIV (PWH), with prevalence estimates of 25-85%. Research in this area is growing, but significant gaps remain. A Global Task Force of HIV experts was organized to brainstorm a scientific agenda and identify measurement domains critical to advancing research in this field. Experts were identified through literature searches and snowball sampling. Two online questionnaires were developed by Task Force members. Questionnaire 1 asked participants to identify knowledge gaps in the field of HIV and chronic pain and identify measurement domains in studies of chronic pain in PWH. Responses were ranked in order of importance in Questionnaire 2, which was followed by a group discussion. 29 experts completed Questionnaire 1, 25 completed Questionnaire 2, and 21 participated in the group. Many important clinical and research priorities emerged, including the need to examine etiologies of chronic pain in PWH. Pain-related measurement domains were discussed, with a primary focus on domains that could be assessed in a standardized manner across various cohorts that include PWH in different countries. We collaboratively identified clinical and research priorities, as well as gaps in standardization of measurement domains, that can be used to move the field forward.

Generation of functional human serotonergic neurons from fibroblasts.

The brain's serotonergic system centrally regulates several physiological processes and its dysfunction has been implicated in the pathophysiology of several neuropsychiatric disorders. While in the past our understanding of serotonergic neurotransmission has come mainly from mouse models, the development of pluripotent stem cell and induced fibroblast-to-neuron (iN) transdifferentiation technologies has revolutionized our ability to generate human neurons in vitro. Utilizing these techniques and a novel lentiviral reporter for serotonergic neurons, we identified and overexpressed key transcription factors to successfully generate human serotonergic neurons. We found that overexpressing the transcription factors NKX2.2, FEV, GATA2 and LMX1B in combination with ASCL1 and NGN2 directly and efficiently generated serotonergic neurons from human fibroblasts. Induced serotonergic neurons (iSNs) showed increased expression of specific serotonergic genes that are known to be expressed in raphe nuclei. iSNs displayed spontaneous action potentials, released serotonin in vitro and functionally responded to selective serotonin reuptake inhibitors (SSRIs). Here, we demonstrate the efficient generation of functional human serotonergic neurons from human fibroblasts as a novel tool for studying human serotonergic neurotransmission in health and disease.

[Is the Intrahepatic Sound Speed an Indicator of the Fat Content of the Liver in Children?]. / Die intrahepatische Schallgeschwindigkeit als möglicher Parameter zur Abschätzung der Steatosis hepatis bei Kindern?

PURPOSE: Can the sonographically estimated intrahepatic sound speed give hints on the hepatic fat content in children? MATERIALS AND METHODS: In 75 children and adolescents the intrahepatic sound speed was estimated during routine sonography of the liver as a result of an image reconstruction algorithm. It was correlated with weight, age, size, and body mass index (BMI) oft he children, respectively. RESULTS: The average hepatic sound speed in children of normal weight was 1 566 m/s (standard deviation (STD) 29 m/s, in overweight or obese children it was 1 501 m/s (STD 22 m/s), and in obese children it was 1 497 ms (STD 24 m/s). The strongest correlation was found between sound speed and BMI of the children, respectively. The difference of sound speed in normal weighing subjects and overweight/obese children was statistically significant. CONCLUSION: There is a good correlation between the estimated intrahepatic sound speed and the fat content of the liver. Further examinations are encouraged.

Mid-infrared emissivity of partially dehydrated asteroid (162173) Ryugu shows strong signs of aqueous alteration.

The near-Earth asteroid (162173) Ryugu, the target of Hayabusa2 space mission, was observed via both orbiter and the lander instruments. The infrared radiometer on the MASCOT lander (MARA) is the only instrument providing spectrally resolved mid-infrared (MIR) data, which is crucial for establishing a link between the asteroid material and meteorites found on Earth. Earlier studies revealed that the single boulder investigated by the lander belongs to the most common type found on Ryugu. Here we show the spectral variation of Ryugu's emissivity using the complete set of in-situ MIR data and compare it to those of various carbonaceous chondritic meteorites, revealing similarities to the most aqueously altered ones, as well as to asteroid (101955) Bennu. The results show that Ryugu experienced strong aqueous alteration prior to any dehydration.

