Curiosity for information predicts wellbeing mediated by loneliness during COVID-19 pandemic.

The COVID-19 pandemic confronted humans with high uncertainty and lockdowns, which severely disrupted people's daily social and health lifestyles, enhanced loneliness, and reduced well-being. Curiosity and information-seeking are central to behavior, fostering well-being and adaptation in changing environments. They may be particularly important to maintain well-being during the pandemic. Here, we investigated which motives drive information-seeking, and whether and how curiosity and information-seeking related to well-being and mood (excitement, anxiety). Additionally, we tested whether daily diet contributed to this relationship during lockdown. Participants (N = 183) completed questionnaires measuring curiosity, information-seeking, social and mental health. Using a smartphone app, participants submitted their daily food intake and lifestyle ratings for a week. We found participants had highest motivation to seek positive (vs. negative) information, concerning themselves more than others. Both trait curiosity and information-seeking predicted higher well-being, mediated by loneliness. Trait curiosity also predicted well-being and excitement days later. Considering diet, participants with lower trait curiosity ate food containing more tyrosine (i.e., dopamine precursor). Furthermore, participants consuming food high in sugar reported higher anxiety, which was specifically found in participants with relatively low, but not high, trait curiosity. Taken together, curiosity and information-seeking may benefit well-being and mood in high uncertain and challenging times, by interacting with lifestyle measures (loneliness and nutrition).

Genetic testing and surveillance guidelines in hereditary pheochromocytoma and paraganglioma.

Pheochromocytoma and paraganglioma (PPGL) are rare tumours and at least 30% are part of hereditary syndromes. Approximately 20% of hereditary PPGL are caused by pathogenic germ line variants in genes of the succinate dehydrogenase complex (SDHx), TMEM127 or MAX. Herein we present guidelines regarding genetic testing of family members and their surveillance based on a thorough literature review. All cases of PPGL are recommended genetic testing for germ line variants regardless of patient and family characteristics. At minimum, FH, NF1, RET, SDHB, SDHD and VHL should be tested. In addition, testing of MEN1, SDHA, SDHAF2, SDHC, TMEM127 and MAX is recommended. Healthy first-degree relatives (and second-degree relatives in the case of SDHD and SDHAF2 which are maternally imprinted) should be offered carrier testing. Carriers of pathogenic variants should be offered surveillance with annual biochemical measurements of methoxy-catecholamines and bi-annual rapid whole-body magnetic resonance imaging and clinical examination. Surveillance should start 5 years before the earliest age of onset in the family and thus only children eligible for surveillance should be offered pre-symptomatic genetic testing. The surveillance of children younger than 15 years needs to be individually designed. Our guidelines will provide a framework for patient management with the possibility to follow outcome via national registries and/or follow-up studies. Together with improved insights into the disease, this may enable optimisation of the surveillance scheme in order to minimise both anxiety and medical complications while ensuring early disease detection.

Colorectal cancer liver metastatic growth depends on PAD4-driven citrullination of the extracellular matrix.

Citrullination of proteins, a post-translational conversion of arginine residues to citrulline, is recognized in rheumatoid arthritis, but largely undocumented in cancer. Here we show that citrullination of the extracellular matrix by cancer cell derived peptidylarginine deiminase 4 (PAD4) is essential for the growth of liver metastases from colorectal cancer (CRC). Using proteomics, we demonstrate that liver metastases exhibit higher levels of citrullination and PAD4 than unaffected liver, primary CRC or adjacent colonic mucosa. Functional significance for citrullination in metastatic growth is evident in murine models where inhibition of citrullination substantially reduces liver metastatic burden. Additionally, citrullination of a key matrix component collagen type I promotes greater adhesion and decreased migration of CRC cells along with increased expression of characteristic epithelial markers, suggesting a role for citrullination in promoting mesenchymal-to-epithelial transition and liver metastasis. Overall, our study reveals the potential for PAD4-dependant citrullination to drive the progression of CRC liver metastasis.

Systematic review of surgery and outcomes in patients with primary aldosteronism.

