Phospholipid flipping involves a central cavity in P4 ATPases.

P4 ATPase flippases translocate phospholipids across biomembranes, thus contributing to the establishment of transmembrane lipid asymmetry, a feature important for multiple cellular processes. The mechanism by which such phospholipid flipping occurs remains elusive as P4 ATPases transport a giant substrate very different from that of other P-type ATPases such as Na+/K+- and Ca2+-ATPases. Based on available crystal structures of cation-transporting P-type ATPases, we generated a structural model of the broad-specificity flippase ALA10. In this model, a cavity delimited by transmembrane segments TM3, TM4, and TM5 is present in the transmembrane domain at a similar position as the cation-binding region in related P-type ATPases. Docking of a phosphatidylcholine headgroup in silico showed that the cavity can accommodate a phospholipid headgroup, likely leaving the fatty acid tails in contact with the hydrophobic portion of the lipid bilayer. Mutagenesis data support this interpretation and suggests that two residues in TM4 (Y374 and F375) are important for coordination of the phospholipid headgroup. Our results point to a general mechanism of lipid translocation by P4 ATPases, which closely resembles that of cation-transporting pumps, through coordination of the hydrophilic portion of the substrate in a central membrane cavity.

Flippases: still more questions than answers.

Our understanding of flippase-mediated lipid translocation and membrane vesiculation, and the involvement of P-type ATPases in these processes is just beginning to emerge. The results obtained so far demonstrate significant complexity within this field and point to major tasks for future research. Most importantly, biochemical characterization of P(4)-ATPases is required in order to clarify whether these transporters indeed are capable of catalyzing transmembrane phospholipid flipping. The beta-subunit of P(4)-ATPases shows unexpected similarities between the beta- and gamma-subunits of the Na+/K+-ATPase. It is likely that these proteins provide a similar solution to similar problems, and might have adopted similar structures to accomplish these tasks. No P(4)-ATPases have been identified in the endoplasmic reticulum and it remains an intriguing possibility that, in this compartment, P(5A)-ATPases are functional homologues of P(4)-ATPases.

Serum thyroglobulin in chronic renal failure--effects of haemodialysis.

The influence of chronic renal failure (CRF) on serum thyroglobulin concentration (Tg) was investigated in 37 patients (29 on haemodialysis) and compared with results obtained from matched controls. Serum Tg did not differ significantly between CRF patients not on haemodialysis: median 24.1 micrograms/l, (range 2.5-47.0) and controls: median 23.6 micrograms/l, (range 2.1-53.0). Patients on haemodialysis had a significantly lower serum Tg level: median 11.4 micrograms/l (range 2.1-54.0) compared to controls (p less than 0.01) but no change in serum Tg level could be demonstrated after a single haemodialysis. A possible explanation for the low serum Tg level in patients with CRF on haemodialysis is decreased production parallelling the decreased production rate of T4 and T3. Since CRF patients not on haemodialysis had an unchanged serum Tg level compared to controls, haemodialysis was associated with small changes in serum Tg level, and since none of the patients had a serum Tg value above the upper reference limit we conclude that these changes were not of a magnitude likely to cause misinterpretation of results in routine clinical situations.

Thyroid gland volume and serum concentrations of thyroid hormones in chronic renal failure.

Thyroid gland volume, ultrasonically determined, and thyroid function were investigated in 40 patients with chronic renal failure (33 of these on hemodialysis) and 40 sex-, age- and weight-matched healthy controls. None had thyroid autoantibodies or a clinically detectable goiter. The median thyroid gland volume was significantly elevated in the uremic patients: 24 ml (range 8-43 ml) compared with the healthy controls 17 ml (range 10-22 ml) (p less than 0.005). The serum concentrations of thyroxine (T4), triiodothyronine (T3), free thyroxine index (FT4I) and free triiodothyronine index (FT3I) were significantly decreased in uremic subjects compared with the controls. The serum concentration of thyrotropin did not differ significantly between patients and controls. None of the thyroid function variables correlated with thyroid gland volume. In conclusion, thyroid gland volume was increased in patients with chronic renal failure. The alterations in thyroid hormone concentrations could, however, not explain this finding.

The determination of thyroid volume by ultrasound and its relationship to body weight, age, and sex in normal subjects.

Using a precise and accurate ultrasonic scanning technique we have measured the volume of the thyroid gland in vivo in 271 healthy subjects (13-91 yr old). In these subjects the mean (+/- SD) thyroid volume was 18.6 +/- 4.5 ml. A significant difference between males (19.6 +/- 4.7 ml; n = 139) and females (17.5 +/- 4.2 ml; n = 132) was found (P less than 0.001). The thyroid volume was significantly correlated with both body weight and age, described by: Y = 1.97 + 0.21 . x1 + 0.06 . x2, where Y is the thyroid volume (milliters), x1 is the body weight (kilograms), and x2 is the age (years). The influence of body weight on the thyroid volume was about 3 times that of age. The difference in thyroid gland volume between males and females was explained solely by a difference in body weight.

The influence of wound drainage on the infection rate in kidney transplant patients.

The frequency of wound infection was studied in 92 patients who had received cadaver kidneys. Wound drainage was performed in 26 patients and not performed in 66 patients. Wound infection was found in 31% of the wounds with drainage and in 14% of wounds without primary drainage. The results were compared with the frequency of 34% infected wounds in a previous report where wound drainage was performed routinely. It is advised that, when possible, wound drainage should be avoided.

The effect of blood-transfusions on renal allograft survival.

The relation between previous bloodtransfusions and renal allograft survival was studied retrospectively in 88 patients, who had been transplanted for the first time. The allograft survival rate was higher in the group who had received bloodtransfusion than in the group who had not. This difference was significantly greater when considering patients who had not previously been pregnant, e.g. patients without previous stimulation of the immuno system. The material shows no difference in allograft survival between previously transfused and non transfused patients, when considering age, sex or disease of kidney. In this retrospective study it is concluded that previous transfusions improved the prognosis of the transplantation. A prospective study has yet to be done, in order to enlighten the influence of various other factors on the allograft survival rate such as length of period or uraemia and of dialysis.