In monoaminergic neurons, the vesicular transporters and the plasma membrane transporters operate in a relay. Amphetamine and its congeners target this relay to elicit their actions: most amphetamines are substrates, which pervert the relay to elicit efflux of monoamines into the synaptic cleft. However, some amphetamines act as transporter inhibitors. Both compound classes elicit profound psychostimulant effects, which render them liable to recreational abuse. Currently, a surge of new psychoactive substances occurs on a global scale. Chemists bypass drug bans by ingenuous structural variations, resulting in a rich pharmacology. A credible transport model must account for their distinct mode of action and link this to subtle differences in activity and undesired, potentially deleterious effects.

In contrast to its close homolog CDK4, the cell cycle kinase CDK6 is expressed at high levels in lymphoid malignancies. In a model for p185BCR-ABL+ B-acute lymphoid leukemia, we show that CDK6 is part of a transcription complex that induces the expression of the tumor suppressor p16INK4a and the pro-angiogenic factor VEGF-A. This function is independent of CDK6's kinase activity. High CDK6 expression thus suppresses proliferation by upregulating p16INK4a, providing an internal safeguard. However, in the absence of p16INK4a, CDK6 can exert its full tumor-promoting function by enhancing proliferation and stimulating angiogenesis. The finding that CDK6 connects cell-cycle progression to angiogenesis confirms CDK6's central role in hematopoietic malignancies and could underlie the selection pressure to upregulate CDK6 and silence p16INK4a.

To evaluate the effect of recurrent nerve dissection on the incidence of recurrent laryngeal nerve injury (RLNI) and to analyze the performance of individual surgeons. Dissection of the recurrent nerve is mandatory in total thyroidectomy, but its relative merit in less extensive resections is not clear. The reported rates of RLNI differ widely; this may reflect a variation in the performance of individual surgeons. The authors studied the incidence of RLNI in primary surgery for benign thyroid disease during three periods in a single center. In period 1 (1979–1990; 9,385 consecutive patients, 15,865 nerves at risk), the recurrent nerve was not exposed. In period 2 (1991–1998; 6,128 patients, 10,548 nerves at risk), dissection of the recurrent nerve was the standard procedure. Global outcome and individual performance in these two periods were compared and presented to the surgeons. The effect of this quality control procedure was tested in 1999 (period 3; 930 patients, 1,561 nerves at risk). Exposure of the recurrent nerve significantly reduced the global rate of postoperative and permanent RLNI. Some but not all surgeons improved their results by recurrent nerve dissection (e.g., permanent RLNI rates ranged from 0% to 1.1%). The documented significant differences in individual performances did not affect the outcome in period 3. The extent of nerve dissection was a source of variability; the rate of permanent RLNI averaged 0.9%, 0.3%, and 0.1% for surgeons who only localized, partially exposed, and completely dissected the recurrent nerve, respectively. Recurrent nerve dissection significantly reduces the risk of RLNI. Extensive dissection facilitates visual control of nerve integrity during resection and is therefore superior to a more limited exposure of the nerve. Quality control can improve the global outcome and identify the variability in individual performance. This cannot be eliminated by merely confronting surgeons with comparative data; hence, it is important to search for the underlying causes.

We evaluated the ability of neuromonitoring to predict postoperative outcome in patients undergoing thyroid surgery for different indications. Neuromonitoring has been advocated to reduce the risk of vocal cord palsy and to predict postoperative vocal cord function. Three hundred twenty-eight patients (502 nerves at risk) were studied prospectively at a single center. Neuromonitoring was performed with the Neurosign 100® device by transligamental placement of the recording electrode into the vocalis muscles. Cumulative distribution of stimulation thresholds was determined by stepwise decreases in current (1 mA to 0.05 mA) for both the vagus and the recurrent nerve. Patients were grouped according to surgical risk (benign and malignant disease, reoperation for benign and for malignant disease). If the electrophysiological response was correlated to postoperative vocal cord function, the sensitivity of neuromonitoring was modest (86% in surgery for benign disease) to low (25% in reoperation for malignant disease); the positive predictive value was modest (overall rate 62%) but acceptable (87%) if corrected for technical problems. Specificity and negative predictive values were high (ie, overall >95%). Stimulation thresholds were not augmented in 11 patients, in whom postoperative palsy developed despite normal intraoperative recordings. Similarly, an electrical field response was elicited in 14 of 21 patients with preoperative vocal cord palsy. Electromyographic recordings did not reveal an abnormal amplitude or a decline in nerve conduction velocity. Neuromonitoring is useful for identifying the recurrent laryngeal nerve, in particular if the anatomic situation is complicated by prior surgery, large tissue masses, aberrant nerve course. However, neuromonitoring does not reliably predict postoperative outcome.

Recent biochemical studies indicate that the serotonin transporter can form oligomers. We investigated whether the human serotonin transporter (hSERT) can be visualized as an oligomer in the plasma membrane of intact cells. For this purpose, we generated fusion proteins of hSERT and spectral variants of the green fluorescent protein (cyan and yellow fluorescent proteins, CFP and YFP, respectively). When expressed in human embryonic kidney 293 cells, the resulting fusion proteins (CFP-hSERT and YFP-hSERT) were efficiently inserted into the plasma membrane and were functionally indistinguishable from wild-type hSERT. Oligomers were visualized by fluorescence resonance energy transfer microscopy in living cells using two complementary methods, i.e. ratio imaging and donor photobleaching. Interestingly, oligomerization was not confined to hSERT; fluorescence resonance energy transfer was also observed between CFP- and YFP-labeled rat γ-aminobutyric acid transporter. The bulk of serotonin transporters was recovered as high molecular weight complexes upon gel filtration in detergent solution. In contrast, the monomers of CFP-hSERT and YFP-hSERT were essentially undetectable. This indicates that the homo-oligomeric form is the favored state of hSERT in living cells, which is not significantly affected by coincubation with transporter substrates or blockers. Based on our observations, we conclude that constitutive oligomer formation might be a general property of Na⁺/Cl⁻-dependent neurotransmitter transporters.