BACKGROUND: Primary aldosteronism (PA) is the most common cause of secondary hypertension. The main aims of this paper were to review outcome after surgical versus medical treatment of PA and partial versus total adrenalectomy in patients with PA. METHODS: Relevant medical literature from PubMed, the Cochrane Library and Embase OvidSP from 1985 to June 2014 was reviewed. RESULTS: Of 2036 records, 43 articles were included in the final analysis. Twenty-one addressed surgical versus medical treatment of PA, four considered partial versus total adrenalectomy for unilateral PA, and 18 series reported on surgical outcomes. Owing to the heterogeneity of protocols and reported outcomes, only a qualitative analysis was performed. In six studies, surgical and medical treatment had comparable outcomes concerning blood pressure, whereas six showed better outcome after surgery. No differences were seen in cardiovascular complications, but surgery was associated with the use of fewer antihypertensive medications after surgery, improved quality of life, and (possibly) lower all-cause mortality compared with medical treatment. Randomized studies indicate a role for partial adrenalectomy in PA, but the high rate of multiple adenomas or adenoma combined with hyperplasia in localized disease is disconcerting. Surgery for unilateral dominant PA normalized BP in a mean of 42 (range 20-72) per cent and the biochemical profile in 96-100 per cent of patients. The mean complication rate in 1056 patients was 4·7 per cent. CONCLUSION: Recommendations for treatment of PA are hampered by the lack of randomized trials, but support surgical resection of unilateral disease. Partial adrenalectomy may be an option in selected patients.

Cohort study of patients with adrenal lesions discovered incidentally.

BACKGROUND: This prospective cohort study investigated the incidence, clinical features and natural history of incidentally discovered adrenal mass lesions (adrenal incidentaloma, AI) in an unselected population undergoing radiological examination. METHODS: During an 18-month period, all patients with AI were reported prospectively from all 19 radiology departments in western Sweden. Inclusion criteria were: incidentally discovered adrenal enlargement or mass lesion in patients without extra-adrenal malignancy on detection. Clinical and biochemical evaluation was performed on inclusion and after 24 months. Computed tomography (CT) of the adrenals was scheduled at 4, 12 and 24 months. Magnetic resonance imaging was performed for lesions larger than 20 mm. The indications for surgical excision were: hormone activity, lesion diameter more than 30 mm, lesion growth or other radiological features suspicious of malignancy. RESULTS: Of 534 patients assessed for eligibility, 226 (mean age 67 years, 62·4 per cent women; mean lesion diameter 23·9 mm, 22·6 per cent bilateral) fulfilled the inclusion criteria. Mean follow-up was 19·0 months. After baseline evaluation, 14 patients had surgery owing to primary hyperaldosteronism (3), catecholamine-producing tumour (1), tumour size (6), size and indication of subclinical hypercortisolism (3) and metastasis (1). No hypersecreting lesions were confirmed during follow-up; one patient underwent adrenalectomy for a suspected phaeochromocytoma (adrenocortical adenoma at histopathology). No primary adrenal malignancy was found. CONCLUSION: In this prospective cohort study 6·6 per cent of patients with an AI had surgery and benign hormone-producing tumours were verified in 3·1 per cent. Repeat CT and hormone evaluation after 2 years did not increase the sensitivity for diagnosis of malignant or hormone-producing tumours.

Prognostic factors for survival after surgery for adrenal metastasis.

AIM: To better define the indications for adrenalectomy for adrenal metastasis we have analysed factors predicting survival in our institutional series. METHODS: A consecutive series of 30 patients undergoing adrenalectomy for metastasis (1996-2007), excluding patients with simultaneous ipsilateral renal cell carcinoma (RCC), was studied. Metastases were regarded as synchronous (<6 mo), or metachronous (>6 mo), depending on the interval after primary surgery. Survival was calculated from time of adrenalectomy and factors influencing survival were identified. RESULTS: The tumour diagnoses were RCC n = 9, malignant melanoma n = 5, non-small-cell lung cancer n = 5, colorectal carcinoma n = 4, foregut carcinoid n = 2, adrenocortical carcinoma, breast cancer, hepatocellular carcinoma, urothelial carcinoma, and liposarcoma (one each); nine adrenal metastases were synchronous and 21 metachronous. Ten patients had undergone previous surgery for extra-adrenal metastases. Out of 30 adrenalectomies 10 were laparoscopic (LAdx) and 20 open (OAdx) procedures without surgical complications. The local recurrence rate was low: LAdx 1/10, OAdx 1/20, and the median survival was 23 months. Independent prognosticators of favourable survival were adrenalectomy for potential cure (p = 0.01), no previous metastasis surgery (p = 0.02), and tumour type (p = 0.043), with better prognosis for patients with adrenal metastasis from colorectal carcinoma and RCC and worse prognosis in non-small-cell lung cancer and malignant melanoma. CONCLUSIONS: Surgery for adrenal metastasis is safe and the indication for this procedure in an individual patient can be supported by several prognostic factors. The survival benefit in patients with adrenalectomy for potential cure indicates a therapeutic value of adrenalectomy in selected patients.

