Supporting individuals with intellectual and developmental disability during the first 100 days of the COVID-19 outbreak in the USA.

BACKGROUND: It is unknown how the novel Coronavirus SARS-CoV-2, the cause of the current acute respiratory illness COVID-19 pandemic that has infected millions of people, affects people with intellectual and developmental disability (IDD). The aim of this study is to describe how individuals with IDD have been affected in the first 100 days of the COVID-19 pandemic. METHODS: Shortly after the first COVID-19 case was reported in the USA, our organisation, which provides continuous support for over 11 000 individuals with IDD, assembled an outbreak committee composed of senior leaders from across the health care organisation. The committee led the development and deployment of a comprehensive COVID-19 prevention and suppression strategy, utilising current evidence-based practice, while surveilling the global and local situation daily. We implemented enhanced infection control procedures across 2400 homes, which were communicated to our employees using multi-faceted channels including an electronic resource library, mobile and web applications, paper postings in locations, live webinars and direct mail. Using custom-built software applications enabling us to track patient, client and employee cases and exposures, we leveraged current public health recommendations to identify cases and to suppress transmission, which included the use of personal protective equipment. A COVID-19 case was defined as a positive nucleic acid test for SARS-CoV-2 RNA. RESULTS: In the 100-day period between 20 January 2020 and 30 April 2020, we provided continuous support for 11 540 individuals with IDD. Sixty-four per cent of the individuals were in residential, community settings, and 36% were in intermediate care facilities. The average age of the cohort was 46 ± 12 years, and 60% were male. One hundred twenty-two individuals with IDD were placed in quarantine for exhibiting symptoms and signs of acute infection such as fever or cough. Sixty-six individuals tested positive for SARS-CoV-2, and their average age was 50. The positive individuals were located in 30 different homes (1.3% of total) across 14 states. Fifteen homes have had single cases, and 15 have had more than one case. Fifteen COVID-19-positive individuals were hospitalised. As of 30 April, seven of the individuals hospitalised have been discharged back to home and are recovering. Five remain hospitalised, with three improving and two remaining in intensive care and on mechanical ventilation. There have been three deaths. We found that among COVID-19-positive individuals with IDD, a higher number of chronic medical conditions and male sex were characteristics associated with a greater likelihood of hospitalisation. CONCLUSIONS: In the first 100 days of the COVID-19 outbreak in the USA, we observed that people with IDD living in congregate care settings can benefit from a coordinated approach to infection control, case identification and cohorting, as evidenced by the low relative case rate reported. Male individuals with higher numbers of chronic medical conditions were more likely to be hospitalised, while most younger, less chronically ill individuals recovered spontaneously at home.

Human Factors Results for Fentanyl Iontophoretic Transdermal System (ITS) With Enhanced Controller for Postoperative Pain Management.

PURPOSE: The purpose of this analysis was to conduct summative usability evaluations, including behavioral and subjective evaluations, for the fentanyl iontophoretic transdermal system (ITS). DESIGN: Four usability studies were conducted in representative users. METHODS: The first three studies were conducted with (1) health care professionals (HCPs; N = 31), (2) patients who received placebo fentanyl ITS (N = 30), and (3) healthy volunteers (N = 30), and focused on the understanding and use of fentanyl ITS. The fourth study included HCPs (N = 31) and healthy volunteers (N = 30), and focused on the effectiveness of formal training regarding the use of fentanyl ITS. FINDINGS: Overall, user groups found the fentanyl ITS easy to use. There were no use errors that could potentially have safety implications. In the three early studies, there were some minor difficulties experienced; however, the introduction of a structured training reduced these difficulties. CONCLUSIONS: Patients, nurses, and pharmacists were able to use fentanyl ITS with ease.

The effect of size ratio on the sphere structure factor in colloidal sphere-plate mixtures.

Binary mixtures of colloidal particles of sufficiently different sizes or shapes tend to demix at high concentration. Already at low concentration, excluded volume interactions between the two species give rise to structuring effects. Here, a new theoretical description is proposed of the structure of colloidal sphere-plate mixtures, based on a density expansion of the work needed to insert a pair of spheres and a single sphere in a sea of them, in the presence or not of plates. The theory is first validated using computer simulations. The predictions are then compared to experimental observations using silica spheres and gibbsite platelets. Small-angle neutron scattering was used to determine the change of the structure factor of spheres on addition of platelets, under solvent contrast conditions where the platelets were invisible. Theory and experiment agreed very well for a platelet/sphere diameter ratio D∕d = 2.2 and reasonably well for D∕d = 5. The sphere structure factor increases at low scattering vector Q in the presence of platelets; a weak reduction of the sphere structure factor was predicted at larger Q, and for the system with D∕d = 2.2 was indeed observed experimentally. At fixed particle volume fraction, an increase in diameter ratio leads to a large change in structure factor. Systems with a larger diameter ratio also phase separate at lower concentrations.

