Photosensitisation, crystal-associated cholangiohepatopathy, and acute renal tubular necrosis in calves following ingestion of Phytolacca octandra (inkweed).

CASE HISTORY: In March 2006, an outbreak of photosensitivity affecting 6-8-month-old Friesian heifer calves on a farm in the Rangitikei district of New Zealand was investigated. The calves were grazing wheat stubble paddocks that also had a variety of weeds, especially Phytolacca octandra (inkweed). They also had access to pond water that contained potentially toxic concentrations of the cyanobacteria (blue-green algae) Microcystis and Planktothrix spp. CLINICAL FINDINGS: Initially, affected animals showed acute irritation, agitation, reluctance to walk, recumbency in some animals, hyperaemia of unpigmented skin and jaundice. Serum chemistry revealed elevated liver enzyme activities and azotaemia. Later in the outbreak, exudative dermatitis with formation of crusts on unpigmented skin, dehydration and inappetence were notable signs, as well as occasional diarrhoea. PATHOLOGICAL AND TOXICOLOGICAL FINDINGS: Post-mortem examinations following euthanasia of four severely affected calves and a fifth animal that died naturally revealed livers that were grossly orange brown and mildly enlarged, and kidneys that were enlarged and pale brown. Microscopic lesions in the liver were mild; however, small birefringent crystals in the bile ducts were noted in the first two cases. In contrast, renal lesions were moderate to severe, and included prominent segmental tubular necrosis, granular and cellular casts, and mild interstitial non-suppurative inflammation. In the kidneys of animals examined later in the outbreak, there was early interstitial fibrosis as well as tubular regeneration, with numerous hyaline casts in the renal medulla. Inkweed plants had been heavily browsed, and recognisable portions of the plant were found in the gastrointestinal tracts of affected calves. Chemical analysis of inkweed material revealed triterpene saponins. No known hepatotoxic or nephrotoxic plants were identified in the paddocks. The hepatic lesions were not consistent with published descriptions of cyanobacterial toxicity. Sporidesmin toxicity was ruled out. DIAGNOSIS: Hepatogenous photosensitivity, crystal-associated cholangiohepatopathy, toxic acute renal tubular necrosis, associated with the ingestion of P. octandra, and possibly complicated by cyanobacteria in the water. CLINICAL RELEVANCE: Crystal-associated cholangiohepatopathy with photosensitivity in cattle is rare, and has only been reported in steroidal saponin-containing Brachiaria decumbens poisoning, in Brazil. The consistent pattern of toxic acute renal tubular necrosis was similar to that caused by the ingestion of Quercus, Amaranthus or Lantana spp. A combination of toxicities was conceivable but circumstantial evidence strongly implicated P. octandra. Further toxicological investigation of this plant is warranted before it can be listed as a known nephrotoxin of cattle.

Immunologic responses of bison to vaccination with Brucella abortus strain RB51: comparison of parenteral to ballistic delivery via compressed pellets or photopolymerized hydrogels.

This study compared responses of bison calves to 10(10)CFU of Brucella abortus strain RB51 (SRB51) delivered by parenteral or ballistic methods. Two types of biobullet payloads were evaluated; compacted SRB51 pellets or SRB51 encapsulated in photopolymerized poly(ethylene glycol) hydrogels. Bison were vaccinated with saline, parenteral SRB51 alone, or in combination with Spirovac, or ballistically with compressed SRB51 or hydrogel biobullets. Bison parenterally vaccinated with SRB51 had greater (P<0.05) immunologic responses when compared to control bison. Co-administration of Spirovac as an adjuvant did not influence immunologic responses. As compared to compressed SRB51 biobullets, ballistic vaccination with hydrogel biobullets increased cellular immune responses at some sampling times. Our data suggest that hydrogel formulations of SRB51 may be a superior alternative to compressed SRB51 tablets for ballistic vaccination of bison. Although preliminary, data suggests that immunologic responses of bison to SRB51 hydrogel bullets are similar to responses after parenteral vaccination with SRB51.