[Metastases from a malignant melanoma as extensive, space-occupying lesion in the trachea]. / Metastasen eines malignen Melanoms als ausgedehnte Raumforderung in der Trachea.

We report the case of a 71-year-old man, who was transferred to our clinic with rapidly increasing dyspnea. On examination by flexible bronchoscopy the trachea was found to be almost completely obstructed by metastatic masses of a malignant melanoma. After endoscopic removal of the obstruction, we inserted a covered nitinol stent which led to instantaneous relief of symptoms. Chemotherapy and local radiotherapy were instituted. During the next 9 months there were no signs of recurrence of the tumour in regular pneumological control exams.

[Sentinel lymph node dissection in prostate cancer. Experience after more than 800 interventions]. / Sentinel-Lymphadenektomie beim Prostatakarzinom. Erfahrungen nach über 800 Eingriffen.

There is no consensus on which prostate cancer patients should undergo lymph node removal and which lymph nodes should be included. Therefore, most clinicians rely on nomograms and dispense with lymph node dissection in patients with low-risk disease. Meanwhile, there are some studies which prove that there are also lymph node metastases in patients with low-risk prostate cancer and that lymph node metastases are predominantly localized outside the region of standard lymphadenectomy. In more than 800 men we could show that lymph node metastases were found more often than shown in the Partin tables. These lymph node metastases were detected by sentinel lymph node dissection outside the region of standard and extended lymphadenectomy. Because of insufficient preoperative diagnostics it is unclear which patients have positive lymph nodes. Therefore, it is useful to perform lymph node dissection in every patient. Men with positive nodes could have a better prognosis, when sentinel and extended lymph node dissection are performed.

Dietary cholesterol and the activity of stearoyl CoA desaturase in rats: evidence for an indirect regulatory effect.

The effect of cholesterol on stearoyl CoA desaturase (SCD) was investigated. Previous work had shown that the addition of cholesterol to the diet of rats produced higher liver SCD activity compared to non-cholesterol-fed controls. We have confirmed this result and investigated the mechanism responsible for this cholesterol-induced higher SCD activity. Rats were fed either a 10% corn oil (CO) or a 10% corn oil/1% cholesterol (CO/CH) diet for 1, 3, or 7 days. SCD mRNA abundance was 3.3, 1.9, and 2.4 times greater in livers from CO/CH-fed animals after 1, 3, and 7 days, respectively. Northern hybridization of RNA from kidney, intestinal mucosa, heart, adipose, and liver demonstrated that cholesterol feeding specifically altered liver SCD mRNA. Liver esterified cholesterol content increased 27-fold with cholesterol feeding. This esterified cholesterol increase was accompanied by a proportionately greater increase in oleic acid compared to other fatty acids. These studies indicate that cholesterol does influence the expression of SCD specifically in the liver and suggest that the product, oleic acid, is preferentially esterified to cholesterol in the liver. Preliminary liver nuclear run-on assays from rats fed CO or CO/CH diets for 1 and 3 days indicate that transcription regulation is not a factor.

The binding of palmitoyl-CoA to bovine serum albumin.

