Mark S Gold, M.D.

Neuro-psychopharmacogenetics and Neurological Antecedents of Posttraumatic Stress Disorder: Unlocking the Mysteries of Resilience and Vulnerability
Bowirrat, Abdalla; Chen, Thomas J H; Blum, Kenneth; Madigan, Margaret; Bailey, John A; Chuan Chen, Amanda Lih; Downs, B William; Braverman, Eric R; Radi, Shahien; Waite, Roger L; Kerner, Mallory; Giordano, John; Morse, Siohban; Oscar-Berman, Marlene; Gold, Mark
2010 Dec;8(4):335-358, Current Neuropharmacology
BACKGROUND AND HYPOTHESIS: Although the biological underpinnings of immediate and protracted trauma-related responses are extremely complex, 40 years of research on humans and other mammals have demonstrated that trauma (particularly trauma early in the life cycle) has long-term effects on neurochemical responses to stressful events. These effects include the magnitude of the catecholamine response and the duration and extent of the cortisol response. In addition, a number of other biological systems are involved, including mesolimbic brain structures and various neurotransmitters. An understanding of the many genetic and environmental interactions contributing to stress-related responses will provide a diagnostic and treatment map, which will illuminate the vulnerability and resilience of individuals to Posttraumatic Stress Disorder (PTSD). PROPOSAL AND CONCLUSIONS: We propose that successful treatment of PTSD will involve preliminary genetic testing for specific polymorphisms. Early detection is especially important, because early treatment can improve outcome. When genetic testing reveals deficiencies, vulnerable individuals can be recommended for treatment with 'body friendly' pharmacologic substances and/or nutrients. Results of our research suggest the following genes should be tested: serotoninergic, dopaminergic (DRD2, DAT, DBH), glucocorticoid, GABAergic (GABRB), apolipoprotein systems (APOE2), brain-derived neurotrophic factor, Monamine B, CNR1, Myo6, CRF-1 and CRF-2 receptors, and neuropeptide Y (NPY). Treatment in part should be developed that would up-regulate the expression of these genes to bring about a feeling of well being as well as a reduction in the frequency and intensity of the symptoms of PTSD
— id: 138041, year: 2010, vol: 8, page: 335, stat: Journal Article,

Neurogenetics of dopaminergic receptor supersensitivity in activation of brain reward circuitry and relapse: proposing "deprivation-amplification relapse therapy" (DART)
Blum, Kenneth; Chen, Thomas J H; Downs, B William; Bowirrat, Abdalla; Waite, Roger L; Braverman, Eric R; Madigan, Margaret; Oscar-Berman, Marlene; DiNubile, Nicholas; Stice, Eric; Giordano, John; Morse, Siobhan; Gold, Mark
2009 Nov;121(6):176-196, Postgraduate medicine
BACKGROUND AND HYPOTHESIS: It is well known that after prolonged abstinence, individuals who use their drug of choice experience a powerful euphoria that often precipitates relapse. While a biological explanation for this conundrum has remained elusive, we hypothesize that this clinically observed 'supersensitivity' might be tied to genetic dopaminergic polymorphisms. Another therapeutic conundrum relates to the paradoxical finding that the dopaminergic agonist bromocriptine induces stronger activation of brain reward circuitry in individuals who carry the DRD2 A1 allele compared with DRD2 A2 allele carriers. Because carriers of the A1 allele relative to the A2 allele of the DRD2 gene have significantly lower D2 receptor density, a reduced sensitivity to dopamine agonist activity would be expected in the former. Thus, it is perplexing that with low D2 density there is an increase in reward sensitivity with the dopamine D2 agonist bromocriptine. Moreover, under chronic or long-term therapy with D2 agonists, such as bromocriptine, it has been shown in vitro that there is a proliferation of D2 receptors. One explanation for this relates to the demonstration that the A1 allele of the DRD2 gene is associated with increased striatal activity of L-amino acid decarboxylase, the final step in the biosynthesis of dopamine. This appears to be a protective mechanism against low receptor density and would favor the utilization of an amino acid neurotransmitter precursor like L-tyrosine for preferential synthesis of dopamine. This seems to lead to receptor proliferation to normal levels and results in significantly better treatment compliance only in A1 carriers. PROPOSAL AND CONCLUSION: We propose that low D2 receptor density and polymorphisms of the D2 gene are associated with risk for relapse of substance abuse, including alcohol dependence, heroin craving, cocaine dependence, methamphetamine abuse, nicotine sensitization, and glucose craving. With this in mind, we suggest a putative physiological mechanism that may help to explain the enhanced sensitivity following intense acute dopaminergic D2 receptor activation: 'denervation supersensitivity.' Rats with unilateral depletions of neostriatal dopamine display increased sensitivity to dopamine agonists estimated to be 30 to 100 x in the 6-hydroxydopamine (6-OHDA) rotational model. Given that mild striatal dopamine D2 receptor proliferation occurs (20%-40%), it is difficult to explain the extent of behavioral supersensitivity by a simple increase in receptor density. Thus, the administration of dopamine D2 agonists would target D2 sensitization and attenuate relapse, especially in D2 receptor A1 allele carriers. This hypothesized mechanism is supported by clinical trials utilizing amino acid neurotransmitter precursors, enkephalinase, and catechol-O-methyltransferase (COMT) enzyme inhibition, which have resulted in attenuated relapse rates in reward deficiency syndrome (RDS) probands. If future translational research reveals that dopamine agonist therapy reduces relapse in RDS, it would support the proposed concept, which we term 'deprivation-amplification relapse therapy' (DART). This term couples the mechanism for relapse, which is 'deprivation-amplification,' especially in DRD2 A1 allele carriers with natural D2 agonist therapy utilizing amino acid precursors and COMT and enkepalinase inhibition therapy
— id: 133751, year: 2009, vol: 121, page: 176, stat: Journal Article,