Photopolymerized hydrogel carriers for live vaccine ballistic delivery.

Photopolymerized poly(ethylene glycol) (PEG)-crosslinked hydrogels were assessed for their ability to serve as a payload vehicle to deliver a viable bacterial vaccine (Brucella abortus strain RB51 (RB51) to bison in Yellowstone National Park) ballistically using thermoplastic degradable Biobullets. PEG modified with degradable glycolide or lactide oligomers capped with photopolymerizable methacrylate groups served to crosslink the hydrogel vaccine carrier inside commercial hydroxypropylcellulose Biobullets. Release of 1 microm diameter model fluorescent particles from hydrogels followed known degradation trends for glycolide- and lactide-modified PEG hydrogels. All particles were released from PEG-co-glycolide hydrogels after approximately 10 days and PEG-co-lactide hydrogels after approximately 45 days following gel degradation. Minimal particle release was observed from pure PEG dimethacrylate hydrogels over 40 days. P. aeruginosa (strain PAO1) and RB51 live vaccines exhibit excellent viability following exposure to photopolymerization encapsulation within these gel matrices. Hydrogels photopolymerized into the payload chamber of Biobullets exhibit similar ballistic properties to commercially available Biobullets and penetrate and remain intact when fired intramuscularly into live elk for release of their gel payload in the host.

Design and synthesis of a new polymer drug delivery conjugate.

This work describes the design and synthesis of a novel polymer conjugate to facilitate intracellular release of attached cargo. Water soluble poly[N(2-hydroxypropyl) methacrylamide] with derivatizable pendant side chains was used as the polymer carrier. The membrane active Tat peptide was masked with poly(ethylene glycol) to inhibit non-specific interactions with exterior cell membranes, and then covalently linked to poly[N-(2-hydroxypropyl) methacrylamide]. A novel heterobifunctional crosslinker was synthesized containing both maleimide and aldehyde functionality to allow attachment of peptides to the polymer backbone through a pH sensitive bond. Analysis of the proposed conjugate by gel permeation chromatography, nuclear absorbance spectroscopy, and absorbance measurements indicate that the desired compound has been synthesized.

Design strategies to improve soluble macromolecular delivery constructs.

Macromolecular therapeutics provide numerous benefits for the delivery of cytotoxic or poorly soluble drugs in vivo. However, these constructs often encounter barriers for drug delivery on both the systemic and subcellular level. Many soluble polymer carriers have been designed to surmount specific physiological barriers individually, but less work has been dedicated to designing an all-encompassing construct that addresses multiple therapeutic barriers at once. Incorporation of multiple agents already individually known to increase effectiveness into one carrier could further improve current drug delivery technology. Recent developments in subcellular delivery of therapeutic agents in soluble macromolecular carriers are discussed in the context of the future possibility for the design of an all-encompassing soluble multi-functional drug delivery vehicle.

Mechanical ventilation in hematopoietic stem cell transplantation: can We effectively predict outcomes?

BACKGROUND: Survival rates from mechanical ventilation (MV) in allogeneic bone marrow transplantation are poor, but little is known about the need for and outcomes from MV in patients who undergo autologous hematopoietic stem cell transplantation (AHSCT). STUDY OBJECTIVE: To determine the frequency of and risk factors for the use of MV in recipients of AHSCT and to identify predictors of survival in mechanically ventilated AHSCT patients. DESIGN: Retrospective, cohort analysis SETTING: Tertiary-care, university-affiliated medical center. PATIENTS: One hundred fifty-nine consecutive patients who underwent AHSCT. INTERVENTIONS: Patient surveillance and data collection. MEASUREMENTS AND RESULTS: The primary outcome measure was the need for MV, and the secondary end point was survival after MV. Of 159 patients, 17 required MV (10. 7%). Three variables were associated with the need for MV: increasing age, use of total body irradiation in the conditioning regimen, and treatment with amphotericin B. As a screening test to predict the need for MV, no risk factor had a sensitivity or specificity > 82%. Three of the 17 mechanically ventilated patients (17.6%) survived to discharge. Only the mean APACHE (acute physiology and chronic health evaluation) II score separated survivors from nonsurvivors (21.7 vs 31.4; p = 0.029). Both the duration of MV and the length of stay in the ICU were similar in survivors and nonsurvivors. CONCLUSIONS: We conclude that MV is infrequently needed following AHSCT. Although survival after MV in these patients is limited, clinical variables do not reliably allow clinicians to prospectively identify patients destined to die.