EBV reactivation and post transplant lymphoproliferative disorders following allogeneic SCT.

Fatal problems encountered in allogeneic stem cell transplantation include EBV reactivation and post transplant lymphoproliferative disorders (PTLDs) with high mortality rates. We performed a retrospective analysis in all consecutive adult and pediatric EBV reactivations and PTLD during a period of 8.5 years. There were 26 patients with EBV reactivation/PTLD out of a total of 854 transplantations giving an overall incidence of 3.0%. Specifically, the incidence of EBV-PTLD was 1.3%, whereas that of EBV reactivation was 1.8%. Median age was 46.0 and 11.0 years in the adult and pediatric patients, respectively. There were high rates (54%) of concomitant bacterial, viral, fungal and parasitic infections at the time of EBV manifestation. Variable treatment regimens were applied including in most cases an anti-CD20 regimen often in combination with virustatic compounds, polychemotherapy or donor lymphocytes. The mortality rates were 9 of 11 (82%) in patients with EBV-PTLD and 10 of 15 (67%) in patients with reactivation. Only 7 of 26 patients (27%) are alive after a median follow-up of 758 days (range 24-2751). The high mortality rates of EBV reactivation and of EBV-PTLD irrespective of multimodal treatment approaches emphasize standardization and optimization of post transplant surveillance and treatment strategies to improve control of these often fatal complications.

[29-year-old female patient with pneumonia and enlarged abdominal lymph nodes]. / 29-jährige Patientin mit Pneumonie und grossen abdominellen Lymphknoten.

Common variable immunodeficiency (CVID) is the most common clinically manifested primary immunodeficiency disease. A 29-year-old female patient presented with pneumonia and enlarged thoracal and abdominal lymph nodes. Frequently recurring infections, especially in the respiratory tract were observed in the patient's history. A hypogammaglobulinaemia could be detected. By exclusion of other disorders and a complete analysis of the immune status a CVID Ib/B was diagnosed. Regular ambulatory treatment with immune globulin substitution reduced the incidence and severity of infections.

The Ki67 index a prognostic marker in medullary thyroid carcinoma.

Our objective was to examine the usefulness of the Ki67 proliferation index as a prognostic marker in patients with medullary thyroid carcinoma (MTC). It is difficult to predict the prognosis of MTC by using conventional prognostic factors. Immunocytochemical analysis of tumour proliferation has been used as a prognostic tool in some tumours, but only rarely in MTC. In all, 71 tumours from 36 patients were investigated, by using a semiautomatic image analysis programme. On average 10,000 nuclear profiles were counted per tumour, and the percentage of tumour cells expressing the proliferation marker, Ki67, was calculated. Primary tumours that had metastasised had higher Ki67 indices than primary tumours that had not metastasised. Recurrent lymph node metastasis had higher Ki67 indices than the primary tumours. By using a Poisson model, it was possible to estimate the median survival time for individual patients if the Ki67 index for the primary tumour and the age at surgery were known. The higher the Ki67 index and the age at operation were, the shorter was the survival. Estimating the median survival of individual patients will be of help for planning the patients' life and postoperative follow-up and treatment.

Stereoselective analysis of 2-hydroxysebacic acid in urine of patients with Zellweger syndrome and of premature infants fed with medium-chain triglycerides.