Bovine serum albumin (BSA) is routinely utilized in vitro to prevent the adverse detergent effects of long-chain acyl-CoA esters (i.e., palmitoyl-CoA) in enzyme assays. Determination of substrate saturation kinetics in the presence of albumin would only be valid if the relationship between bound and free substrate concentrations was known. To elucidate the relationship between bound and free palmitoyl-CoA concentrations in the presence of BSA, several different techniques including equilibrium dialysis, equilibrium partitioning, fluorescence polarization and direct fluorescence enhancement were investigated. Direct fluorescence enhancement using a custom synthesized fluorescent probe, 16-(9-anthroyloxy)palmitoyl-CoA (AP-CoA), was the best approach to this question. Measurement of the relationship between mol of palmitoyl-CoA bound per mol of BSA (nu) versus -log[free palmitoyl-CoA] revealed that the binding of palmitoyl-CoA to BSA, like palmitate was nonlinear, suggesting the presence of more than one class of acyl-CoA binding sites. Computer analyses of the binding data gave a best fit to the 2,4 two-class Scatchard model, suggesting the presence of two high-affinity primary binding sites (k1 = (1.55 +/- 0.46) x 10(-6) M-1) and four lower affinity secondary binding sites (k2 = (1.90 +/- 0.09) x 10(-8) M-1). Further analyses using the six parameter stoichiometric (stepwise) ligand binding model supports the existence of six binding sites with the higher affinities associated with the binding of the first mole of palmitoyl-CoA and weaker binding occurring after the first two sites are occupied. The association constants from this model of multiple binding diminish sequentially (i.e., K1 greater than K2 greater than K3 greater than...greater than or equal to K6), suggesting that each mol of long-chain acyl-CoA binds to BSA with decreasing affinities.

The effect of palmitoyl-CoA binding to albumin on the apparent kinetic behavior of carnitine palmitoyltransferase I.

Substrate saturation plots of carnitine palmitoyltransferase I activity from isolated rat liver mitochondria vs. palmitoyl-CoA concentration in the presence of bovine serum albumin have been reported to yield sigmoidal kinetics. Under identical assay conditions we have confirmed these observations as reflected by nonlinear Lineweaver-Burke plots (1/vi vs. 1/[S]) an average Hill coefficient of napp. = 1.98 +/- 0.09 (Mean +/- S.E. from four separate experiments). For these determinations the enzyme activity was plotted against the total [palmitoyl-CoA] in the presence of 0.13% bovine serum albumin. Utilizing the total [palmitoyl-CoA] to determine the kinetic properties of carnitine palmitoyltransferase I would be valid only if the relationship between total and free [palmitoyl-CoA] was linear, which is not the case as we have previously shown. When carnitine palmitoyltransferase I substrate saturation kinetics were reanalyzed using the previously determined free [palmitoyl-CoA]'s, the plots revealed a shift to standard hyperbolic kinetics. This observation was confirmed by an average Hill coefficient of napp. = 1.04 +/- 0.10 (Mean +/- S.E.) and linear Lineweaver-Burke plots. The double-reciprocal plots from these analyses yielded an average S0.5 of 2.55 +/- 0.82 microM (Mean +/- S.E.) palmitoyl-CoA and Vmax of 19.69 +/- 5.48 nmol/min per mg protein. These studies clearly demonstrate the importance of defining the free [palmitoyl-CoA] when analyzing the kinetics of carnitine palmitoyltransferase I in the presence of bovine serum albumin.

Transport and metabolism of pyridoxine in rat liver.

Evidence, obtained with in situ perfused rat liver, indicated that pyridoxine is taken up from the perfusate by a non-concentrative process, followed by metabolic trapping. These conclusions were reached on the basis of the fact that at low concentrations (0.125 microM), the 3H of [3H]pyridoxine accumulated against a concentration gradient, but high concentrations (333 microM) of pyridoxine or 4-deoxypyridoxine prevented this apparent concentrative uptake. Under no conditions did the tissue water:perfusate concentration ratio of [3H]pyridoxine exceed unity. The perfused liver rapidly converted the labeled pyridoxine to pyridoxine phosphate, pyridoxal phosphate and pyridoxamine phosphate and released a substantial amount of pyridoxal and some pyridoxal phosphate into the perfusate. Since muscle and erythrocytes failed to oxidize pyridoxine phosphate to pyridoxal phosphate, it is suggested that the liver plays a major role in oxidizing dietary pyridoxine and pyridoxamine as their phosphate esters to supply pyridoxal phosphate which then reaches to other organs chiefly as circulating pyridoxal.

