CT perfusion measurement of postictal hypoperfusion: localization of the seizure onset zone and patterns of spread.

PURPOSE: Seizures are often followed by a period of transient neurological dysfunction and postictal alterations in cerebral blood flow may underlie these symptoms. Recent animal studies have shown reduced local cerebral blood flow at the seizure onset zone (SOZ) lasting approximately 1 h following seizures. Using arterial spin labelling (ASL) MRI, we observed postictal hypoperfusion at the SOZ in 75% of patients. The clinical implementation of ASL as a tool to identify the SOZ is hampered by the limited availability of MRI on short notice. Computed tomography perfusion (CTP) also measures blood flow and may circumvent the logistical limitations of MRI. Thus, we aimed to measure the extent of postictal hypoperfusion using CTP. METHODS: Fourteen adult patients with refractory focal epilepsy admitted for presurgical evaluation were prospectively recruited and underwent CTP scanning within 80 min of a habitual seizure. Patients also underwent a baseline scan after they were seizure-free for > 24 h. The acquired scans were qualitatively assessed by two reviewers by visual inspection and quantitatively assessed through a subtraction pipeline to identify areas of significant postictal hypoperfusion. RESULTS: Postictal blood flow reductions of > 15 ml/100 g-1/min-1 were seen in 12/13 patients using the quantitative method of analysis. In 10/12 patients, the location of the hypoperfusion was partially or fully concordant with the presumed SOZ. In all patients, additional areas of scattered hypoperfusion were seen in areas corresponding to seizure spread. CONCLUSION: CTP can reliably measure postictal hypoperfusion which is maximal at the presumed SOZ.

Ion transport and signalling in human labial glands.

Recent reports characterizing the physiological properties of normal human labial acini are reviewed with particular emphasis on mechanisms related to fluid secretion. In contrast to the salivary glands of several experimental animals, human labial acinar cells do not appear to have a1-adrenergic receptors, substance P peptidergic receptors, or significant levels of Cl-/HCO3- exchange. Nor do they appear to secrete HCO3- in response to Ca2+ mobilizing stimuli. The data presently available indicates that fluid secretion by these glands is mainly under muscarinic control and is due to acinar Cl- secretion driven by a basolateral Na+ -K+ -2Cl- cotansporter.

Late effects in long-term survivors of high-grade non-Hodgkin's lymphomas.

PURPOSE: To evaluate long-term survivors of high-grade non-Hodgkin's lymphomas (NHLs) for late effects and to attempt to assess the relative contributions of the primary treatment modalities to these late effects. PATIENTS AND METHODS: Of 103 young survivors followed up for 1 to 20 years, 74 patients were interviewed and underwent various investigations, and an additional 12 patients were interviewed only. Of the 86 patients, 65 had previously suffered from small non-cleaved-cell lymphoma, 16 from lymphoblastic lymphoma, and five from large-cell lymphoma. RESULTS: Left ventricular dysfunction was identified in eight of 57 (14.0%) patients who had received doxorubicin (DOX) in doses greater than 200 mg/m2, of whom four were symptomatic and four were asymptomatic. A ninth patient required a pacemaker. Of the 86 patients, 23 (26.7%) reported pregnancies, 18 of whom had 30 children. Two of the 86 (2.3%) patients developed second cancers. Other major late effects included posttransfusion viral hepatitis, eight patients; CNS toxicity, two patients; endocrine impairment, 14 patients; vitamin B12 deficiency, two patients; esophageal stricture, one patient; urinary tract problems, two patients; and musculoskeletal defects, three patients. Major late effects occurred in 11 of 21 (52.4%) patients who had received radiation as well as chemotherapy, eight of 22 (36.4%) patients who had surgical resections as well as chemotherapy, and 17 of 74 (23.0%) patients who had received chemotherapy alone. CONCLUSION: The predominant major late effects observed were late cardiac toxicity related to DOX therapy and hepatitis C virus infection that presumably resulted from blood product transfusions administered before the introduction of screening for the hepatitis C virus. Fertility was not greatly impaired, and second malignancies were uncommon. No patient had clinically significant impairment of growth. Radiation appeared to increase the likelihood of late effects.