Distinctive gut microbiomes of ankylosing spondylitis and inflammatory bowel disease patients suggest differing roles in pathogenesis and correlate with disease activity.

BACKGROUND: Multiple studies have confirmed dysbiosis in ankylosing spondylitis (AS) and inflammatory bowel disease (IBD); however, due to methodological differences across studies, it has not been possible to determine if these diseases have similar or different gut microbiomes. RESULTS: In this study, faecal and intestinal biopsies were obtained from 33 Australian AS patients (including 5 with concomitant IBD, 'AS-IBD'), 59 IBD patients and 105 healthy controls. Stool samples were also obtained from 16 Italian AS patients and 136 Swedish AS patients. Focusing on the Australian cohort, AS, AS-IBD and IBD patients differed from one another and from healthy controls in both alpha and beta diversity. AS patients with and without clinical IBD could be distinguished from one another with moderate accuracy using stool microbiome (AUC=0.754). Stool microbiome also accurately distinguished IBD patients from healthy controls (AUC=0.757). Microbiome composition was correlated with disease activity measured by BASDAI and faecal calprotectin (FCP) levels. Enrichment of potentially pathogenic Streptococcus was noted in AS, AS-IBD and IBD patients. Furthermore, enrichment of another potentially pathogenic genus, Haemophilus, was observed in AS, AS-IBD, IBD, AS patients with increased BASDAI, and IBD patients with faecal calprotectin >100 µg/mg. Apart from these genera, no other taxa were shared between AS and IBD patients. CONCLUSIONS: In conclusion, the distinct gut microbiome of AS and AS-IBD patients compared to IBD patients and healthy controls is consistent with immunological and genetic evidence suggesting that the gut plays a different role in driving AS compared with IBD. However, enrichment of two potentially pathogenic genera in both diseases suggests that the presence of a shared/common microbial trigger of disease cannot be discounted.

Predictability of intranasal pharmacokinetics in man using pre-clinical pharmacokinetic data with a dopamine 3 receptor agonist, PF-219061.

(R)-3-(4-propylmorpholin-2-yl) phenol (PF-219061) is a potent, selective agonist of the dopamine 3 receptor for the treatment of female sexual dysfunction. In vivo, PF-219061 exhibits liver blood flow clearance in both rat and dog. Oral bioavailability was 0.7% in dog and less than 5% in rat. Intranasal dosing was investigated to improve bioavailability. Pre-clinical assessments in rat and dog demonstrated intranasal bioavailabilities of 16-38% in rat and 54-61% in dog with very rapid absorption. It was predicted that an intranasal dose in man would give approximately 25-50% bioavailability. The clinical data verified the preclinical predictions demonstrating rapid absorption and approximately dose-proportional increases in exposure. The intranasal bioavailability in man was estimated to be 26-38%. These findings indicate the potential utility of intranasal dosing as a route that circumvents the first-pass effects for PF-219061 resulting in high exposures.

Autofluorescence lifetime augmented reality as a means for real-time robotic surgery guidance in human patients.

Due to loss of tactile feedback the assessment of tumor margins during robotic surgery is based only on visual inspection, which is neither significantly sensitive nor specific. Here we demonstrate time-resolved fluorescence spectroscopy (TRFS) as a novel technique to complement the visual inspection of oral cancers during transoral robotic surgery (TORS) in real-time and without the need for exogenous contrast agents. TRFS enables identification of cancerous tissue by its distinct autofluorescence signature that is associated with the alteration of tissue structure and biochemical profile. A prototype TRFS instrument was integrated synergistically with the da Vinci Surgical robot and the combined system was validated in swine and human patients. Label-free and real-time assessment and visualization of tissue biochemical features during robotic surgery procedure, as demonstrated here, not only has the potential to improve the intraoperative decision making during TORS but also other robotic procedures without modification of conventional clinical protocols.

The kallikrein-kinin system in diabetic retinopathy: lessons for the kidney.

