The interaction of the Chrna5 D398N variant with developmental nicotine exposure.

A single nucleotide polymorphism (SNP) in CHRNA5 (rs16969968, change from an aspartic acid [D] to asparagine [N] at position 398 of the human α5 nicotinic acetylcholine receptor subunit) has been associated with increased risk for nicotine dependence. Consequently, carriers of the risk variant may be at elevated risk for in utero nicotine exposure. To assess whether this gene-environment interaction might impact nicotine intake in developmental nicotine-exposed offspring, we utilized a mouse expressing this human SNP. D and N dams drank nicotine (100 µg/mL) in 0.2% saccharin water or 0.2% saccharin water alone (vehicle) as their sole source of fluid from 30 days prior to breeding until weaning of offspring. The nicotine (D Nic, N Nic) or vehicle (D Veh, N Veh) exposed offspring underwent a 2-bottle choice test between postnatal ages of 30 to 46 days. N Nic offspring consumed the most nicotine at the highest concentration (400 µg/mL) compared with all other groups. In contrast, D Nic offspring drank the least amount of nicotine at all concentrations tested. Nicotine-stimulated dopamine (DA) release measured from striatal synaptosomes was increased in D Nic offspring, while decreased in N Nic offspring relative to their genotype-matched controls. These data suggest that the α5 variant influences the effect of developmental nicotine exposure on nicotine intake of exposed offspring. This gene-environment interaction on striatal DA release may provide motivation for increased nicotine seeking in N Nic offspring and reduced consumption in D Nic offspring.

Midwakh/dokha tobacco use in the Middle East: much to learn.

Many alternative tobacco products (ATPs), such as hookahs, have grown in popularity and use beyond their locale of origin and are therefore becoming a significant global public health concern. This article provides an overview of an under-reported and understudied ATP, dokha, which is smoked in a midwakh pipe. It describes the state of tobacco control in the Arabian Gulf region where midwakh smoking appears to be most common, the history of midwakh and dokha use, and what is known about midwakh smoking from the published literature. On the basis of the stark lack of data on midwakh use, we suggest priority areas to focus future research. Preliminary data and observations from health providers and the public health sector suggest that midwakh smoking may pose challenges to the tobacco control efforts in the Arabian Gulf region. If it is emerging as a new ATP outside this region, there could be a significant impact on tobacco control strategies globally.

Comparison of past versus recent physical activity in the prevention of premature death and coronary artery disease.

BACKGROUND: People who are physically active live longer, but it is unclear whether this is because of physical activity in the distant or more recent past. METHODS: We assessed activity levels in 5209 men and women in the Framingham Heart Study from 1956 to 1958 and again from 1969 to 1973. We included individuals who were alive and without cardiovascular disease in the period 1969 to 1973. The primary outcome was death from all causes during the 16 years after the 1969 to 1973 assessment. Secondary outcomes were incidence and mortality rate of cardiovascular disease. We used Cox proportional hazards regression to calculate the relative risk of being sedentary, both unadjusted and controlling for smoking, weight, systolic blood pressure, cholesterol, glucose intolerance, left ventricular hypertrophy, chronic obstructive pulmonary disease, and cancer. RESULTS: The overall 16-year mortality rate was 37% for men and 27% for women. When both distant and recent activity levels were included along with major cardiovascular disease risk factors, for recent activity the most active tertile had lower overall mortality rate than the least active tertile for men (risk ratio 0.58, 95% confidence interval, 0.43-0.79) and women (risk ratio 0.61, 95% confidence interval, 0.45-0.82). For distant activity there was no difference in overall mortality rate between the most and least active tertiles either for men or for women. Adjusting for major cardiovascular disease risk factors had little effect on the results. CONCLUSIONS: The reduction in overall mortality rates is more associated with recent activity than distant activity. These results suggest that for sedentary patients, it may never be too late to begin exercising.

Health habit counseling amidst competing demands: effects of patient health habits and visit characteristics.