[Nocardia brasiliensis leg ulcer and nodular lymphangitis in France]. / Ulcère de jambe et lymphangite nodulaire à Nocardia brasiliensis en France métropolitaine.

INTRODUCTION: Nocardia brasiliensis is a very rarely reported cause of chronic phagedenic ulcerations. We report the case of an elderly woman who developed such an infection after falling on her right leg on the road in the Bresse country (an essentially agricultural and bovine-cattle breading region) and developed a chronic phagedenic ulcer secondarily complicated by nodular lymphangitis of the thigh. CASE REPORT: A 75 year-old woman fell on her right leg on the side of the main road outside her hamlet in the Bresse country and secondarily developed a chronique phagedenic ulceration. We first considered her as suffering from pyoderma gangrenosum. A complete scanning only revealed an autoimmune thyroiditis and a rapidly healing gastric ulceration, and none of the treatments, either local or systemic, helped the skin condition to heal. After 3 weeks of application of a local corticoid ointment, the patient developed fever, general malaise, an exacerbation of her wound and an infiltration of the skin round her knee, together with nodular lymphangitic dissemination. A supplementary bacterial swab disclosed massive proliferation of a slow-growing Gram-positive bacillus, which proved to be Nocardia brasiliensis, together with a methicillino-sensitive Staphylococcus aureus. The treatment with sulfamethoxazole-trimetoprim gave a rash after 12 hours and was changed to amoxicillin and clavulanic acid, which rapidly proved to be permanently effective. DISCUSSION: The revelation of this particular slow-growing bacteria is difficult and requires bacterial swabs. Nocardia brasiliensis is relatively rare in primary skin ulcerations and we discuss the reasons why an elderly women should find this bacteria on the road outside her hamlet in the French countryside. This particular infectious condition requires general scanning, to make sure that the primary skin condition does not extend to other organs. We review the therapeutical options for patients who exhibit allergic reactions to the classically effective antibiotic drugs.

COMETARY SCIENCE. The structure of the regolith on 67P/Churyumov-Gerasimenko from ROLIS descent imaging.

The structure of the upper layer of a comet is a product of its surface activity. The Rosetta Lander Imaging System (ROLIS) on board Philae acquired close-range images of the Agilkia site during its descent onto comet 67P/Churyumov-Gerasimenko. These images reveal a photometrically uniform surface covered by regolith composed of debris and blocks ranging in size from centimeters to 5 meters. At the highest resolution of 1 centimeter per pixel, the surface appears granular, with no apparent deposits of unresolved sand-sized particles. The thickness of the regolith varies across the imaged field from 0 to 1 to 2 meters. The presence of aeolian-like features resembling wind tails hints at regolith mobilization and erosion processes. Modeling suggests that abrasion driven by airfall-induced particle "splashing" is responsible for the observed formations.

Macrophage phagocytosis and membrane fluidity in mice: the effect of age and dietary protein.

Male C57BL/6NNia mice were used to investigate the effects of age and dietary protein intake on Fc and C3b receptor-mediated phagocytosis and on membrane fluidity. Six-month-old (adult) and 24-month-old (aged) mice were fed a 6% or 25% protein diet for 3, 5, or 6 weeks at which time thioglycollate elicited peritoneal macrophages were isolated. Both binding of IgG-coated sheep red blood cells to the macrophages and ingestion via the Fc-receptor were identical in all 4 groups after 3 and 6 weeks of feeding but were decreased at 5 weeks in the aged animals fed 6% protein. Phagocytosis via the C3b receptor was not depressed in either age group fed the low protein diet; it was, however, augmented significantly in the aged animals fed the 25% protein diet for 5 and 6 weeks. Membrane fluidity of the plasma membrane outer hemileaflet was monitored with an impermeant fluorescent probe. No changes were observed between adult and aged mice maintained up to 6 weeks on the diets.