Diabetic retinopathy and diabetic nephropathy are common microvascular complications of diabetes. The kallikrein-kinin system (KKS) has been implicated in the development of both conditions, and, in particular, bradykinin and its receptors have been shown to exert angiogenic and proinflammatory actions. Several of the key processes that underlie the development of diabetic retinopathy, such as increased vascular permeability, edema, neovascularization, and inflammatory changes, have been associated with the KKS, and recent work has shown that components of the KKS, including plasma kallikrein, factor XIIa, and high-molecular-weight kininogen, are present in the vitreous of people with diabetic retinopathy. The role of the KKS in the development of diabetic nephropathy is controversial, with both adverse and protective effects of bradykinin and its receptors reported. The review examines the role of the KKS in pathways central to the development of diabetic retinopathy and compares this with reported actions of this system in diabetic nephropathy. The possibility of therapeutic intervention targeting bradykinin and its receptors as treatment for diabetic microvascular conditions is considered.

Leptin improves pulmonary bacterial clearance and survival in ob/ob mice during pneumococcal pneumonia.

The adipocyte-derived hormone leptin is an important regulator of appetite and energy expenditure and is now appreciated for its ability to control innate and adaptive immune responses. We have reported previously that the leptin-deficient ob/ob mouse exhibited increased susceptibility to the Gram-negative bacterium Klebsiella pneumoniae. In this report we assessed the impact of chronic leptin deficiency, using ob/ob mice, on pneumococcal pneumonia and examined whether restoring circulating leptin to physiological levels in vivo could improve host defences against this pathogen. We observed that ob/ob mice, compared with wild-type (WT) animals, exhibited enhanced lethality and reduced pulmonary bacterial clearance following Streptococcus pneumoniae challenge. These impairments in host defence in ob/ob mice were associated with elevated levels of lung tumour necrosis factor (TNF)-alpha, macrophage inflammatory peptide (MIP)-2 [correction added after online publication 28 September 2007: definition of MIP corrected], prostaglandin E(2) (PGE(2)), lung neutrophil polymorphonuclear leukocyte (PMN) counts, defective alveolar macrophage (AM) phagocytosis and PMN killing of S. pneumoniae in vitro. Exogenous leptin administration to ob/ob mice in vivo improved survival and greatly improved pulmonary bacterial clearance, reduced bacteraemia, reconstituted AM phagocytosis and PMN H(2)O(2) production and killing of S. pneumoniae in vitro. Our results demonstrate, for the first time, that leptin improves pulmonary bacterial clearance and survival in ob/ob mice during pneumococcal pneumonia. Further investigations are warranted to determine whether there is a potential therapeutic role for this adipokine in immunocompromised patients.

High Body Mass Index and Use of Fentanyl Iontophoretic Transdermal System in Postoperative Pain Management: Results of a Pooled Analysis of Six Phase 3/3B Trials.

INTRODUCTION: Postoperative pain management can be challenging in patients with a high body mass index (BMI) especially as a result of poor venous access and delayed ambulation that can result in serious complications. Fentanyl iontophoretic transdermal system (ITS) is a needle-free, patient-controlled analgesic method available for use in acute postoperative pain. The primary objective of these analyses was to determine if there were any differences between patients with high BMI (>40 kg/m2) and lower BMIs (<30 kg/m2 and 35-40 kg/m2) in terms of efficacy or safety. METHODS: Data from three registration, placebo-controlled trials and three active-comparator trials using fentanyl ITS (IONSYS®, The Medicines Company, Parsippany, NJ) for the management of postoperative pain were analyzed using BMI categories of <35 kg/m2, 35-40 kg/m2, and >40 kg/m2. The majority of patients had lower abdominal or orthopedic surgery. For these analyses, the primary efficacy variables were assessed via patient global assessment of pain control (PGA) at 24 h and investigator global assessment (IGA) at study discharge. PGA and IGA are categorical 4-point scales (excellent, good, fair, or poor) with treatment "success" defined as either excellent or good. Safety was evaluated via treatment emergent adverse events (TEAEs). RESULTS: There were 1403 patients randomly assigned and treated with fentanyl ITS for at least 3 h (BMI <35 kg/m2: 1180; 35-40 kg/m2: 136, BMI >40 kg/m2: 85; and 2 missing). PGA treatment success, which evaluates the method of pain control, at 24 h was consistent in the high and low BMI groups in patients treated with fentanyl ITS (<35 kg/m2: 946/1180 [80.2%]; 35-40 kg/m2: 103/136 [75.7%]; and >40 kg/m2: 65/85 [76.5%]). The IGA results at study discharge were similar to the PGA. Safety appeared similar with fentanyl ITS across the BMI groups. CONCLUSION: In these analyses, fentanyl ITS was as efficacious, as assessed by the PGA ratings of treatment "success", in patients with high BMI (>40 kg/m2) as it was for those with lower BMIs (<35 kg/m2 or 35-40 kg/m2) and was generally well tolerated across all BMI categories.