OBJECTIVE: This study assesses the effects of competing demands, such as poor health habits or new medical problems, on health-habit counseling during a primary care visit. METHODS: We surveyed a consecutive sample of 1,259 patients visiting primary care clinicians at an academic VA medical center. Before the visit, patients reported their health status, health habits, and sociodemographics; immediately after the visit, patients reported reasons for the visit and whether they had been counseled about specific health habits. We scored visit acuity ranging from visits for unscheduled walk-in care or new medical problems to scheduled visits for check-ups or old problems. We defined counseling "triggers" as clinical indications for counseling about particular health habits (e.g., smoking). We developed a logistic model predicting primary care provider counseling during a visit. RESULTS: Over two-thirds of patients (68.9%) received some health habit counseling. Controlling for other independent variables, patients with more triggers were more likely to report being counseled. Counseling rates went up as visit acuity went down; patients with the lowest visit acuity having 67% greater odds of being counseled than patients with the highest visit acuity. CONCLUSIONS: Physicians set priorities for health-habit counseling during a visit based on patients' health habit problems or triggers; whether the visit is scheduled or walk-in; and whether the patient has new or acute problems. Future research about primary care performance of health habit counseling should account for these patient and visit characteristics, and prevention-oriented health care organizations should ensure access to scheduled "check-up" visits.

Measures of functional status in community-dwelling elders.

OBJECTIVE: To evaluate two performance-based measures of functional status and assess their correlation with self-report measures. DESIGN: Cross-sectional study. PARTICIPANTS: Of the 363 community-dwelling elders enrolled in a trial of comprehensive geriatric assessment who participated, all had at least one of four target conditions (urinary incontinence, depression, impaired functional status, or history of falling). MEASUREMENTS: Two performance-based measures, National Institute on Aging (NIA) Battery, and Physical Performance Test (PPT), and three self-report functional status measures, basic and intermediate activities of daily living and the Short-Form-36 (SF-36) physical functioning subscale, were used. Measures of restricted activity days, patient satisfaction and perceived efficacy were also used. MAIN RESULTS: All measures were internally consistent. There was a high correlation between the NIA and PPT (kappa = 0.71), while correlations between the performance-based and self-report measures ranged from 0.37 to 0.50. When patients with values above the median on the two performance-based measures were compared with those below, there were significant differences (p

Altered receptive fields and sensory modalities of rat VPL thalamic neurons during spinal strychnine-induced allodynia.

Altered receptive fields and sensory modalities of rat VPL thalamic neurons during spinal strychnine-induced allodynia. J. Neurophysiol. 78: 2296-2308, 1997. Allodynia is an unpleasant sequela of neural injury or neuropathy that is characterized by the inappropriate perception of light tactile stimuli as pain. This condition may be modeled experimentally in animals by the intrathecal (i.t.) administration of strychnine, a glycine receptor antagonist. Thus after i.t. strychnine, otherwise innocuous tactile stimuli evoke behavioral and autonomic responses that normally are elicited only by noxious stimuli. The current study was undertaken to determine how i.t. strychnine alters the spinal processing of somatosensory input by examining the responses of neurons in the ventroposterolateral thalamic nucleus. Extracellular, single-unit recordings were conducted in the lateral thalamus of 19 urethan-anaesthetized, male, Wistar rats (342 +/- 44 g; mean +/- SD). Receptive fields and responses to noxious and innocuous cutaneous stimuli were determined for 19 units (1 per animal) before and immediately after i.t. strychnine (40 microgram). Eighteen of the animals developed allodynia as evidenced by the ability of otherwise innocuous brush or air jet stimuli to evoke cardiovascular and/or motor reflexes. All (3) of the nociceptive-specific units became responsive to brush stimulation after i.t. strychnine, and one became sensitive to brushing over an expanded receptive field. Expansion of the receptive field, as determined by brush stimulation, also was exhibited by all of the low-threshold mechanoreceptive units (14) and wide dynamic range units (2) after i.t. strychnine. The use of air jet stimuli at fixed cutaneous sites also provided evidence of receptive field expansion, because significant unit responses to air jet developed at 13 cutaneous sites (on 7 animals) where an identical stimulus was ineffective in evoking a unit response before i.t. strychnine. However, the magnitude of the unit response to cutaneous air jet stimulation was not changed at sites that already had been sensitive to this stimulus before i.t. strychnine. The onset of allodynia corresponded with the onset of the altered unit responses (i.e., lowered threshold/receptive field expansion) for the majority of animals (9), but the altered unit response either terminated concurrently with symptoms of allodynia (6) or, more frequently, outlasted the symptoms of allodynia (10) as the effects of strychnine declined. The present results demonstrate that the direct, receptor-mediated actions of strychnine on the spinal processing of sensory information are reflected by changes in the receptive fields and response properties of nociceptive and nonnociceptive thalamic neurons. These changes are consistent with the involvement of thalamocortical mechanisms in the expression of strychnine-induced allodynia and, moreover, suggest that i.t. strychnine also produces changes in innocuous tactile sensation.