Improved survival of heterotopic cardiac allografts in rats with dietary n-3 polyunsaturated fatty acids.

A heterotopic cardiac transplant model, with male Fischer 344 rats as donors and Long Evans rats as recipients, was utilized to investigate the effect of dietary n-3 polyunsaturated fatty acids on acute rejection. Both donor and recipient rats were fed purified diets high in either n-3 polyunsaturated fatty acids (from concentrated n-3 ethyl esters [EE] or fish oil [FO]) or n-6 polyunsaturated fatty acids (from corn oil [CO]) for either 2-3 or 3-4 weeks before transplant. The recipient rats continued on their diets until rejection. The AIN-76A-based diets (with 30% of calories as fat) had adequate essential fatty acids and were balanced for sterols and antioxidants. Allograft survival was significantly increased by 45% when recipient rats were fed EE as compared to the control (CO diet fed to both donor and recipient), regardless of the diet fed to the donor. There was a slight but significant increase in allograft survival when only donor rats were fed the EE diet 2-3 weeks before transplant. With the FO diet (containing one third of the n-3 fatty acids in the EE diet), only the group fed FO to both donor and recipient (starting 2-3 weeks before transplant) showed a significant increase in allograft survival over the control. However, if the FO diets were fed for 3-4 weeks before transplant, increased survival was seen in groups fed FO to either the donor or recipient alone. In this case, allograft survival with FO feeding to both donor and recipient was not different from recipient treatment alone. In all the studies there was a significant and direct correlation between allograft survival and the donor heart phospholipid n-3/n-6 fatty acid ratio and the n-3 fatty acid content (at rejection). There was an indirect relationship with the n-6 fatty acid content. There was no detectable 20:3 (n-9) in the cardiac phospholipids, indicating the absence of essential fatty acid deficiency. Recipient diets were the strongest determinant of the fatty acid composition in the transplanted donor heart. The data indicate that providing dietary n-3 polyunsaturated fatty acids before and after cardiac transplant to recipient animals provides a significant protection against acute rejection.

Evaluation of lung function during pulmonary rejection and infection in heart-lung transplant patients. Hannover Lung Transplant Group.

Pulmonary rejection and infection are the most important complications after lung transplantation. To evaluate the diagnostic value of pulmonary function testing for early detection and discrimination of these complications, seven heart-lung recipients were examined. The diagnosis of each complication was confirmed by clinical and laboratory findings including transbronchial biopsies and bronchoalveolar lavage. Eight episodes of rejection, ten episodes of viral infection and six episodes of bacterial pneumonia were analyzed. Pulmonary rejection was associated with a significant fall in the FEV1/IVC% and the FEF50%. In viral infection, the most impressive finding was a reduction in the DCO, whereas no obstructive or restrictive airway dynamics were observed. During bacterial pneumonia, pulmonary function measurement revealed a decrease in IVC without signs of obstructive airway dynamics. Adequate treatment resulted in reconstitution of pretreatment values. Assessment of lung function provides valuable information for the diagnosis of pulmonary complications following HLTx.

Preoperative corticosteroids. A contraindication to lung transplantation?

Regular preoperative application of corticosteroids has been considered as a contraindication to lung transplantation for fear of an increased risk of postoperative morbidity and mortality. Recently, however, we have accepted patients for transplantation in whom treatment with steroid medication could not be terminated preoperatively. Up to February 1991, 27 unilateral and bilateral transplantations in 26 patients were analyzed. Corticosteroid therapy was discontinued at least three months prior to transplantation in 13 patients (group 1), whereas in 14 cases, the patients continued their daily corticosteroid therapy to the time of transplantation (prednisolone, 0.1 to 0.3 mg/kg/day; group 2). There were no significant differences between the groups with respect to sex, age, diagnosis, or type of transplantation. One limited bronchial dehiscence occurred; the incidence of postoperative bronchial stenosis was identical in both cohorts; one patient died in each group. In conclusion, no increased morbidity or mortality could be found following lung transplantation with regular preoperative administration of prednisolone up to 0.3 mg/kg/day. Thus, patients who cannot be weaned from their steroid medication but who otherwise are acceptable candidates should not be excluded from lung transplantation.