Microprocessor controlled transdermal drug delivery.

Transdermal drug delivery via iontophoresis is reviewed with special focus on the delivery of lidocaine for local anesthesia and fentanyl for patient controlled acute therapy such as postoperative pain. The role of the microprocessor controller in achieving dosimetry, alternating/reverse polarity, pre-programmed, and sensor-based delivery is highlighted. Unique features such as the use of tactile signaling, telemetry control, and pulsatile waveforms in iontophoretic drug delivery are described briefly.

Pharmacokinetic characteristics of fentanyl iontophoretic trandermal system over a range of applied current.

OBJECTIVE: To evaluate the pharmacokinetic (PK) characteristics of a modified fentanyl iontophoretic transdermal system (ITS). RESEARCH DESIGN AND METHODS: This was a prospective, open-label, single-center, randomized, 3-period, 5-treatment, 6-sequence study. Each subject was randomly assigned to receive three treatments in a sequence consisting of intravenous fentanyl citrate, fentanyl ITS at 170 µA, and then one of three other fentanyl ITS treatments at 140, 200 or 230 µA. MAIN OUTCOME MEASURES: The following PK parameters were determined: Cmax, tmax, t1/2, AUC23 - 25 and amount of fentanyl absorbed into systemic circulation (i.e., Dose Absorbed). RESULTS: Fifty-two subjects received at least one fentanyl treatment. Serum exposure (Cmax and AUC23 - 25) and Dose Absorbed increased with increasing current. The median tmax ranged from 23.0 to 23.2 h across the 4 ITS groups. Mean t1/2 values ranged from 11.0 to 13.0 h. The Dose Absorbed from the fentanyl ITS at 170 µA met bioequivalence criteria when compared to data from an earlier version of the fentanyl ITS. CONCLUSIONS: Exposure of fentanyl and the amount of fentanyl absorbed increased with the magnitude of applied current with the ITS. The fentanyl ITS at 170 µA is bioequivalent to an earlier version of the system.

Direct imaging of molecular transport through skin.

Scanning electrochemical microscopy (SECM) was used to image spatial variations in the molecular flux of Fe(CN)6(-4) across excised hairless and nude mouse skin. The SECM response is specific to electroactive molecules, allowing selective imaging of the flux of Fe(CN)6(-4) in multicomponent ionic solutions. Quantitative SECM image analysis demonstrated that 40% to 60% of the total Fe(CN)6(-4) flux occurred through appendages in the skin. SECM analysis of skin samples exposed to a known transport enhancer, sodium dodecylsulfate, indicated that the increase in the ion transport rate occurred exclusively in nonporous skin tissue.

Dopamine-1 receptor coupling defect in renal proximal tubule cells in hypertension.

The ability of the dopamine-1 (D1)-like receptor to stimulate adenylyl cyclase (AC) and phospholipase C (PLC), inhibit sodium transport in the renal proximal tubule (RPT), and produce natriuresis is attenuated in several rat models of hypertension. Since the inhibitory effect of D1-like receptors on RPT sodium transport is also reduced in some patients with essential hypertension, we measured D1-like receptor coupling to AC and PLC in cultures of human RPT cells from normotensive (NT) and hypertensive (HT) subjects. Basal cAMP concentrations were the same in NT (n=6) and HT (n=4). However, the D1-like receptor agonist fenoldopam increased cAMP production to a greater extent in NT (maximum response=67+/-1%) than in HT (maximum response=17+/-5%), with a potency ratio of 105. Dopamine also increased cAMP production to a greater extent in NT (32+/-3%) than in HT (14+/-3%). The fenoldopam-mediated increase in cAMP production was blocked by SCH23390 (a D1-like receptor antagonist) and by antisense D1 oligonucleotides in both HT and NT, indicating action at the D1 receptor. The stimulatory effects of forskolin and parathyroid hormone-related protein of cAMP accumulation were not statistically different in NT and HT, indicating receptor specificity and an intact G-protein/AC pathway. The fenoldopam-stimulated PLC activity was not impaired in HT, and the primary sequence and expression of the D1 receptor were the same in NT and HT. However, D1 receptor serine phosphorylation in the basal state was greater in HT than in NT and was not responsive to fenoldopam stimulation in HT. These studies demonstrate the expression of D1 receptors in human RPT cells in culture. The uncoupling of the D1 receptor in both rats (previously described) and humans (described here) suggests that this mechanism may be involved in the pathogenesis of hypertension; the uncoupling may be due to ligand-independent phosphorylation of the D1 receptor in hypertension.