Spinal strychnine alters response properties of nociceptive-specific neurons in rat medial thalamus.

Experiments in both conscious and anesthetized animals indicate that intrathecal (i.t.) strychnine (STR; glycine receptor antagonist) produces acute, reversible allodynia, as evidenced by inappropriate behavioral and autonomic responses to cutaneous tactile stimuli. Although STR is known to produce disinhibition of afferent input to the spinal cord, changes in spinal reflexes cannot fully explain the complex behaviors observed following i.t. STR. Which supraspinal sites are involved in STR-dependent allodynia and how this abnormal somatosensory message is relayed to these sites remain to be determined. The medial thalamus contains many nociceptive-specific (NS) neurons and is believed to be involved in mediating the affective-motivational aspects of pain. It is thus important to determine whether spinally administered STR elicits changes in the responses of medial thalamic NS neurons. Extracellular single-unit recordings were conducted in urethan-anesthetized rats (290-490 g). A detailed characterization of 20 thalamic NS units (1 per rat; 2 in 1 case) was conducted before and immediately after i.t. STR (40 microg). Initially, all of the units in this study were classified as NS, because they were excited by noxious pinch but not by innocuous tactile stimuli. After i.t. STR, all (formerly NS) units exhibited significant responses to innocuous tactile stimuli (brush and/or air jet) applied to lumbar or sacral dermatomes. This effect of STR on thalamic NS neurons was acute and reversible. The majority of units (11 of 20) also exhibited an increase in spontaneous firing rate. Although the complete pinch receptive field (RF) could not be determined for all units, the available data indicate that the RFs for brush stimulation after i.t. STR were substantially different from the pre-STR pinch RFs for all but three units. The same i.t. STR injection that caused the observed changes in medial thalamus also produced allodynia, in the form of brush-evoked cardiovascular or motor responses, in 18 of the 19 rats. The ability of NS cells in medial thalamus to respond to tactile input after i.t. STR suggests that the STR lowers the threshold of nociceptive neurons that project directly and/or indirectly to medial thalamus. These observations suggest that ascending nociceptive pathways and medial thalamic structures contribute to the expression of STR-dependent allodynia.

The safety of transdermal nicotine as an aid to smoking cessation in patients with cardiac disease.

BACKGROUND: Transdermal nicotine therapy is widely used to aid smoking cessation, but there is uncertainty about its safety in patients with cardiac disease. METHODS: In a randomized, double-blind, placebo-controlled trial at 10 Veterans Affairs medical centers, we randomly assigned 584 outpatients (of whom 576 were men) with at least one diagnosis of cardiovascular disease to a 10-week course of transdermal nicotine or placebo as an aid to smoking cessation. The subjects were monitored for a total of 14 weeks for the primary end points of the study (death, myocardial infarction, cardiac arrest, and admission to the hospital due to increased severity of angina, arrhythmia, or congestive heart failure); the secondary end points (admission to the hospital for other reasons and outpatient visits necessitated by increased severity of heart disease); any side effects of therapy; and abstinence from smoking. RESULTS: There were 48 primary and 78 secondary end points noted in a total of 95 subjects. At least one of the primary end points was reached by 5.4 percent of the subjects in the nicotine group and 7.9 percent of the subjects in the placebo group (difference, 2.5 percent; 95 percent confidence interval, -1.6 to 6.5 percent; P=0.23). In the nicotine group, 11.9 percent of the subjects had at least one of the secondary end points, as compared with 9.7 percent in the placebo group (difference, 2.2 percent; 95 percent confidence interval, -2.2 to 7.4 percent; P= 0.37). After 14 weeks the rate of abstinence from smoking was 21 percent in the nicotine group, as compared with 9 percent in the placebo group (P=0.001), but after 24 weeks the abstinence rates were not significantly different (14 percent vs. 11 percent, P= 0.67). CONCLUSIONS: Transdermal nicotine does not cause a significant increase in cardiovascular events in high-risk outpatients with cardiac disease. However, the efficacy of transdermal nicotine as an aid to smoking cessation in such patients is limited and may not be sustained over time.

Predictors of success in a smoking cessation clinic.