The chiral metabolite 2-hydroxysebacic acid (2-HS) is considered to be an important diagnostic marker for peroxisomal disorders. The pathway of formation of 2-HS, excreted in increased amounts in patients with peroxisomal diseases, is not absolutely clear. Moreover, there is no information about the enantiomeric distribution of 2-HS in human urine. Here, we describe the stereodifferentiation of 2-HS in urine samples of nine patients with Zellweger syndrome (ZS), and for the first time in urine samples of premature infants fed a medium-chain triglyceride (MCT)-containing diet. Using enantioselective multidimensional gas chromatography-mass spectrometry, an increased excretion of 2R-HS was observed in all investigated ZS patients. 2-HS was also present in urine samples of premature infants fed MCT. Analogously to the ZS patients, a dominant 2R-HS excretion in the urine samples of the premature infants was identified. The formation of 2-HS is expected to result from the same or similar pathways as described for ZS patients. Additionally, we determined the absolute configuration of urinary 3-hydroxysebacic acid (3-HS) in the cases investigated. The enantioselective analysis provides further information for the diagnosis and treatment of patients with impaired peroxisomal fatty acid oxidation. Further insight into the metabolic origin and the biochemical pathway leading to these urinary metabolites is provided.

Interferon-alpha before allogeneic bone marrow transplantation in chronic myelogenous leukemia does not affect outcome adversely, provided it is discontinued at least 90 days before the procedure.

The influence of interferon-alpha (IFN) pretreatment on the outcome after allogeneic bone marrow transplantation (BMT) in chronic myelogenous leukemia (CML) is controversial. One goal of the German randomized CML Studies I and II, which compare IFN +/- chemotherapy versus chemotherapy alone, was the analysis of whether treatment with IFN as compared to chemotherapy had an influence on the outcome after BMT. One hundred ninety-seven (23%) of 856 Ph/bcr-abl-positive CML patients were transplanted. One hundred fifty-two patients transplanted in first chronic phase were analyzed: 86 had received IFN, 46 hydroxyurea, and 20 busulfan. Forty-eight patients (32%) had received transplants from unrelated donors. Median observation time after BMT was 4.7 (0.7 to 13.5) years. IFN and chemotherapy cohorts were compared with regard to transplantation risks, duration of treatments, interval from discontinuation of pretransplant treatment to BMT, conditioning therapy, graft-versus-host disease prophylaxis and risk profiles at diagnosis and transplantation, and IFN cohorts also with regard to performance and resistance to IFN. Outcome of patients receiving related or unrelated transplants pretreated with IFN, hydroxyurea, or busulfan was not significantly different. Five-year survival after transplantation was 58% for all patients (57% for IFN, 60% for hydroxyurea and busulfan patients). The outcome within the IFN group was not different by duration of prior IFN therapy more or less than 5 months, 1 year, or 2 years. In contrast, a different impact was observed in IFN-pretreated patients depending on the time of discontinuation of IFN before transplantation. Five-year survival was 46% for the 50 patients who received IFN within the last 90 days before BMT and 71% for the 36 patients who did not (P =.0057). Total IFN dosage had no impact on survival after BMT. We conclude that outcome after BMT is not compromised by pretreatment with IFN if it is discontinued at least 3 months before transplantation. Clear candidates for early transplantation should not be pretreated with IFN.

Impulse interval-dependent effect of sympathetic nerve stimulation on evoked acetylcholine release from the rabbit perfused atria preparation.

The aim of the present study was to explore possible prejunctional effects mediated by impulse activity of sympathetic terminals on evoked acetylcholine release in an organ innervated by the autonomic ground plexus. Rabbit atria were isolated with the extrinsic right vagus and sympathetic nerves intact and perfused with Tyrode solution. Acetylcholine overflow was determined after labelling of the transmitter stores with [14C]choline and fractionation of the radioactivity on cation exchange columns. The overflow of endogenous noradrenaline was measured by HPLC and electrochemical detection. The vagus nerve was stimulated at 2 Hz for 3 min four times at intervals of 10 min. During the second stimulation the postganglionic sympathetic nerves were stimulated (2 Hz, 3 min) in such a way that the impulses preceded the vagus stimuli by a fixed time interval which was varied in different experiments (0, 7, 19, 50, 132, and 350 ms). Evoked acetylcholine release was significantly enhanced when the vagus was excited 7, 19 and 50 ms after the sympathetic nerves but it was unaltered at the 132 or 350 ms intervals, and when both nerves were stimulated simultaneously. Noradrenaline release was similar (about 6 ng per stimulation period) in all experimental groups. When sympathetic nerve stimulation had little effect in releasing noradrenaline (< 2.0 ng per stimulation period), facilitation of acetylcholine release at the 19 ms pulse interval was absent. The resting outflow of acetylcholine was unaffected by sympathetic nerve stimulation. The experiments show a facilitation of evoked acetylcholine release by sympathetic activity. As revealed by the pulse-to-pulse method this effect is confined to a relatively brief interval immediately following the excitation of the noradrenergic terminal, and is unlikely to be mimicked by exogenous drug application.