Synthesis and expression in Escherichia coli of cistronic DNA encoding an antibody fragment specific for a Salmonella serotype B O-antigen.

A 1460-bp DNA encoding the two chains of the antigen-binding fragment (Fab) portion of a monoclonal antibody have been chemically synthesized and expressed in Escherichia coli. The antibody, Se155-4, is specific for a Salmonella serogroup B O-antigen and its crystal structure is under investigation. The genes were synthesized according to a strategy that allows for easy manipulation in genetic engineering studies of the Fab-binding site. Each gene is preceded by the ompA secretory signal and a ribosome-binding site, and has been expressed from the two-cistron DNA under the control of the lac promoter. Active Fab of 50 kDa with an inter-chain disulfide bond has been isolated from the periplasm of E. coli in a one-step affinity purification in high yield (2 micrograms/ml of cells). The bacterially produced Fab is as active as purified mouse Fab in antigen-binding and competitive immunoassays. This is the first example of a completely synthetic Fab gene and provides an ideal system to probe the nature of antigen binding by anti-carbohydrate antibodies.

Cerebrovascular and cerebral metabolic effects of alterations in perfusion flow rate during hypothermic cardiopulmonary bypass in man.

Recent experimental and clinical investigations provide conflicting evidence regarding the effects of changes in the systemic flow rate from the pump oxygenator on cerebral blood flow and the cerebral metabolic rate of oxygen consumption. However, the results of existing clinical studies are difficult to interpret because of the confounding effects of differences in management of arterial carbon dioxide tension and use of anesthetic and vasoactive agents during cardiopulmonary bypass. To clarify the relationship among perfusion flow rate, cerebral blood flow, and cerebral metabolic rate of oxygen consumption in man during hypothermic cardiopulmonary bypass, we varied perfusion flow rate in random order to either 1.75 or 2.25 L.min-1.m-2 and studied cerebral blood flow (measured by clearance of xenon 133) and cerebral metabolic rate of oxygen consumption (estimated as the product of cerebral blood flow and the cerebral arteriovenous oxygen content difference) in patients managed with both the alpha-stat (group 1) and the pH-stat (group 2) methods of pH and arterial carbon dioxide tension adjustment. We measured the cerebral arteriovenous oxygen content difference using radial arterial and jugular venous bulb blood samples. In each patient other variables known to exert effects on cerebral blood flow and cerebral metabolic rate of oxygen consumption, including temperature, arterial carbon dioxide tension, arterial oxygen tension, mean arterial pressure, and hematocrit, were maintained constant between measurements. In both groups, mean arterial pressure at both pump flow rates was similar because of spontaneous reciprocal alterations in systemic vascular resistance, that is, as perfusion flow rate declined, systemic vascular resistance increased; as perfusion flow rate increased, systemic vascular resistance declined. Under these tightly controlled conditions, pump flow variation per se exerted no effect on cerebral blood flow or cerebral metabolic rate of oxygen consumption in either group.

Experimental and clinical studies with radiofrequency-induced thermal endometrial ablation for functional menorrhagia.

A method of ablating the endometrium has been introduced into clinical practice that uses radiofrequency electromagnetic energy to heat the endometrium, using a probe inserted through the cervix. Preliminary studies suggest that over 80% of patients treated will develop either amenorrhea or a significant reduction in flow. The advantages of radiofrequency endometrial ablation over laser ablation or resection are the avoidance of intravascular fluid absorption, simplicity (no special operative hysteroscopic skills are required), speed of operation, and reduced cost compared with the Nd:YAG laser. In this paper, we describe the experimental studies performed during development of this new technique.

Upregulation of gap junctional intercellular communication and connexin 43 expression by cyclic-AMP and all-trans-retinoic acid is associated with glutathione depletion and chemosensitivity in neuroblastoma cells.