Ion transport systems in human labial acinar cells.

Human labial acini were assayed for the presence of ion transport systems associated with salivary fluid secretion using microfluorometric methods. Na(+)-K(+)-Cl- contransport and Na+/H+ exchange activities (determined by their bumetanide and amiloride sensitivities, respectively) were found at levels approximately 50% of those seen in similarly assayed rat parotid acini, but little, if any, C1-/HCO3-exchange activity was observed. Also, when human labial acini were stimulated with the muscarinic agonist carbachol, little evidence of the intracellular acidification associated with HCO3- secretion by other salivary glands was found. Na+/H+ exchange activity in human labial acini was downregulated (approximately 40%) by beta-adrenergic stimulation and upregulated (approximately threefold) by muscarinic stimulation. In contrast, beta-adrenergic stimulation produced only a marginally significant increase in Na(+)-K(+)-Cl- cotransport activity, and muscarinic stimulation was without effect. We include that basolateral Na(+)-K(+)-Cl- cotransport appears to be the dominant mechanism driving Cl- secretion and thereby fluid secretion in this tissue.

Kinetic analysis of muscarinic receptors in human brain and salivary gland in vivo.

Previous studies in rats have suggested that the muscarinic acetylcholine receptor (mAChR) antagonist (S)-3-quinuclidinyl-(S)-4-[123I]iodobenzilate [(SS)-IQNB] may be useful for the in vivo evaluation of mAChRs in humans as a control for the higher-affinity compound (RR)-IQNB. We have directly tested this hypothesis and examined the distribution of mAChRs in brain regions and parotid glands of healthy human volunteers in vivo using (RR)- and (SS)-IQNB (relatively high- and low-affinity antagonists, respectively), planar imaging, and pharmacokinetic analysis. This is the first in vivo study of mAChRs in humans that has employed stereoisomeric ligands and metabolic analysis to determine specific receptor binding. We observed that (SS)-IQNB showed much faster clearance from blood than (RR)-IQNB and different metabolite profiles. Also, the transport kinetics of the enantiomers were different. The estimated binding potential (approximately Bmax/Kd) of (RR)-IQNB was highest in two cortical regions, intermediate in parotid gland, and lowest in cerebellum. The aggregate results show that in humans (SS)-IQNB does not act as an ideal general probe to measure the nonspecific IQNB distribution. However, (RR)-IQNB does appear to have value when used for studies of human brain mAChRs.

Microfluorometric studies of intracellular Ca2+ and Na+ concentrations in normal human labial gland acini.

The responses of human labial salivary acini to muscarinic, adrenergic, and substance P peptidergic stimulation were studied using the fluorescent indicators fura 2 for intracellular Ca2+ concentration ([Ca2+]i) and sodium-binding benzofuran isophthalate for intracellular Na+ concentration ([Na+]i). Of the agents tested (carbachol, epinephrine, isoproterenol, and substance P) only the muscarinic agonist carbachol increased [Ca2+]i substantially above basal levels (three to fourfold; half-maximal effect approximatley 1 microM). Experiments with the Ca(2+)-adenosinetriphosphatase inhibitor thapsigargin indicated the presence of both thapsigargin-sensitive and thapsigargin-insensitive intracellular Ca2+ stores, both of which were mobilized by carbachol. [Na+]i in resting labial acini was approximately 20 mM. On stimulation with carbachol, [Na+]i rose transiently to more than three times this value and then partially recovered. This carbachol-induced rise in [Na+]i was largely blocked by bumetanide, a specific inhibitor of the Na(+)-K(+)-2Cl- cotransporter. These results are consistent with an intact muscarinic fluid secretory response in human labial acini with transepithelial Cl- secretion driven via Na(+)-K(+)-2Cl- cotransport and the secretion of fluid presumably following Cl- loss via an apical Ca(2+)-dependent anion channel, as observed in salivary acini from other species.