Co-transmitter mediated facilitation by sympathetic nerve stimulation of evoked acetylcholine release from the rabbit perfused atria preparation.

Rabbit atria were isolated with the extrinsic right sympathetic and vagus nerves attached and perfused with Tyrode solution. Acetylcholine overflow was determined after labelling of the transmitter stores with [14C]choline and fractionation of the radioactivity on cation exchange columns. Sympathetic nerve stimulation (SNS, 2 Hz, 3 min) carried out together with vagus nerve stimulation (VNS, 2 Hz, 3 min), but each SNS pulse preceding a vagal one by 19 ms, caused a facilitation of acetylcholine overflow of about 60% versus independent controls in the absence of SNS. Antagonists of putative neurotransmitters were tested to find out the prejunctional mediator involved in the facilitation. The facilitation was not significantly reduced by prazosin, rauwolscine, idazoxan, or propranolol, excluding mediation by alpha- or beta-adrenoceptors. However, guanethidine abolished evoked noradrenaline release and facilitation, suggesting that it is due to a compound co-released with noradrenaline from postganglionic noradrenergic nerves. Pretreatment of rabbits with reserpine which reduced noradrenaline content of atria and SNS evoked overflow by 94% did not affect the facilitation of acetylcholine release which, due to the cardiostimulatory action of SNS being absent, resulted in enhanced depression of atrial force. We conclude that the facilitation is due to release of a reserpine-resistant co-transmitter from sympathetic nerves. Possible mediation of the facilitation by ATP through P2X- or P2Y-purinoceptors was excluded by ineffectiveness of alpha, beta-methylene ATP-preperfusion, of suramin and cibacron blue, respectively. However, the selective A2 adenosine receptor antagonist CP 66,713 reduced the facilitation by 25% whereas DPCPX (A1-selective) had no effect.(ABSTRACT TRUNCATED AT 250 WORDS)

[Indications for bipolar prosthesis in femoral neck fractures. A retrospective study of the prognosis in geriatric patients with bipolar prostheses with reference to the preoperative health status]. / Die Indikation zur Duokopfprothese bei Schenkelhalsfrakturen. Eine retrospektive Studie zur Prognose des geriatrischen Patienten mit Duokopfprothese unter Berücksichtigung des präoperativen Gesundheitszustandes.

In Germany the decision to implant a bipolar prosthesis in patients with femoral neck fracture depends mainly on the patient's age and general condition. Taking into account the clinical results to date, however, these criteria alone appear not to be adequate. In our hospital 182 patients were provided with a bipolar prosthesis between January 1986 and February 1989 after traumatic hip fracture. By June 1990, the end of this investigation, 56% had died. In a retrospective study of the 67 surviving patients 25 (6-48) months postoperatively, we found that the results obtained with this bipolar prosthesis were comparable to those seen with total hip endoprostheses according to the Harris hip function score and to radiological findings regarding the frequency of loose stems and protrusion. We also employed a standardized system to evaluate the clinical condition of each patient preoperatively as well as the intra- and postoperative complications. These clinical data were compared with the postoperative survival and the Harris hip score. We found: (1) Good to excellent results in 45% (greater than 80 points), satisfactory results in 52% (51-80 points) and poor results in 3% after a period of up to 48 months. Good to excellent functional results were frequently obtained in healthy older patients. (2) Life expectancy in our group of 182 patients was shorter than in the normal population of the same age. (3) The reduced life expectancy was not attributable to the fracture trauma or the operation but rather to preexisting unrelated causes. In fact the fracture trauma itself often appeared to be a result of the patient's preexisting bad health.(ABSTRACT TRUNCATED AT 250 WORDS)

A presynaptic excitatory M1 muscarine receptor at postganglionic cardiac noradrenergic nerve fibres that is activated by endogenous acetylcholine.