We identified factors associated with success among the first 531 patients referred to a Veterans Affairs Medical Center smoking cessation clinic. Both patients and providers completed questionnaires covering smoking history, other health habits, and comorbidity. The 3-month success rate was 23% of all referrals or 42% of clinic attendees. Among those referred, factors associated with their success were being at least 50 years of age, having hyperlipidemia, and not currently drinking alcohol. Among those who attended the clinic at least once, factors associated with success were being at least 50 years of age, being less physically active, and not currently drinking alcohol. Neither patients nor providers could predict who would successfully stop smoking.

Strychnine-sensitive modulation is selective for non-noxious somatosensory input in the spinal cord of the rat.

Touch-evoked allodynia, an important symptom of clinical neural injury pain, can be modelled acutely and reversibly in the urethane-anesthetized rat using intrathecal (i.t.) strychnine (STR). Allodynia, after i.t. STR (40 micrograms), is manifest as a significant enhancement of cardiovascular and motor responses evoked by normally innocuous brushing of the hair (hair deflection), as compared to responses evoked by either hair deflection after i.t. saline (SAL), or to i.t. STR (40 micrograms) with no tactile stimulus. The present study investigated: (1) the pharmacology of afferent neural inputs involved in STR-dependent allodynia using neonatal capsaicin and the non-NMDA receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline (NBQX); and (2) the effect of i.t. STR on responses evoked by peripheral noxious stimulation. Neonatal capsaicin (25 mg/kg, s.c., post-natal day (PND) 1, and 50 mg/kg, s.c., PND 2, 3, 4, 11, 25, 55 and 85) significantly attenuated the responses evoked by noxious mechanical, thermal or chemical stimuli, but had no effect on STR-dependent allodynia. All hair deflection-evoked, STR-dependent responses were dose-dependently inhibited by i.t. NBQX. The ED50 values and 95% confidence intervals were 10.4 micrograms (5.5-19.6) for the motor withdrawal response, 14.4 micrograms (8.6-24.0) for changes in MAP and 12.2 micrograms (6.8-21.8) for changes in HR. Cortical EEG synchrony was unchanged by i.t. NBQX confirming its spinal locus of action. Intrathecal STR neither reduced nor enhanced the responses elicited by noxious stimuli in capsaicin- or vehicle-pretreated rats. These results indicate that STR-dependent allodynia is initiated by primary afferents not normally involved in nociception (possibly A beta-fibers), and that STR-sensitive modulation in the spinal cord is selective for non-noxious sensory input. The sensitivity of STR-dependent allodynia to non-NMDA receptor antagonists, and the failure of i.t. STR to produce hyperalgesia to mechanical, thermal or chemical noxious stimuli, confirm the independence of nociceptive pathways and STR-sensitive afferent inputs in this model.

Strychnine-dependent allodynia in the urethane-anesthetized rat is segmentally distributed and prevented by intrathecal glycine and betaine.

The blockade of spinal glycine receptors with intrathecal strychnine produces a reversible allodynia-like state in the rat. Thus, hair deflection, in the presence of intrathecal strychnine, induces cardiovascular and motor withdrawal responses comparable with those evoked by noxious thermal, mechanical, or chemical stimulation in the absence of strychnine. In the present study, we mapped the cutaneous sites of abnormal sensitivity to hair deflection throughout the strychnine time course to investigate the segmental distribution of strychnine-induced allodynia. The ability of intrathecal glycine and the glycine derivative betaine to reverse strychnine-induced allodynia was also determined using dose-response analysis. Following intrathecal strychnine (40 micrograms), stroking the legs, flanks, lower back, and tail with a cotton-tipped applicator evoked a pronounced increase in mean arterial pressure, tachycardia, and an abrupt motor withdrawal response in urethane-anesthetized rats. These abnormal responses were only evoked by hair deflection at discrete sites, corresponding to the cutaneous dermatomes innervated by spinal segments near the site of strychnine injection. In rats with intrathecal catheters lying laterally in the subarachnoid space, allodynic sites were observed unilaterally on the ipsilateral side of intrathecal strychnine injection. Recovery from strychnine was complete by 30 min in all affected dermatomes. The cardiovascular and motor withdrawal responses to hair deflection were dose dependently inhibited by intrathecal glycine and intrathecal betaine. The ED50 (95% confidence interval) for intrathecal glycine was 609 (429-865) micrograms for the heart rate response, 694 (548-878) micrograms for the pressor response, and 549 (458-658) micrograms for the motor withdrawal response. The corresponding values for intrathecal betaine were 981 (509-1889), 1045 (740-1476), and 1083 (843-1391) micrograms, respectively. There was no difference in the effect of betaine on sensory-evoked cardiovascular and motor responses. Cortical electroencephalographic activity was not affected by intrathecal glycine or betaine, consistent with a spinal locus of action in reversing strychnine-induced allodynia. These results support the hypothesis that removal of spinal glycinergic modulation from low threshold afferent input with intrathecal strychnine results in segmentally localized, tactile-evoked allodynia.