Oral health of pediatric AIDS patients: a hospital-based study.

The prevalence of acquired immunodeficiency syndrome (AIDS) is steadily increasing among American children. The dental needs of these patients are significant. This study evaluated the oral health of forty children being treated for HIV-infection at the National Institutes of Health (NIH). Eight of twenty-two patients in primary dentition (36 percent) had baby bottle tooth decay (BBTD). These cases required extensive dental restoration usually under general anesthesia. Tooth development was delayed in 31 percent of patients. Candidiasis was the most common soft tissue abnormality, found in 35 percent of children. Preventive and therapeutic dental programs should be instituted to meet the special needs of pediatric AIDS patients.

Beta-adrenergic stimulation and cAMP mobilize Ca2+ from an IP3-insensitive pool in rat submandibular granular ducts.

The beta-adrenergic agonist isoproterenol induced an increase in intracellular calcium concentration ([Ca2+]i) in rat submandibular granular ducts that was blocked by beta-adrenergic but not by alpha-adrenergic or muscarinic antagonists. This effect was only partially inhibited by the selective beta 1- and beta 2-adrenergic antagonists atenolol and ICI-118,551, but was completely blocked by the combination of the two, suggesting the involvement of multiple (or atypical) beta-adrenergic receptor subtypes. The response to isoproterenol was mimicked by forskolin, 3-isobutyl-1-methylxanthine, and dibutyryl adenosine 3',5'-cyclic monophosphate, but it was blocked by protein kinase inhibitors. The response of [Ca2+]i to isoproterenol was sustained in Ca(2+)-replete replete medium but transient in Ca(2+)-free medium, indicating the involvement of both Ca2+ entry and release from intracellular stores. However, isoproterenol stimulation produced no increase in ductal inositol phosphate levels. In addition, isoproterenol was still able to increase [Ca2+]i after the carbachol-induced depletion of inositol 1,4,5-trisphosphate (IP3)-sensitive calcium stores. We conclude that isoproterenol, acting through cAMP, releases Ca2+ from an IP3-insensitive intracellular store in salivary granular ducts.

Oral pilocarpine for post-irradiation xerostomia in patients with head and neck cancer.

BACKGROUND AND METHODS: We evaluated pilocarpine hydrochloride for the treatment of radiation-induced xerostomia, a common complication of irradiation of the head and neck. A prospective, randomized, double-blind, placebo-controlled trial was undertaken to test the safety and efficacy of pilocarpine, particularly in reversing the decrease in the production of saliva and other manifestations of xerostomia. Patients received either placebo or pilocarpine (5 mg or 10 mg orally three times a day) for 12 weeks and were evaluated at base line and every 4 weeks. RESULTS: We studied 207 patients who had each received > or = 4000 cGy of radiation to the head and neck. In the patients receiving the 5-mg dose of pilocarpine, oral dryness improved in 44 percent, as compared with 25 percent of the patients receiving placebo (P = 0.027). There was overall improvement in 54 percent of the 5-mg group as compared with 25 percent of the placebo group (P = 0.003), and 31 percent of the 5-mg group had improved comfort of the mouth and tongue, as compared with 10 percent of the placebo group (P = 0.002). Speaking ability improved in 33 percent of the 5-mg group as compared with 18 percent of the placebo group (P = 0.037). Saliva production was improved, but it did not correlate with symptomatic relief. There were comparable improvements in the group receiving the 10-mg dose. The primary adverse effect was sweating, in addition to other minor cholinergic effects. Six and 29 percent of the patients in the 5-mg and 10-mg groups, respectively, withdrew from the study because of adverse effects. There were no serious adverse effects related to pilocarpine. CONCLUSIONS: Pilocarpine improved saliva production and relieved symptoms of xerostomia after irradiation for cancer of the head and neck, with minor side effects that were predominantly limited to sweating.

New approaches for determining the site of salivary fluid secretory disorders.