Rabbit atria were isolated with the extrinsic right vagus and sympathetic nerves intact and perfused with Tyrode solution. Noradrenaline overflow evoked by sympathetic nerve stimulation (SNS) at 3 Hz for 3 min was determined before, during, and after vagus nerve stimulation (VNS), also at 3 Hz and for 3 min. The VNS pulses preceded the SNS pulses by 3, 100 and 233 ms. Acetylcholine overflow was determined after labelling of the transmitter stores with [14C]choline. Pirenzepine 80 nmol/l failed to alter the muscarinic inhibition of noradrenaline overflow when the vago-sympathetic impulse intervals were 3 and 233 ms. At an interval of 100 ms VNS did not significantly inhibit noradrenaline overflow in the absence of pirenzepine but produced an inhibition in the presence of the drug. When the pirenzepine concentration was varied (0.4-300 nmol/l) the largest inhibition of noradrenaline overflow was observed at 5.7 nmol/l whereas 300 nmol/l fully antagonized the inhibition. Acetylcholine overflow evoked by VNS was not altered by pirenzepine 0.4-300 nmol/l. AF-DX 116 (11-[(2[(diethylamino)methyl]-1-piperidinyl)-acetyl]-5, 11-dihydro-6H-pyrido-[2,3-b]-[1,4]benzodiazepine-6-one), an M2 receptor selective antagonist, concentration-dependently (100-800 nmol/l) inhibited the decrease of tension development elicited by VNS. At the 100 ms vago-sympathetic impulse interval noradrenaline overflow was enhanced in the presence of AF-DX 116 400 and 800 nmol/l. However, already 100 nmol/l of the drug caused a maximum (fourfold) increase of acetylcholine overflow. It is concluded that acetylcholine released onto noradrenergic nerve fibres causes a small facilitation of noradrenaline overflow at a vago-sympathetic impulse interval of 100 ms.(ABSTRACT TRUNCATED AT 250 WORDS)

Short- and long-latency muscarinic inhibition of noradrenaline release from rabbit atria induced by vagal stimulation.

1. The influence of the time interval between vagal and sympathetic nerve stimuli on the magnitude of muscarinic inhibition of noradrenaline release was studied in the isolated perfused rabbit atria preparation. The transmitter stores were labelled with [14C]choline and [3H]noradrenaline. 2. The right cardiac postganglionic sympathetic nerves were stimulated at 3 Hz for 3 min three times at intervals of 10 min. The [3H]noradrenaline outflow evoked by the second stimulation equalled the averaged means of the log values of amine outflows evoked by the first and third stimulations. 3. During the second sympathetic stimulation the right vagus nerve was stimulated (3 Hz, 3 min) in such a way that the impulses preceded the sympathetic stimuli by a fixed time interval varying within the range 0.3-283 ms. Outflow of [3H]noradrenaline was then compared with the individual 'expected value' calculated from the first and the third nerve stimulations. 4. [3H]Noradrenaline outflow was significantly decreased when the sympathetic impulses were delayed for between 3 and 10 ms or between 200 and 283 ms with respect to the vagus impulses. No significant inhibition of [3H]noradrenaline outflow occurred with delay times between 0.3 and 1.7 or 30 and 167 ms. Acetylcholine release was unaffected by varying the impulse delay time. 5. Atropine (1-300 nM) decreased and eventually abolished vagally mediated inhibition of [3H]noradrenaline outflow at both the 3 and 233 ms impulse delay periods and the evoked outflow of [14C]choline and [14C]acetylcholine was then approximately doubled. No enhancement of [3H]noradrenaline outflow was observed at an intermediate impulse delay time (100 ms) in the presence of atropine. 6. In the presence of (+)-tubocurarine (10 microM) [3H]noradrenaline outflow was unaffected by vagal stimulation at either the short or the long impulse delay time whereas that of [14C]choline and [14C]acetylcholine dropped to 3.4% (short) and 4.6% (long) of the control values. 7. Allowing for estimated conduction times in the vagal and sympathetic nerve pathways, the initial peak of muscarinic inhibition of noradrenaline release corresponds with excitation of the terminal cholinergic fibres occurring 20 ms before their adrenergic counterparts. A 'silent period' follows and then a second phase of muscarinic presynaptic inhibition occurs, peaking 250 ms after excitation of the cholinergic nerve terminals and levelling off completely within 100 ms. 8. It is concluded that both inhibitory peak responses are caused by a single volley of acetylcholine that affects two separate populations of muscarinic receptors.(ABSTRACT TRUNCATED AT 400 WORDS)

The choice to end life as a ventilator-dependent quadriplegic.