A survey method for investigating ethical decision making in family practice.

BACKGROUND: The tension between respect for patient autonomy versus concern for patient welfare is a challenging ethical issue for physicians. The purpose of this research was to describe a method for analyzing ethical decisions and to report the results of a survey of ethical decision making among family physicians. METHODS: We developed a survey instrument that used simulated case scenarios, each of which posed an ethical dilemma. The ethical problems on the survey included the extent to which diagnostic information should be revealed to patients, the extent to which physicians should become involved in patients' life-style issues, and how to deal with patients' family problems. We mailed the questionnaire to 1,300 US family physicians. RESULTS: Six hundred seventy-four physicians responded. Respondents did not deal with the simulated ethical problems in a uniform manner and often tended to respond more to specific details of a case rather than the overall ethical dilemma posed. Physicians who chose a course of action giving patients more control were motivated by factors that showed respect for patient autonomy. On the other hand, physicians who chose a course of action giving patients less control were not motivated by factors suggesting a concern for patient welfare. CONCLUSIONS: Based on responses to simulated case scenarios, family physicians did not demonstrate a uniform approach but rather a more contextual one. Respect for patient autonomy was linked to family physicians' reported courses of action.

Ethical decision making by family doctors in Canada, Britain and the United States.

Family doctors in Canada and the U.S. and general practitioners in England and Wales were sent a questionnaire containing six cases that raised moral issues. The doctors were asked to select the most appropriate course of action for each case as well as reasons for that decision. The ethical problems concerned how much information to divulge to patients, how extensively a physician should become involved in the lifestyles of patients, and how to deal with a possible family problem. The respondents selected different courses of action for the cases. More U.S. than Canadian or British physicians chose to divulge information, while more British than Canadian or U.S. physicians chose not to become involved in patients' lifestyles. Physicians who chose to divulge information were likely to be young, male, live in a small community, and have no academic affiliation. Physicians who chose not to become involved in lifestyle issues were likely to be young, church attenders, and in group practice in a small community.

Ethical decision making by British general practitioners.

General practitioners in England and Wales were sent a questionnaire asking how they would handle the ethical problems posed by six case vignettes and their reasons for their decisions. The ethical problems included: how much information to divulge to patients, how extensively a physician should become involved in the lifestyles of patients and how to deal with a possible family problem. The varying patterns of response to the six cases suggested that ethical issues are resolved in a case-by-case, not a theoretical, basis.

Meperidine and normeperidine distribution in the rhesus monkey.

Previous work has shown that both meperidine and normeperidine are transferred across the placenta to the fetus. Little is known in primates, however, about the tissue deposition of these compounds. Four pregnant, dated rhesus monkeys within one week of term were anesthetized for cesarean delivery. An equal mixture of meperidine and normeperidine was administered as an intravenous bolus 10 minutes before delivery (1.25 mg/kg). The infants were then sacrificed at 20 minutes after birth and the concentration of the compounds in various organ systems were analyzed by gas-liquid chromatography and mass spectroscopy (GLC-MS). The infant serum 20 minutes after delivery revealed a meperidine concentration of 2.23 micrograms/ml and a normeperidine level of 0.67 micrograms/ml (3:1). In contrast, the tissues analyzed showed a much higher concentration of the metabolite in the liver (1:7), gallbladder (1:3), and brain (1:2). Other tissues, such as muscle and kidney, demonstrated equal levels of the two compounds. The authors conclude that normeperidine is quickly transferred to fetal tissues and to a greater degree than the parent compound in certain organs. The increased distribution, particularly in the brain, could account for the toxic actions in the cerebrum of the derivatives of meperidine.