Dexmedetomidine does not increase the incidence of intracarotid shunting in patients undergoing awake carotid endarterectomy
Bekker, Alex; Gold, Mark; Ahmed, Raza; Kim, Jung; Rockman, Caron; Jacobovitz, Glenn; Riles, Thomas; Fisch, Gene
2006 Oct;103(4):955-958, Anesthesia & analgesia
Systemic administration of dexmedetomidine (DEX) decreases cerebral bloodflow (CBF) via direct alpha-2-mediated constriction of cerebral blood vessels and indirectly via its effect on the intrinsic neural pathway modulating vascular smooth muscle. Reduction in CBF without a concomitant decrease in cerebral metabolic rate has raised concerns that DEX may limit adequate cerebral oxygenation of brain tissue in patients with already compromised cerebral circulation (e.g., carotid endarterectomy [CEA]). In this study, we established the incidence of intraarterial shunting used as a sign of inadequate oxygen delivery in a consecutive series of 123 awake CEA performed in our institution using DEX as a primary sedative. Data were prospectively recorded in 151 patients who underwent CEA during the study period. Eighteen patients were sedated with midazolam and fentanyl (M/F) for medical or logistical reasons. Patients thought to be at risk of an intraoperative stroke were treated with a prophylactic intraarterial shunt. These patients, as well as those who required general anesthesia, were excluded from the final analysis. Five patients (4.3%) in the DEX group required intraarterial shunts. The incidence of shunting in patient undergoing awake CEA in our institution is 10% (historical control). No patients developed a stroke or other serious complications. It appears that the use of DEX as a primary sedative drug for CEA does not increase the incidence of intraarterial shunts
— id: 68990, year: 2006, vol: 103, page: 955, stat: Journal Article,

Dexmedetomidine as primary sedative in CEA patients - In reply
Bekker, A; Gold, M
2004 OCT ;16(4):320-321, Journal of neurosurgical anesthesiology
— id: 46484, year: 2004, vol: 16, page: 320, stat: Journal Article,

