Genetic or acquired deficits in norepinephrine inactivation may underlie hyperadrenergic states that lead to orthostatic intolerance.

A long-term reduction in mean IOP occurred in PFX eyes with and without glaucoma. The IOP reduction was proportional to the preoperative IOP; higher preoperative IOP was associated with a greater reduction in IOP. Glaucoma progression in both groups was low, suggesting a protective effect of phacoemulsification on IOP in these eyes.

The responses of the pancreatic ␣-and ␤-cells to small changes in glucose were examined in overnight-fasted conscious dogs. Each study consisted of an equilibration (-140 to -40 min), a control (-40 to 0 min), and a test period (0 to 180 min), during which BAY R3401 (10 mg/kg), a glycogen phosphorylase inhibitor, was administered orally, either alone to create mild hypoglycemia or with peripheral glucose infusion to maintain euglycemia or create mild hyperglycemia. Drug administration in the hypoglycemic group decreased net hepatic glucose output (NHGO) from 8.9 ± 1.7 (basal) to 6.0 ± 1.7 and 5.8 ± 1.0 µmol · kg -1 · min -1 by 30 and 90 min. As a result, the arterial plasma glucose level decreased from 5.8 ± 0.2 (basal) to 5.2 ± 0.3 and 4.4 ± 0.3 mmol/l by 30 and 90 min, respectively (P < 0.01). Arterial plasma insulin levels and the hepatic portalarterial difference in plasma insulin decreased (P < 0.01) from 78 ± 18 and 90 ± 24 to 24 ± 6 and 12 ± 12 pmol/l over the first 30 min of the test period and decreased to 18 ± 6 and 0 pmol/l by 90 min, respectively. The arterial glucagon levels and the hepatic portal-arterial difference in plasma glucagon increased from 43 ± 5 and 4 ± 2 to 51 ± 5 and 10 ± 5 ng/l by 30 min (P < 0.05) and to 79 ± 16 and 31 ± 15 ng/l by 90 min (P < 0.05), respectively. In euglycemic dogs, the arterial plasma glucose level remained at 5.9 ± 0.1 mmol/l, and the NHGO decreased from 10 ± 0.6 to -3.3 ± 0.6 µmol · kg -1 · min -1 (180 min). The insulin and glucagon levels and the hepatic portal-arterial differences remained constant. In hyperglycemic dogs, the arterial plasma glucose level increased from 5.9 ± 0.2 to 6.2 ± 0.2 mmol/l by 30 min, and the NHGO decreased from 10 ± 1.7 to 0 µmol · kg -1 · min -1 by 30 min. The arterial plasma insulin levels and the hepatic portal-arterial difference in plasma insulin increased from 60 ± 18 and 78 ± 24 to 126 ± 30 and 192 ± 42 pmol/l by 30 min, after which they averaged 138 ± 24 and 282 ± 30 pmol/l, respectively. The arterial plasma glucagon levels and the hepatic portal-arterial difference in plasma glucagon decreased slightly from 41 ± 7 and 4 ± 3 to 34 ± 7 and 3 ± 2 ng/l during the test period. These data show that the ␣-and ␤-cells of the pancreas respond as a coupled unit to very small decreases in the plasma glucose level. Diabetes 50:367-375, 2001 G lucagon secretion increases in response to a decrease in the plasma glucose concentration and decreases in response to a rise in the plasma glucose level. Furthermore, insulin has been postulated to exert a paracrine influence on glucagon secretion when its release is modified in response to changes in the plasma glucose concentration. To date, studies have not provided a complete understanding of the relationship between a decrement in the plasma glucose level and glucagon or insulin secretion, because the insulin level itself has been elevated to decrease the glucose level, and insulin per se can affect not only its own secretion (1), but also the release of other counterregulatory hormones, inclu...

Orthostatic intolerance (OI) or postural tachycardia syndrome (POTS) is a syndrome primarily affecting young females, and is characterized by lightheadedness, palpitations, fatigue, altered mentation, and syncope primarily occurring with upright posture and being relieved by lying down. There is typically tachycardia and raised plasma norepinephrine levels on upright posture, but little or no orthostatic hypotension. The pathophysiology of OI is believed to be very heterogeneous. Most studies of the syndrome have focused on abnormalities in norepinephrine release. Here the hypothesis that abnormal norepinephrine transporter (NET) function might contribute to the pathophysiology in some patients with OI was tested. In a proband with significant orthostatic symptoms and tachycardia, disproportionately elevated plasma norepinephrine with standing, impaired systemic, and local clearance of infused tritiated norepinephrine, impaired tyramine responsiveness, and a dissociataion between stimulated plasma norepinephrine and DHPG elevation were found. Studies of NET gene structure in the proband revealed a coding mutation that converts a highly conserved transmembrane domain Ala residue to Pro. Analysis of the protein produced by the mutant cDNA in transfected cells demonstrated greater than 98% reduction in activity relative to normal. NE, DHPG/NE, and heart rate correlated with the mutant allele in this family. Conclusion: These results represent the first identification of a specific genetic defect in OI and the first disease linked to a coding alteration in a Na+/Cl−‐dependent neurotransmitter transporter. Identification of this mechanism may facilitate our understanding of genetic causes of OI and lead to the development of more effective therapeutic modalities.

Recently, several studies have reported an association between anxiety traits, affective disorders and autism and alleles of a functional promoter polymorphism (5HTT-LPR) in the human serotonin transporter (5HTT, SERT). [1][2][3] The mechanistic basis for allelic differences in transporter transcription are presently unknown. To explore this issue, we cloned the human 5HTT promoter region from a PAC genomic library 4 and now describe an unreported 381-bp insert between the polymorphic region and the transcription start site. We verified the presence of this novel sequence by Southern hybridization of genomic digests and PCR amplifications from multiple unrelated individuals. Sequence analysis of the novel region reveals a number of canonical transcription factor binding sites (eg AP1, Elk1, NF B) that may be important in controlling the response of the 5HTT gene to regulatory factors. PCR studies of genomic templates reveal a low level of amplification of a deleted template matching the size of the originally reported 5HTT promoter. This deleted template is absent from PAC amplifications, suggesting that the human 5HTT promoter may exhibit in vivo instability. Molecular Psychiatry (2000) 5, 110-115.

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