Ethical decision making by Canadian family physicians.

Canadian family physicians were sent questionnaires that asked how they would handle the ethical problems posed by six sample cases and what reasons were relevant to their decisions. The ethical problems concerned how much information to divulge to patients, how extensively a physician should become involved in the lifestyles of patients and how to deal with a possible family problem. The study identified characteristics of family physicians that affect their ethical decision making and tested a theoretical model that regards ethical problems as conflicts between respecting patient autonomy and promoting patient welfare. The varied responses suggested that ethical issues are resolved on a case-by-case, rather than a theoretical, basis. Certification in family medicine was the only characteristic associated with a consistent pattern of responses; certificants were more likely than other physicians to involve patients in decisions.

Meperidine and normeperidine metabolism in the rhesus monkey.

Meperidine and its principle metabolite, normeperidine, were given intravenously to four non-human primates prior to cesarean delivery in an equivalent dose for human parturients. The status of the infants regarding neonatal depression was assessed at delivery. Repeated blood samples from both the mother and the neonate were obtained over a period of 4 days. The levels of meperidine and normeperidine were analyzed. The results showed that the metabolism of meperidine and normeperidine in the non-human primate was essentially the same as that observed in the human parturient. In addition, normeperidine appeared to be more toxic than meperidine to the neonate. Finally, there does not appear to be an evidence for neonatal metabolism of meperidine to normeperidine.

How family physicians approach ethical problems.

The defining features of family medicine as described in the literature have important ethical implications. In an attempt to study the day-to-day practice of family physicians regarding these ethical issues, a 28-item questionnaire was sent to 95 part-time and 17 full-time family physician teachers associated with the University of Western Ontario's Department of Family Medicine. Of the 112 questionnaires mailed out, 97 were returned for a response rate of 86.6 percent. There was a significant spread of answers, suggesting there is no uniform opinion in the sample population. The findings suggest that there are important differences between the description of family medicine in the literature and what the family physicians in this study do in their day-to-day practice. The family physicians in this study, while prepared to coerce patients, were not prepared to discharge from their practices patients who were noncompliant. Physician age is an important variable in some ethical decisions, but not in others.

Sex and the mentally retarded: is sterilization the answer?

The sexuality of the mentally handicapped concerns them, their parents, their family physicians and other health professionals. Parents need advice, and the well-informed family physician who has the family's trust is in a good position to give it. However, the physician must protect the rights and autonomy of the mentally handicapped patient concerning contraception, surgical sterilization and hysterectomy. Before recommending a method of contraception, the physician must identify any medical risks and be satisfied that the patient clearly understands risks and advantages. Sterilization as a method of contraception should never be considered unless the patient chooses it; involuntary sterilization can produce serious and significant psychological damage. The physician must give a detailed explanation to make sure the patient electing to be surgically sterilized understands the procedure and has fully consented without coercion. Hysterectomy should never be used as a method of sterilization.

Well Baby Care: The Nurse's Job?

The traditional content of the well baby examination has changed to include more health screening, emotional support and educational input. It has been suggested that the well baby care should now be done by nurses. Fifty-five mothers surveyed at the University of Western Ontario indicated that for them, the nurse was as important a source of information as the doctor. In some cases, such as advice on the telephone, nurses scored higher than doctors; however, younger mothers appeared to view the nurse less positively than older mothers did. Experienced mothers viewed the nurse more positively than did first-time mothers. Results suggest that mothers' perceptions would be compatible with a new and expanded role in well baby care for the family practice nurse.

Well child care in family medicine part 2: immunization and nutrition.

Part 1 of this article, published last month, outlined the work of a University of Western Ontario committee in establishing criteria for the well child examination. This final section describes the committee's schedule for immunization, emphasizing that the schedule itself is far less important than the need to ensure completion of an immunization program. It also outlines the committee's findings on infant nutrition, with strategies for promotion of breast-feeding.