Dexmedetomidine for awake carotid endarterectomy: efficacy, hemodynamic profile, and side effects
Bekker, Alex Y; Basile, John; Gold, Mark; Riles, Thomas; Adelman, Mark; Cuff, Germaine; Mathew, Jomol P; Goldberg, Judith D
2004 Apr;16(2):126-135, Journal of neurosurgical anesthesiology
: A randomized, double-masked, placebo-controlled study was designed to compare dexmedetomidine as a primary sedative agent with a commonly used drug combination in patients undergoing awake carotid endarterectomy (CEA). Sixty-six patients undergoing CEA (ASA II-IV) were randomly assigned to receive either dexmedetomidine (total dose of 97.5 +/- 54.7 mcg) or normal saline (control). Supplemental doses of midazolam, fentanyl, and/or propofol were administered as deemed necessary by the anesthesiologist. An observer blinded to the study drug assessed sedation level (Observer's Assessment of Alertness-Sedation [OAA/S] scale). The primary outcomes were defined as the number of patients with an OAA/S score of 4 intraoperatively and an OAA/S score of 5 postoperatively. The authors also compared cardiorespiratory parameters, intra- and postoperative side effects, and complications. Chi-square tests were used to analyze the primary endpoints. All secondary parameters were analyzed using the Wilcoxon rank sum test. Three patients in the dexmedetomidine group (10%) had an OAA/S score of 4 at all four time points assessed intraoperatively, while no patient in the control group had a score of 4 at all the time points considered. Thirteen patients in the dexmedetomidine group had a score of 4 at three or more time points (42%) compared with six patients (19%) in the control group. Four patients in the control group (13%) and one patient in the dexmedetomidine group (3%) did not achieve a score of 4 at any of the four critical intraoperative time points (chi for association = 9.9, P < 0.05; chi for a trend = 8.6, P < 0.004, with the trend favoring dexmedetomidine). More patients in the control group required treatment with metoprolol (26% vs. 6%, P = 0.04) and labetalol (48% vs/ 6%, P < 0.01). Plasma levels of norepinephrine were significantly lower in the dexmedetomidine group during and after surgery compared with the control group. Six patients (19%) in the dexmedetomidine group required intra-arterial shunts, while only two patients (6%) required shunts in the control group (P = 0.16). These data show that the use of dexmedetomidine in patients undergoing awake CEA resulted in fewer fluctuations from the desired sedation level. Patients receiving dexmedetomidine required less antihypertensive therapy compared with the midazolam/fentanyl/propofol combination. The effect of dexmedetomidine on cerebrovascular circulation in the study population needs further investigation
— id: 43212, year: 2004, vol: 16, page: 126, stat: Journal Article,

Regional anesthesia in carotid surgery: technique and results
Imparato AM; Rockman CB; Riles TS; Gold M; Lamparello PJ; Giangola G; Ramirez A; Landis R
Perioperative monitoring in carotid surgery: methods, limits, and results: long-term results in carotid surgery Darmstadt : Steinkopff; Springer, 1998,
— id: 3379, year: 1998, vol: , page: ?, stat: Chapter,

Comparison of lumbar and thoracic epidural narcotics for postoperative analgesia in patients undergoing abdominal aortic aneurysm repair [see comments]
Gold MS; Rockman CB; Riles TS
1997 Apr;11(2):137-140, Journal of cardiothoracic & vascular anesthesia
OBJECTIVE: To determine whether there is an advantage of thoracic over lumbar epidural narcotics for postoperative analgesia in patients undergoing abdominal aortic aneurysm repair. DESIGN: A prospective randomized study. SETTING: Subjects were inpatients at an academic medical center. PARTICIPANTS: Fifty-two patients scheduled for elective abdominal aortic aneurysm repair. INTERVENTIONS: Subjects were randomly assigned to receive lumbar or thoracic epidural narcotics. Group 1 (n = 26) had lumbar, and group 2 (n = 26) had thoracic epidural catheters placed preoperatively. All patients were monitored with pulmonary artery catheters and arterial catheters, and had general endotracheal anesthesia, in addition to epidural anesthesia with 2% lidocaine. All patients received 5 mg of epidural morphine after intubation. Pain scores were monitored hourly for 36 hours using a visual analog scale, and additional narcotics were given, depending on the level of pain. Complications caused by epidural narcotics were recorded. RESULTS: There was no difference between groups as to the daily dose of narcotics or the time between narcotic doses. Hourly pain scores showed significant differences during hours 6, 7, 8, 20, 34, and 36, with pain scores being lower in group 1. There was no difference in the rate of complications between the groups. CONCLUSION: There is no advantage of thoracic over lumbar epidural analgesia using morphine in patients undergoing abdominal aortic aneurysm repair
— id: 7155, year: 1997, vol: 11, page: 137, stat: Journal Article,

Regional anesthesia for carotid endarterectomy
Riles TS; Gold MS; Lamparello PJ; Adelman MA
Management of extracranial cerebrovascular disease Philadelphia : Lippincott-Raven, 1997,
— id: 3455, year: 1997, vol: , page: 111, stat: Chapter,