Considerable progress has been made in understanding the events which underlie salivary fluid secretion. We have utilized novel approaches to evaluate the functional status of three distinct sites in the secretory cascade. First, salivary sympathetic nerve function studies used isotopic dopamine to measure catecholamine uptake and metabolism in vivo. Second, salivary muscarinic-cholinergic receptors were characterized in vivo by use of stereo-specific ligands and pharmacokinetic analyses. Finally, microfluorometric methods were used to study intracellular Ca2+ signaling in dispersed cells prepared from biopsied tissue. We conclude that it is possible to determine the functional status of key steps in salivary fluid generation with isotopic and fluorometric imaging techniques.

Taste intensity performance in patients irradiated to the head and neck.

Decrements in taste-detection thresholds during radiotherapy and subsequent recovery in the months after therapy are well documented. However, few studies have explored suprathreshold taste intensity perception in radiation patients. This cross-sectional study compared taste function in 15 men postradiation with a group of 23 healthy, nonirradiated male volunteers. A direct-scaling procedure was used to assess taste intensity perception of the four basic taste qualities. Patients performed nearly as well as control subjects on objective measures of suprathreshold functioning. Postradiation intensity judgments of salty (sodium chloride), sweet (sucrose), and bitter (quinine sulfate) solutions were not significantly reduced. Subtle, age-related taste impairments were identified for sour perception (citric acid) postradiotherapy. Younger patients judged citric acid to be more intense than did age-appropriate control subjects, whereas older patients judged it to be less intense. Moreover, younger patients were likely to be midly dysgeusic, whereas older patients appeared to be hypogeusic for citric acid. This study provides evidence for near normal suprathreshold taste intensity perception in patients who have received head and neck irradiation.

Prednisone and piroxicam for treatment of primary Sjögren's syndrome.

Primary Sjögren's syndrome is a systemic autoimmune exocrinopathy characterized by a lymphoplasmacytic infiltrate and destruction of salivary and lacrimal glandular tissues. There is no widely accepted or effective systemic therapy for this disorder. The purpose of this 6-month randomized, double-blinded, placebo-controlled study was to examine the effects of prednisone (30 mg, alternate days), piroxicam (20 mg, daily), or placebo on the salivary, lacrimal and immunologic alterations of primary Sjögren's syndrome. Eight patients were enrolled in each group. Salivary and lacrimal function were assessed at entry and at the completion of treatment. Labial minor salivary gland tissue was obtained at these times and examined for intensity of infiltration (focus scores) and for the relative proportion of glandular elements. Serologic and subjective evaluations were done as well, and patients were monitored for therapy-related side effects. Neither active treatment led to significant improvement in salivary or lacrimal function, although prednisone improved salivary flow in selected patients and was associated with positive subjective responses. Prednisone also significantly decreased the serum total protein, IgG, IgA, and sedimentation rate and increased the white cell count. There were no significant alterations in either focus scores or the percentage of glandular component tissues of minor glands with either active treatment. This study demonstrated that 6 months of prednisone or piroxicam at the doses utilized failed to improve the histological or functional parameters of salivary and lacrimal glands in primary Sjögren's syndrome.

Use of pilocarpine during head and neck radiation therapy to reduce xerostomia and salivary dysfunction.

BACKGROUND: Salivary gland hypofunction commonly develops during radiation therapy to the head and neck region. This study evaluated whether the sialogogue pilocarpine given during radiation therapy may reduce the severity of xerostomia and salivary dysfunction. METHODS: Nine patients requiring head, neck, or mantle radiation therapy participated in this double-blind, placebo-controlled trial. The patients took either 5 mg of pilocarpine or placebo four times daily for 3 months, beginning the day before radiation therapy. Subjective complaints and salivary functions were assessed. RESULTS: The pilocarpine-treated group had a lower frequency of oral symptoms during treatment than the placebo-treated group. Although salivary flow decreased in all patients, the pilocarpine-treated group had smaller reductions in flow. No drug effect was observed in glands that were irradiated completely. Thus, pilocarpine appeared to stimulate salivary tissues outside the radiation field. CONCLUSIONS: These results suggest that stimulation with pilocarpine may reduce the severity of salivary dysfunction and associated oral symptoms during radiation therapy.