PURPOSE: Downregulation of gap junctional intercellular communication (GJIC) has been implicated in carcinogenesis. This is a result of altered expression of connexins, the proteins that mediate GJIC, including connexin 43 (Cx43). Our aim was to evaluate the effect of known inducers of Cx43 on the chemosensitivity of the human neuroblastoma cell line IMR-32 to chemotherapeutic agents. METHODS: We examined the effect of dibutyryl-cyclic AMP (db-cAMP) and all-trans-retinoic acid (tRA) on Cx43 and GJIC, glutathione (GSH) and gamma-glutamyl-cysteine-synthetase (gamma-GCS) levels, and glutathione S-transferase (GST) activity. Finally, we performed cell survival assays to measure the response of IMR-32 cells to the chemotherapeutic drugs doxorubicin, melphalan and bis-chloronitrosourea (BCNU), after treatment with db-cAMP and/or tRA. RESULTS: Exposure to db-cAMP led to the upregulation of GJIC and Cx43 expression and phosphorylation. On the other hand, exposure to tRA led to the upregulation of GJIC but Cx43 expression and phosphorylation were not greatly affected. The combination of both agents was more potent in inducing GJIC in comparison to treatment with db-cAMP or tRA alone. Treatment with db-cAMP, but not with tRA, was associated with a significant increase in the cytotoxic effects of the anticancer drugs doxorubicin, melphalan and BCNU as shown by a decrease in their IC50 values. Concomitant exposure to db-cAMP and tRA, however, had a more pronounced effect on cell sensitization to chemotherapy drugs (particularly doxorubicin) than exposure to db-cAMP or tRA alone. Under the db-cAMP and tRA treatment conditions (which upregulate GJIC and modulate drug response), GSH levels were significantly reduced while the levels of GST and gamma-GCS activities remained unchanged. CONCLUSIONS: This study suggests that GJIC plays a role in cellular drug resistance, and highlights the potential use of GJIC modulators in combination with chemotherapy. Also, this is the first study exploring the ability of both db-cAMP and tRA to enhance cell chemosensitivity.

Laparoscopic hysterectomy and cancer.

Laparoscopic hysterectomy with or without oophorectomy is a procedure which is now gaining popularity in the UK. It has been clearly demonstrated that this technique is superior to abdominal hysterectomy and oophorectomy via laparotomy, and often replaces this procedure. In cases where vaginal hysterectomy is likely to prove difficult or impossible in the hands of most surgeons, the laparoscopic route is of value. In those cases where dense pelvic adhesions or poor vaginal access exist, or where oophorectomy is co-indicated, laparoscopic surgery converts operation via laparotomy to a less invasive procedure, with consequent benefits in terms of both patient care and bed occupancy. In the case of malignant disease, laparoscopic hysterectomy and oophorectomy is a viable alternative to open abdominal hysterectomy, but great care must be taken that patients with malignant disease are not under-treated.

STUDIES IN CRATAEGUS (ROSACEAE: MALOIDEAE) XIV. THE BREEDING SYSTEM OF CRATAEGUS CRUS-GALLI SENSU LATO IN ONTARIO.

Crataegus crus-galli L. sensu lato in southern Ontario is a complex of taxa, two of which appear to consist exclusively of both triploid and tetraploid individuals. While pollen fertility is reduced in triploids, both ploidy levels are characterized by production of eight nucleate aposporous embryo-sacs and hence remain seed-fertile; in addition, single, apparently sexual, embryo-sacs are found in the ovules of tetraploids. Agamospermy is shown experimentally to be pseudogamous. Polyploidy in C. crus-galli s.l. is accompanied by self-compatibility, in contrast to the self-incompatibility of diploid Crataegus species such as C. punctata, with which comparison is made. The weediness of the component taxa of C. crus-galli s.l., in general, and their tendency toward uniparental reproduction, in particular, may explain the homogeneity of their topodemes, and the way in which these topodemes may be markedly differentiated from one another even within a single taxon.

Iontophoretic delivery of model inorganic and drug ions.

The in vitro delivery of the inorganic ions Li+, Na+, K+, Mg2+, and Ca2+, and the model organic ions pyridostigmine and propranolol through various types of excised skin was investigated using a constant current iontophoretic system. The drug delivery rate was found to be linearly dependent on current for each ion. The slope of this linear dependence is defined as the iontophoretic flux and was used to calculate the efficiency of drug delivery which was found to be virtually independent of the type of skin employed. However, the efficiency of drug delivery was affected by the anode material and drug counterion employed in the iontophoretic system. In addition, the efficiency of delivery for divalent magnesium and calcium ions was found to be less than half that observed for the monovalent sodium and potassium ions. The in vivo iontophoretic delivery of pyridostigmine using the domestic weanling pig is also reported. The in vivo results were found to be similar to those observed in vitro.