Perturbation of copper (Cu) homeostasis and expression of Cu-binding proteins in cadmium-resistant lung fibroblasts.

To probe mechanisms of cadmium (Cd) damage to the lung extracellular matrix (ECM), we developed Cd-resistant (CdR) rat lung fibroblasts (RFL6) by incubation with graded concentrations of Cd. CdR cells downregulated lysyl oxidase (LO), a copper (Cu)-dependent enzyme essential for crosslinking of collagen and elastin in the ECM, in conjunction with upregulation of other Cu-binding proteins including Cu,Zn-superoxide dismutase (SOD1), copper chaperone for SOD1 (CCS1), metallothionein (MT), and Menkes P-type ATPase (ATP7A), a Cu transporter in the membrane of the Golgi apparatus, as well as gamma-glutamylcysteine synthetase (gamma-GCS), an enzyme for glutathione biosynthesis. Reduction and loss of cytoplasmic distribution of LO in CdR cells were accompanied by its dislocation with the Menkes P-type ATPase and the endoplasmic reticulum marker. CdR cells displayed a defect in LO catalytic activity but an enhancement in Cu,Zn-SOD catalytic activity consistent with the protein expression levels of these enzymes. Although long-term Cd exposure of cells enhanced the Menkes P-type ATPase protein expression, actually, it reduced Cu-dependent catalytic activity of this enzyme in parallel with the deficiency of LO. The low level of 64Cu bound to the LO fraction and the high level of 64Cu bound to the MT fraction provide direct evidence for limitation of Cu bioavailability for LO existing in the CdR cells. These results suggest that downregulation of LO is linked with upregulation of other Cu-binding proteins and with alteration in Cu homeostasis in the CdR phenotype.     

Nursing as science: a critical question.

Nursing is a profound human activity generally influenced by two dynamics--the relationship between patient and nurse and the scientific paradigm. Often overlooked, however, are the incongruities that arise between these two dynamics. The patient-nurse relationship encompasses sameness, closeness, and connection, whereas science requires distance, detachment, and differentiation to fulfil the demands of objectivity. The patient-nurse relationship is both profound and intangible, whereas science attends only to that which can be observed and measured. The authors explore these dynamics and the incongruities between them. They consider the demands made by science on the patient-nurse relationship and, conversely, the place of the patient-nurse relationship in the development of nursing as science. These issues are critical to the advancement and practice of nursing.     

Genetic approach to male meiotic division deficiency: the human macronuclear spermatozoa.

Human macronuclear spermatozoa (also termed large-headed or macrocephalic spermatozoa) are tetraploid and represent a mammalian model of meiotic division deficiency (MDD). Their genetic origin is strongly suggested by the existence of familial cases. They arise from spermatocytes I with a blockage of organelle displacement at the pachytene stage which disables the assembly of a bipolar meiotic spindle. Spermiogenesis can sometimes be complete, showing that meiotic divisions and spermiogenesis can be decoupled. However, the microtubular manchette is unilateral leading to an irregular sperm nucleus. A severe MDD phenotype also exhibits atrophic flagella. Another MDD phenotype is characterized by arrest at the round spermatid stage, suggesting the existence of factors coordinating meiosis and spermatid differentiation. An attempt is made herein to understand why MDD spermatocytes escape the pachytene and spindle-assembly checkpoints. These human MDD are revisited in the light of Drosophila mutants for cell cycle factors, meiosis division-promoting factors and microtubule components. Several human genes are known to be homologous to genes involved in male MDD in Drosophila mutants, and their number will soon be increased. These candidate genes open the way to investigation of human genes possibly mutated in patients with macronuclear spermatozoa and/or macronuclear spermatids.     

General practitioners: child accident prevention and 'The Health of the Nation'

It has recently been suggested in the ‘Health of the Nation’that specific accident prevention activities should be undertakenby general practitioners. This study reports the findings froma survey of general practitioners in Nottinghamshire assessingknowledge, attitudes and current practices in accident prevention.The findings suggest that more than two-thirds of respondinggeneral practitioners are aware of the extent of childhood mortalityfrom accidental injuries and of the risk factors for accidentalinjury. Knowledge scores were higher for women, those aged 44years and under, those on the child health surveillance list,those with experience of hospital or community paediatrics,and those with postgraduate qualifications in paediatrics. Morethan 50% of general practitioners hold positive views towardsthe activities suggested in the ‘Health of the Nation’and more than 40% are already carrying out such activities.Positive attitudes are more commonly held in women and thoseon the child health surveillance list. There was a significantcorrelation between knowledge score and attitude score. Forall accident prevention activities covered in the questionnaire,fewer practitioners undertook an activity than held a positiveattitude towards that activity. Accident prevention work iscurrently more likely to be undertaken by general practitionerson an opportunistic basis than on a systematic population basis.If general practitioner intervention is demonstrated to be effective,a shift towards a population approach may be more successfulin reducing injury rates.     