Diagnosis and management of salivary dysfunction.

Salivary gland dysfunction may occur as a result of common medications, cancer therapy, or Sjögren's syndrome. Affected patients may develop significant oral, dental, and upper gastrointestinal sequelae. This article reviews the basic elements in diagnosis of salivary dysfunction, including initial evaluation and specialized diagnostic procedures. Patient management depends primarily on the severity of salivary dysfunction. More severe permanent forms of dysfunction, such as radiation-induced and Sjögren's syndrome, require long-term care, with preventive measures to maintain the dentition and therapeutic attempts to increase oral fluids.

Major salivary gland function in patients with radiation-induced xerostomia: flow rates and sialochemistry.

Radiation therapy for cancer of the head and neck region often causes salivary gland dysfunction and xerostomia. Several reports suggest that the submandibular/sublingual (SM/SL) glands may be less radiosensitive than the parotid. The purpose of this study was to evaluate differential radiation effects on the major salivary glands. Fifty patients with radiation-induced xerostomia were evaluated (33 males, 17 females; mean age 52.7). The average total tumor dose was 6034 cGy. Major salivary gland function was compared with that of 50 non-irradiated controls. Salivary flow rates included unstimulated and stimulated flows of both the parotid and SM/SL glands. Sialochemical analyses included total protein, lysozyme, lactoferrin, sodium, chloride, and potassium. All four measures of salivary flow were significantly reduced in patients as compared to controls (p = .0001). Like the parotid, submandibular/sublingual gland dysfunction appears to be radiation dose- and field-dependent. Patients in the lowest radiation dose quartile (< or = 5000 cGy) had significantly increased salivary flow compared to those in the highest dose quartile (> or = 6800 cGy; p = .025). Glands that were partially irradiated were more likely to have some residual function than fully irradiated glands (p = .003). Lactoferrin content was increased in parotid saliva of radiation patients (p = .0001). Chloride content was significantly increased also (p = .0001). The SM/SL glands are clearly dysfunctional in post-irradiation xerostomia patients compared to controls, in terms of both flow rates and sialochemistry.

Radiation-induced salivary dysfunction: clinical course and significance.

Salivary gland dysfunction commonly occurs as a result of radiation therapy for cancers of the head and neck region. The effect of radiation on salivary glands is immediate and predictable. Histologic and sialochemical studies indicate both the acini and ducts are affected. The extent of salivary dysfunction is primarily determined by the radiation field and dose. Radiation-induced salivary dysfunction is permanent and leads to a host of clinical sequelae, both oral and systemic.

Effects of secretagogues on cytosolic Ca2+ levels in rat submandibular granular ducts and acini.

Saliva is thought to be formed by a two-stage process, with the secretion of a "primary fluid" by the acinar cells followed by various ionic modifications in the salivary ducts. Both of these processes are under the control of autonomic stimuli. Although the role of the acini in salivary secretion has been studied in some detail, little is known about properties of ducts, particularly the intralobular ducts that make up the bulk of the ductal tissue. In the present study, microfluorometric methods were employed to examine the responses of intracellular Ca2+ concentration ([Ca2+]i) in individual male rat submandibular acini and intralobular (granular) ducts to various fluid secretory stimuli. We show that granular ducts respond to muscarinic (carbachol) and alpha-adrenergic (epinephrine) stimulation by increasing [Ca2+]i in a manner that is qualitatively similar to acini, but that in contrast to acini, these ducts do not respond to substance P. Because the transduction of a substance P peptidergic signal typically occurs via increased [Ca2+]i, this observation suggests that there are no substance P receptors on granular ducts. Ducts were also found to be somewhat more responsive to both carbachol and epinephrine than acini. Although muscarinic, alpha-adrenergic, and vasoactive intestinal peptide (VIP) stimulation are known to induce the secretion of epidermal growth factor from granular ducts, no significant increase in ductal [Ca2+]i in response to VIP (10(-9) to 10(-6) M) was observed.