Physical activity and mortality in women in the Framingham Heart Study.

Men who are more active live longer, but it is not clear if the same is true for women. We monitored 1404 women aged 50 to 74 who were free of cardiovascular disease. We assessed physical activity levels and ranked subjects into quartiles. After 16 years, 319 (23%) women had died. The relative risk of mortality, compared to the least active quartile, was as follows: second quartile, 0.95 (95% confidence interval [CI] 0.72 to 1.26); third quartile, 0.63 (95% CI 0.46 to 0.86); most active quartile, 0.67 (95% CI 0.48 to 0.92). The relative risks were not changed by adjustment for cardiac risk factors, chronic obstructive pulmonary disease, or cancer or by excluding all subjects who died in the first 6 years (to eliminate occult disease at baseline). There was no association between activity levels and cardiovascular morbidity or mortality. We conclude that women who were more active lived longer; this effect was not the result of decreased cardiovascular disease.

Does exercise reduce mortality rates in the elderly? Experience from the Framingham Heart Study.

Regular physical activity decreases the mortality rate in middle-aged men and probably in middle-aged women. It is unknown whether this is also true in the elderly. We studied 285 men and women aged 75 years or older who were free of cardiovascular disease. Subjects were ranked by baseline physical activity levels and grouped into quartiles. After adjustments were made for cardiac risk factors, chronic obstructive pulmonary disease, and cancer, women in the second most active quartile had a much lower risk of mortality at 10 years (relative risk 0.24, 95% confidence interval 0.12 to 0.51). There was no statistically significant difference in men. There appeared to be an excess of sudden cardiac deaths in the most active women, although this group still lived longer than the least active women. We conclude that women aged 75 years or older who are more active live longer. This benefit may be attenuated in those who are extremely active.

Exercise counseling: how do general internists do?

OBJECTIVE: To assess how often physicians counsel patients about exercise and to identify which primary care internists infrequently counsel about it. DESIGN: Cross-sectional survey of a random sample of primary care internists in Massachusetts. Questions covered physicians' attitudes, beliefs, and practices with respect to counseling about exercise; physicians' perceived barriers to counseling about exercise; physicians' personal exercise frequency; and physician demographics. PARTICIPANTS: Of 1,000 physicians, 687 were eligible and 422 returned usable questionnaires (response rate 61%). RESULTS: Data describing physician demographics, practice setting, measures of personal fitness, and beliefs regarding exercise were entered into a logistic regression model. The characteristic that best identified physicians who infrequently counsel about exercise was their perceived lack of success at counseling (OR 22.83, 95% CI 8.36-62.31). Other independent predictors of infrequent counselling were physicians' lack of conviction that exercise is very important (OR 4.86, 95% CI 1.70-13.91), physician age < or = 40 years (OR 3.08, 95% CI 1.33-7.15), and higher physician resting heart rate (OR 3.45, 95% CI 1.46-8.18). CONCLUSIONS: Several factors were found to be independently associated with the likelihood of a physician's counseling about exercise. These included physician perceived success at counseling, physician belief that exercise is important, physician age, and physician resting heart rate. These results suggest possible strategies to improve physician's counseling efforts.

Intrathecal oxymetazoline does not produce neurotoxicity in the spinal cord of the rat.