The use of transcranial doppler to assess the need for shunt placement in awake patients undergoing carotid endarterectomy
Cutler, WM; Gold, MS; Kanchuger, MS
1996 APR ;82(4):SCA64-SCA64, Anesthesia & analgesia
— id: 53010, year: 1996, vol: 82, page: SCA64, stat: Journal Article,

Alternatives to general anesthesia for carotid endarterectomy
Riles TS; Gold MS
Surgery for cerebrovascular disease Philadelphia : W.B. Saunders, 1996,
— id: 3456, year: 1996, vol: , page: 338, stat: Chapter,

A comparison of regional and general anesthesia in patients undergoing carotid endarterectomy
Rockman CB; Riles TS; Gold M; Lamparello PJ; Giangola G; Adelman MA; Landis R; Imparato AM
1996 Dec;24(6):946-953, Journal of vascular surgery
PURPOSE: The optimal anesthetic for use during carotid endarterectomy is controversial. Advocates of regional anesthesia suggest that it may reduce the incidence of perioperative complications in addition to decreasing operative time and hospital costs. To determine whether the anesthetic method correlated with the outcome of the operation, a retrospective review of 3975 carotid operations performed over a 32-year period was performed. METHODS: The records of all patients who underwent carotid endarterectomy at our institution from 1962 to 1994 were retrospectively reviewed. Operations performed with the patient under regional anesthesia were compared with those performed with the patient under general anesthesia with respect to preoperative risk factors and perioperative complications. RESULTS: Regional anesthesia was used in 3382 operations (85.1%). There were no significant differences in the age, gender ratio, or the rates of concomitant medical illness between the two patient populations. The frequency of perioperative stroke in the series was 2.2%; that of myocardial infarction, 1.7%; and that of perioperative death, 1.5%. There were no statistically significant differences in the frequency of perioperative stroke, myocardial infarction, or death on the basis of anesthetic technique. A trend toward higher frequencies of perioperative stroke (3.2% vs 2.0%) and perioperative death (2.0% vs 1.4%) in the general anesthesia group was noted. In examining operative indications, however, there was a significant increase in the percentage of patients receiving general anesthesia who had sustained preoperative strokes when compared with the regional anesthesia patients (36.1% vs 26.4%; p < 0.01). There was also a statistically significant higher frequency of contralateral total occlusion in the general anesthesia group (21.8% vs 15.4%; p = 0.001). The trend toward increased perioperative strokes in the general anesthesia group may be explicable either by the above differences in the patient populations or by actual differences based on anesthetic technique that favor regional anesthesia. CONCLUSIONS: In a retrospective review of a large series of carotid operations, regional anesthesia was shown to be applicable to the vast majority of patients with good clinical outcome. Although the advantages over general anesthesia are perhaps small, the versatility and safety of the technique is sufficient reason for vascular surgeons to include it in their armamentarium of surgical skills. Considering that carotid endarterectomy is a procedure in which complication rates are exceedingly low, a rigidly controlled, prospective randomized trial may be required to accurately assess these differences
— id: 7247, year: 1996, vol: 24, page: 946, stat: Journal Article,

EFFECTS OF PEPTIDE YY ON CCK/CCK ANTAGONIST INTERACTIONS IN CERULEIN-INDUCED PANCREATIC INJURY
TITO, JM; RUDNICKI, M; ROBINSON, DC; GUINEY, WB; ADRIAN, TE; GOLD, MS
1995 ;757(4):410-412, Annals of the New York Academy of Sciences
Cholecystokinin (CCK) receptors have been shown to mediate CCK-induced pancreatic injury.(1) The beneficial effect of the CCK receptor antagonist L-364,718 on acute pancreatitis is well established.(2) We previously demonstrated an amelioration of CCK-induced pancreatic parenchymal changes in rats treated with peptide YY (PYY).(3) PYY is an ileocolonic inhibitor of pancreatic secretion that inhibits CCK-mediated effects on the pancreas.(4) The aim of this study was to investigate the combined effects and possible interactions of PYY and L-364,718 on cerulein-induced pancreatitis. $$:
— id: 115490, year: 1995, vol: 757, page: 410, stat: Journal Article,