A 17-year-old male sustained a C5/6 fracture dislocation and complete C5 quadriplegia in a diving accident. Three days later sensory and motor function deteriorated and he required mechanical ventilation. Surgical exploration found no cause and a fusion was done. Neurologic function stabilized after three weeks with a C1 sensory level, no neck movement, and slight weakness of the tongue. Patient and family were followed closely by the spinal cord injury rehabilitation team from onset of injury. The patient was transferred to the ventilator-dependent pediatric rehabilitation program after ten weeks. Bowel, bladder, skin, and nutritional management were stabilized and taught to his parents who remained with him constantly. Communication was achieved with a "talking tracheostomy." He learned to use "Sip-n-Puff" control for driving an electric wheelchair and for Morse code input to a computer. He was passive but cooperative during hospitalization. Eight months after injury he was discharged to his home, which had been modified to meet his needs. A computer word processor, environmental control unit, and modified van were obtained; nursing care was provided around the clock. The patient enrolled in a community college course. Soon after discharge he contacted an attorney to explore legal actions for ending his life, which he considered intolerable. After obtaining medical and psychiatric reports, a court order was issued, which established his legal competence and directed people taking care of him to follow his directions. A few weeks later, 25 months after his injury, he privately said goodbye to his family, asked to be disconnected from the ventilator, and died. Medical and legal issues raised by this case are discussed.

Glucocorticoid-induced lymphoma cell death: the good and the evil.

Glucocorticoid hormones and their synthetic derivatives are widely used in therapy due to their strong anti-inflammatory and immunosuppressive potential. While the molecular basis of the anti-inflammatory action is to date at least partially understood, knowledge regarding the mechanism underlying glucocorticoid effects on the immune system is rather fragmentary. The immunosuppression could be attributed to at least two distinct processes: inhibition of the production of growth mediators and glucocorticoid-induced cell death. The mechanism of glucocorticoid-induced cell death can be divided into two steps, a reversible growth inhibition and cell lysis. The first step is characterized by many metabolic alterations typical of the catabolic potential of corticosteroids. After a delay of several hours activation of an endonuclease appears to initiate the lytic phase. By the action of this endonuclease the DNA is fragmented. In opposition to the chromatin damage, poly(ADP-ribosyl)ation is activated in order to stabilize the chromatin structure until the antagonistic potential is exhausted and the cells die. Therefore it can be speculated that the lethal event in glucocorticoid-induced cell death is a destruction of the regular chromatin structure.

The effect of physostigmine on the vagally induced muscarinic inhibition of noradrenaline release from the isolated perfused rabbit atria.

1. Presynaptic cholinergic-adrenergic interactions were studied on isolated perfused rabbit atria with the extrinsic right vagus and sympathetic innervation intact. The transmitter stores were labelled with 14C-choline and 3H-noradrenaline. The radioactive compounds were separated on columns and determined by scintillation spectrometry. The stimulation-evoked overflow of both transmitters was calcium-dependent and abolished by tetrodotoxin. 2. Methacholine caused a concentration-dependent decrease of atrial tension development and 3H-noradrenaline overflow evoked by 3 Hz sympathetic stimulation. Vagus nerve stimulation (1-20 Hz), although nearly abolishing tension development at 20 Hz, decreased evoked 3H-noradrenaline overflow by not more than 18%. 3. Physostigmine decreased atrial cholinesterase activity by 80% and increased the fraction of stimulation-evoked unhydrolyzed 14C-acetylcholine in the persufates from 58 to 86%. However, the inhibition by vagus stimulation (1-10 Hz) of evoked 3H-noradrenaline overflow was smaller than in the absence of the drug. This was closely related to a decrease in acetylcholine overflow. Yet for a give fractional rate of acetylcholine release the muscarinic inhibition of noradrenaline overflow still did not exceed that observed in the absence of physostigmine. 4. It is concluded that the vagally induced control of noradrenaline release occurs at discrete sites rather than in a diffuse pattern at multiple terminal axon sites as is the case after exogenous muscarinic agonists.