To determine if intrathecal (i.t.) oxymetazoline (OXY) induces histological evidence of spinal neurotoxicity, male, Sprague-Dawley rats (300-450 g; implanted with an i.t. catheter) were treated with i.t. saline or 100 nmol OXY twice daily for 3 days, or 200 or 300 nmol OXY once daily for 3 days. Spantide (D-Arg1, D-Try7,9, Leu11-substance P; 0.067 nmol = 0.1 microgram, 0.167 nmol = 0.25 microgram or 0.334 nmol = 0.5 microgram) or capsaicin (0.164 mumol = 50 micrograms), given as a single i.t. injection, were used as positive controls. Animals were killed 12 h after the last injection of saline or OXY, and 72 h after spantide or capsaicin. Spinal cord sections (L1 and adjacent segments) were examined by light microscopy for changes in gross morphology, substance P-like immunoreactivity (SP-IR) and calcitonin gene related peptide-like immunoreactivity (CGRP-IR). All doses of i.t. OXY produced antinociception (tail-flick ED50 = 53.7 nmol, paw pressure withdrawal ED50 = 93.3 nmol). Rectal temperature decreased by 1.5-2.4 degrees C up to 12 h after 100 nmol of i.t. OXY. There were no signs of inflammation or necrosis, and no detectable loss or damage to either spinal afferents or motor neurons as judged by SP-IR and CGRP-IR structures in spinal cords of OXY-treated animals (all doses) as compared to i.t. saline controls. Spantide (0.1 microgram) had no antinociceptive or neurotoxic effect; 0.25 microgram induced irreversible loss of the TF reflex and transient hind limb paralysis; 0.5 microgram induced irreversible loss of TF and PP responses, permanent hind limb paralysis, bladder and bowel dysfunction. The spinal cords from these animals showed signs of extensive necrosis, cavitation, and haemorrhage in the ventral horn accompanied by a loss of CGRP-IR motor neurons. Capsaicin-treated rats exhibited a permanent loss of the TF but not the PP response and a marked reduction of SP-IR spinal afferents in the dorsal horn. It is concluded that i.t. OXY produces antinociception in the rat with no detectable spinal neurotoxicity as assessed by parameters which are sensitive to the neurotoxins, spantide and capsaicin.

Long-term diabetes alters the hepatobiliary clearance of acetaminophen, bilirubin and digoxin.

The effect of insulin-dependent diabetes on hepatobiliary clearance of acetaminophen, bilirubin and digoxin was determined using Sprague-Dawley rats that were treated with a 45 mg/kg dose of streptozotocin 28 days before experimentation. Urinary excretion of acetaminophen was increased 280%, whereas biliary excretion was decreased 65% and total clearance was unchanged. Both steady-state volume of distribution and elimination half-life of acetaminophen were decreased in diabetic rats by 23 and 25%, respectively. Biliary excretion of glucuronide and sulfate conjugates was decreased by 75 and 50%, respectively, whereas parent acetaminophen excretion was unchanged. The glutathione conjugate was only detected in normal and insulin-treated rats; however, comparable levels of a cysteine conjugate were detected in bile of diabetic rats. Administration of insulin reversed the hyperglycemia and the changes in volume of distribution, elimination half-life and glutathione excretion. Other diabetes-induced alterations were unchanged. In contrast, digoxin plasma disappearance, volume of distribution and total clearance were significantly increased in diabetic rats, whereas the elimination half-life was decreased. Administration of insulin reversed the changes in serum disappearance and partially reversed the increased biliary excretion of digoxin. No differences were observed for the serum disappearance, glucuronidation or biliary excretion of bilirubin in diabetic vs. normal rats. These data indicate that insulin deficiency for 1 month can alter hepatic excretory function and the pharmacokinetics of commonly used drugs.

Molecular structure of the complex formed between the anticancer drug cisplatin and d(pGpG): C222(1) crystal form.

The three dimensional molecular structure of the adduct formed between the anticancer drug cisplatin and a DNA dinucleotide d(pGpG) has been determined by x-ray diffraction analysis at 1.37 A resolution and refined to a final R-factor of 0.11. This structure, solved by using data from a previously reported crystal form in the space group C222(1), resembles that found in the space group P2(1)2(1)2 (Sherman, et al., Science, 230, 412-417, 1985; ibid, J. Amer. Chem. Soc. 110, 7368-7381, 1988). In both structures, four crystallographically independent cis-[Pt(NH3)2(d(pGpG]] molecules aggregate into a tetrameric cluster that is stabilized by a large number of intermolecular hydrogen bonds and base-base stacking interactions. In each molecule, the platinum atom is coordinated to the N7 atoms of two guanine bases arranged in a head-to-head orientation, resulting in a large dihedral angle between the guanines. Intermolecular guanine-guanine base pairings between different intrastrand crosslinked molecules are used extensively in the crystal lattice.