Electrophysiological Signs of Neurocognitive Deficits in Long-Term Leukemia Survivors

The long-term effects of disease and treatment on electrophysiologicalmeasures of neurocognitive function were studied in childrenwho had survived acute lymphoblastic leukemia (ALL) for at least4 years and were currently in remission. We report here changesin cognitive processing time as shown by the latency of theP3 wave of the auditory event-related EEG potential (ERP). P3latency was significantly prolonged in long-term ALL surivors,as well as in patients successfully trreated for solid tumors(ST)outside the CNS who received similar chemotherapy but did notreceive prophylactic treatment to the CNS. P3 latencies werestrongly correlated with measures of school performance andIQ in these individuals. The similarity in P3 latency betweenthe ALL and ST groups suggests that the treatments used on thesepateints produce changes in electrophysiological responses thatare associated with mild, but significant, cognitive deficits.     

A randomized clinical trial with a 0.6% amino acid/ 1.4% glycerol peritoneal dialysis solution.

BACKGROUND: Glucose is an accepted osmotic agent for peritoneal dialysis (PD) although it has several drawbacks. Some of these drawbacks have been addressed by the introduction of solutions with low glucose degradation products and physiological pH in dual-chambered bags. Despite this achievement, there is a need for alternative osmotic agents.This randomized clinical trial analyzes 3-month's clinical experience with a mixture of 0.6% amino acids and 1.4% glycerol. METHODS: The study was performed at the renal units of the University Hospitals Ghent, Belgium, and Utrecht, The Netherlands. Stable PD patients were randomized for either protocol A (test solution, n = 5) or protocol B (control regimen, n = 5). In both protocols, there was a run-in phase of 1 month with a dialysis regimen of 2 x 2 L 2.27% glucose solution (Dianeal; Baxter, Nivelles, Belgium), 1 x 2 L Extraneal (Baxter), and 1 x 2 L glucose solution (Dianeal). After this month-long run-in period, patients in group A received during 3 months 2 x 2 L amino acid/glycerol solution, 1 x 2 L Extraneal, and at least 1 x 2 L of a classic glucose solution. RESULTS: Glucose absorption decreased in the test group during the test phase (from 84.2 +/- 8.7 to 11.7 +/- 11.6 g/24 hours, p = 0.001). Dialysate levels of cancer antigen 125 (CA125) increased in the test group, from 17.5 +/- 11.0 to 32.4 +/- 4.6 units/L (p = 0.04), whereas, in the control group, the levels remained stable (15.5 +/- 8.7 and 14.9 +/- 9.8 units/L respectively, p = 0.4).There were no differences in serum urea, serum bicarbonate, serum osmolarity, serum albumin, or parameters related to skin-fold thickness or serum glycerol levels between control and test solutions. No differences were observed in obtained ultrafiltration after a 4-hour dwell with 2.27% glucose or the test solution, both measured at week 4 of the run-in period and week 12 of the test period. CONCLUSION: This study demonstrated that the use of a new 0.6% amino acid/1.4% glycerol-containing dialysis solution is safe and well tolerated. Glucose load was reduced significantly and dialysate CA125 levels improved significantly. Ultrafiltration was comparable with that of a 2.27% glucose solution. All these factors, in combination with the potential nutritional benefits, can contribute to a beneficial impact on the success of the PD technique. Further long-term studies in larger patient groups are warranted to explore the potential of this promising new solution.     

Elevated serotonin transporter binding in major depressive disorder assessed using positron emission tomography and [11C]DASB; comparison with bipolar disorder.

BACKGROUND: Altered serotonergic function is thought to play a role in the pathophysiology of major depressive episodes based upon evidence from neuroimaging, pharmacological, postmortem and genetic studies. It remains unclear, however, whether depressed samples that differ with respect to having shown a unipolar versus a bipolar illness course also would show distinct patterns of abnormalities within the serotonergic system. The current study compared serotonin transporter (5-HTT) binding between unipolar-depressives (MDD), bipolar-depressives (BD) and healthy-controls (HC) to assess whether the abnormalities in 5-HTT binding recently found in depressed subjects with BD extend to depressed subjects with MDD. METHODS: The 5-HTT binding-potential (BP) measured using positron emission tomography (PET) and [(11)C]DASB was compared between unmedicated, depressed subjects with MDD (n = 18) or BD (n = 18) and HC (n = 34). RESULTS: Relative to the healthy group both MDD and BD groups showed significantly increased 5-HTT BP in the thalamus (24%, 14%, respectively), insula (15%) and striatum (12%). The unipolar-depressives had elevated 5-HTT BP relative to both BD and HC groups in the vicinity of the periaqueductal gray (PAG, 20%, 22%, respectively). The bipolar-depressives had reduced 5-HTT BP relative to both HC and MDD groups in the vicinity of the pontine raphe nuclei. Depression-severity correlated negatively with 5-HTT BP in the thalamus in MDD-subjects. CONCLUSIONS: The depressed phases of MDD and BD both were associated with elevated 5-HTT binding in the insula, thalamus and striatum, but showed distinct abnormalities in the brainstem. The latter findings conceivably could underlie differences in the patterns of illness symptoms and pharmacological sensitivity observed between MDD and BD.