The effect of lumbar epidural and general anesthesia on plasma catecholamines and hemodynamics during abdominal aortic aneurysm repair
Gold MS; DeCrosta D; Rizzuto C; Ben-Harari RR; Ramanathan S
1994 Feb;78(2):225-230, Anesthesia & analgesia
Twenty-four patients undergoing abdominal aortic aneurysm (AAA) repair were studied to compare the effects of lumbar epidural anesthesia (LEA) and general anesthesia (GA) on plasma catecholamine levels and hemodynamics before and during infrarenal aortic cross-clamping. Patients received either a high dose of opioid anesthetic (GA group, n = 12), or lumbar epidural anesthesia to T4 sensory level with a light general anesthetic (LEA group, n = 12). Systemic vascular resistance (SVR) and norepinephrine (NE) and epinephrine (E) levels were measured before anesthetic induction (before epidural activation in the LEA group, and before general anesthesia induction in the GA group), 15 min before cross-clamping, and 1,5, and 10 min after cross-clamping. There was a large (P < 0.05) increase in NE and E in the GA group by 15 min before aortic cross-clamping, but NE and E levels in the LEA group did not increase. The GA group had significantly higher levels of NE and E than the LEA group 15 min before cross-clamping and also after clamping. NE levels in the LEA group increased after cross-clamping, and NE levels in the GA group remained constant. E levels remained stable in both groups after cross-clamping. After clamping, SVR increased in both groups, but the increase occurred after 1 min in the GA group and took 5 min to become significant in the LEA group. There was no significant correlation between changes in NE or E and changes in SVR in either group. This study shows that epidural anesthesia to T4 prevents NE and E increases in response to abdominal surgery.(ABSTRACT TRUNCATED AT 250 WORDS)
— id: 56534, year: 1994, vol: 78, page: 225, stat: Journal Article,

THORACIC VS LUMBAR ADMINISTRATION OF EPIDURAL NARCOTICS FOR POSTOPERATIVE ANALGESIA IN PATIENTS UNDERGOING ABDOMINAL AORTIC-ANEURYSM REPAIR
GOLD, MS; LIPSITZ, NB
1994 SEP ;81(3A):A1053-A1053, Anesthesiology
— id: 52329, year: 1994, vol: 81, page: A1053, stat: Journal Article,

The effect of epidural/general and cervical plexus block anesthesia on activated clotting time in patients undergoing vascular surgery
Gold MS
1993 Apr;76(4):701-704, Anesthesia & analgesia
The effect of anesthetic induction and surgical incision on activated clotting time (ACT) was determined in patients undergoing vascular surgery. Patients undergoing carotid endarterectomy (CAE) (n = 50) and abdominal aortic aneurysm repair (AAA) (n = 45) were studied. Patients in the CAE group had cervical plexus block anesthesia, whereas patients in the AAA group had a combination of epidural and general anesthesia. The ACT was measured 1) before induction of anesthesia, 2) 5 min after induction, 3) 5 min after incision, 4) 5 min after heparinization, and 5) at the onset of skin closure. Heparin was reversed with protamine only if the ACT after revascularization was > 200 s. Reversal was considered adequate if the ACT was < 200 s and the surgeon felt that hemostasis was adequate. The ACT decreased by 12.26 +/- 1.23 (mean +/- SE) (P = 0.006) in the CAE group and by 12.47 +/- 1.01 (P = 0.002) in the AAA group with induction of anesthesia. There was a further decrease of 5.06 +/- 0.62 (P = 0.26) in the CAE group and 5.17 +/- 0.83 (P = 0.22) in the AAA group with incision. There was a significant difference in ACT in both groups from postinduction and postincision to skin closure (higher at skin closure). No patient in either group required additional protamine or clotting factors post-operatively, or return to the operating room for excessive bleeding. This study demonstrates that anesthetic induction with cervical block or epidural/general anesthesia decreases ACT.(ABSTRACT TRUNCATED AT 250 WORDS)
— id: 13205, year: 1993, vol: 76, page: 701, stat: Journal Article,

Perioperative fluid management
Gold MS
1992 Apr;8(2):409-421, Critical care clinics
The physiologic effects of surgery as well as anesthesia on fluid balance have been discussed. Detailed discussions of some types of surgery and patient populations were included to clarify situations in which fluid management may be unusually difficult. Principles derived from the examination of these situations should make fluid management during the perioperative period easier
— id: 13645, year: 1992, vol: 8, page: 409, stat: Journal Article,

Effect of epidural/general versus general anesthesia on catecholamine levels and hemodynamics during abdominal aortic cross-clamping
Gold MS; Rizzuto C; DeCrosta D
1992 ;77:A97-A97, Anesthesiology
— id: 47348, year: 1992, vol: 77, page: A97, stat: Journal Article,