Radical prostatectomy: survival outcome and correlation to prostate-specific antigen levels.

BACKGROUND: This paper reviews a 10-year experience with radical retropubic prostatectomy (RP) focussing on survival outcome related to pre- and postoperative levels of prostate-specific antigen (PSA). PATIENTS AND METHODS: 739 patients who underwent RP between 1987 and 1998 were prospectively investigated. Kaplan-Meier analyses were performed and correlated to pre- and postoperative PSA concentrations. RESULTS: In a follow up period of 11 years duration, (mean 3 yrs.) 57 of 739 patients died (20 from prostate disease progression, 37 from other causes). Correlation between low pre-operative PSA and pathological organ-confinement was significant (p < 0.001). Of 175 patients with PSA progression, 53 (30%) had never reached undetectable levels of PSA. 57% of PSA relapses were detected during the first year, and 3% later than 5 years post-operatively. Kaplan-Meier analysis yielded an average 3 years advantage in estimated prostate-cancer-specific survival when pre-operative PSA levels were below 50 ng/ml. Overall, prostate-cancer-specific and PSA-free 5-year survival-rates were 88%, 96% and 67% respectively. CONCLUSIONS: Survival-rates after RP are high even in conjunction with unfavourable PSA outcome. Merely one third of deaths resulted from prostate cancer, since men at risk frequently suffer from concomitant diseases that affect survival.

Elimination kinetics of prostate-specific antigen serum and urine.

The serum half-life of prostate-specific antigen (PSA) was calculated in 66 patients subsequent to radical prostatectomy. Comparing serum half-life to disease outcome in 37 patients after a minimum follow-up of two years, it was found that PSA serum half-life identifies patients with residual disease earlier and more reliably than the presence or absence of detectable PSA levels postoperatively. It is suggested that residual tumor affects the half-life by contributing to the serum level of PSA. When PSA serum half-life was calculated solely in potentially cured patients, we found a half-life of 1.6 days, which is considerably shorter than in previous reports based on patient populations regardless of the outcome of disease in the follow-up. To elucidate the route of PSA elimination, serial urine PSA levels were determined before and after radical prostatectomy, revealing strong evidence for the assumption that PSA is not eliminated by the kidneys in its unchanged form.

Neuroendocrine and beta-adrenoceptor response to chronic ethanol and aggression in rats.

Male rats were administered either ethanol (6-8 g/kg/day) or dextrin-maltose, an isocaloric equivalent, for two weeks prior to a 24-hour resident-intruder test. After the first 20 minutes of the aggression test residents showed a greater increase in norepinephrine than intruders (216% vs. 97%), while intruders showed a greater increase in epinephrine (394% vs. 51%) and corticosterone (338% vs. 129%) than residents. Ethanol administration increased the initial epinephrine response of intruders almost two-fold compared to dextrin-maltose intruders. After 24 hours of aggression testing plasma norepinephrine was still elevated in residents (92%) and intruders (71%), however, only intruders continued to show an elevation in plasma corticosterone (98%) and epinephrine (107%). Using a cumulative dose-response technique, the dose of isoproterenol required to produce 50% of the maximal heart rate response (ED50) increased in intruders by 108% following aggression testing with ethanol intruders showing significantly smaller mean change. The increase in ED50 was related to drug type, behavior, and plasma corticosterone and epinephrine levels. Rats treated with ethanol had a greater beta-adrenoceptor density than control rats. However, no relationship was found between receptor density and the other measures in this study.