Crystallization of a salt of a weak organic acid and base: solubility relations, supersaturation control and polymorphic behavior.

Control of crystallization processes for organic salts is of importance to the pharmaceutical industry as many active pharmaceutical materials are marketed as salts. In this study, a method for estimating the solubility product of a salt of a weak acid and weak base from measured pH-solubility data is described for the first time. This allows calculation of the supersaturation of solutions at known pH. Ethylenediammonium 3,5-dinitrobenzoate is a polymorphic organic salt. A detailed study of the effects of pH, supersaturation, and temperature of crystallization on the physical properties of this salt shows that the desired polymorph may be produced by appropriate selection of the pH and supersaturation of crystallization. Crystal morphology is also controlled by these crystallization conditions.

The Health Status Questionnaire: achieving concordance with published disability criteria.

AIM: To compare the Health Status Questionnaire with established methods of assessing disability in preterm and very low birthweight infants. METHOD: All survivors of gestational age <31 weeks or birth weight <1500 g, born in 1994 to women resident in Wales were identified. Assessments were by a single observer at a median corrected age of 28.3 months and included the Health Status Questionnaire and a Griffiths developmental test. Outcome was also described according to criteria for disability used in three published studies. RESULTS: There were 297 survivors of which 279 (94%) were assessed. Using the Health Status Questionnaire, severe disability was found in 12.9% of cases compared to 8.2%, 2.9%, and 3.6% using the Northern, Victorian, and Mersey outcome criteria respectively. Following the simple modifications of removing the growth criteria from the Health Status Questionnaire and reclassifying the severe disability group in the Victorian and Mersey criteria, comparable severe disability rates ranging from 7.9% to 9.3% were found. CONCLUSION: The Health Status Questionnaire requires no formal training, is rapid to perform, and with simple modifications provides comparable results to established methods of assessing disability. Its use in the follow up of preterm and very low birthweight infants should be encouraged.

The pulmonary environment promotes Th2 cell responses after nasal-pulmonary immunization with antigen alone, but Th1 responses are induced during instances of intense immune stimulation.

The purpose of this study was to determine the nature of the CD4(+) Th cell responses induced after nasal-pulmonary immunization, especially those coinciding with previously described pulmonary inflammation associated with the use of the mucosal adjuvant, cholera toxin (CT). The major T cell population in the lungs of naive mice was CD4(+), and these cells were shown to be predominantly of Th2 type as in vitro polyclonal stimulation resulted in IL-4, but not IFN-gamma, production. After nasal immunization with influenza Ag alone, Th2 cytokine mRNA (IL-4 and IL-5) levels were increased, whereas there was no change in Th1 cytokine (IL-2 and IFN-gamma) mRNA expression. The use of the mucosal adjuvant, CT, markedly enhanced pulmonary Th2-type responses; however, there was also a Th1 component to the T cell response. Using in vitro Ag stimulation of pulmonary lymphocytes, influenza virus-specific cytokine production correlated with the mRNA cytokine results. Furthermore, there was a large increase in CD4(+) Th cell numbers in lungs after nasal immunization using CT, correlating with the pulmonary inflammatory infiltrate previously described. Coincidentally, both macrophage-inflammatory protein-1alpha (MIP-1alpha) and MIP-1beta mRNA expression increased in the lungs after immunization with Ag plus CT, while only MIP-1beta expression increased when mice were given influenza Ag alone. Our study suggests a mechanism to foster Th1 cell recruitment into the lung, which may impact on pulmonary immune responses. Thus, while Th2 cell responses may be prevalent in modulating mucosal immunity in the lungs, Th1 cell responses contribute to pulmonary defenses during instances of intense immune stimulation.

Differences in attitudes regarding teaching and research orientations between allied health faculty and administrators in academic health centers.

The congruence between faculty's and administrators' attitudes toward teaching, research, and the rewards associated with them has implications for the practices the groups follow and for the decisions they make related to promotion, tenure, and merit. This article reports the findings from a national study of allied health faculty and administrators at public academic health centers regarding their attitudes toward teaching, research, and the reward systems related to both. The administrators and faculty at the participating academic health centers did not differ in their views regarding research orientation and rewards related to research. The faculty, including tenured and tenure-track, and department chairs indicated a higher teaching orientation than did the deans, while tenure-track faculty expressed less belief that rewards influence teaching than did tenured faculty, department chairs, and deans.

Immunoglobulin A (IgA) responses and IgE-associated inflammation along the respiratory tract after mucosal but not systemic immunization.

The purpose of the present study was to determine the extent of immunologic responses, particularly immunopathologic responses, within the upper and lower respiratory tracts after intranasal immunization using the mucosal adjuvant cholera toxin (CT). BALB/c mice were nasally immunized with influenza virus vaccine combined with CT. The inclusion of the mucosal adjuvant CT clearly enhanced generation of antibody responses in both the nasal passages and lungs. After nasal immunization, antigen-specific immunoglobulin A (IgA) antibody-forming cells dominated antibody responses throughout the respiratory tract. However, IgG responses were significant in lungs but not in nasal passages. Furthermore, parenteral immunization did not enhance humoral immunity in the upper respiratory tract even after a nasal challenge, whereas extrapulmonary lymphoid responses enhanced responses in the lung. After nasal immunization, inflammatory reactions, characterized by mononuclear cell infiltration, developed within the lungs of mice but not in nasal passages. Lowering dosages of CT reduced, but did not eliminate, these adverse reactions without compromising adjuvancy. Serum IgE responses were also enhanced in a dose-dependent manner by inclusion of CT. In summary, there are differences in the generation of humoral immunity between the upper respiratory tract and the lung. As the upper respiratory tract is in a separate compartment of the immune system from that stimulated by parenteral immunization, nasal immunization is an optimal approach to generate immunity throughout the respiratory tract. Despite the promise of nasal immunization, there is also the potential to develop adverse immunopathologic reactions characterized by pulmonary airway inflammation and IgE production.

Rupture of the pectoralis major muscle. Outcome after repair of acute and chronic injuries.

We retrospectively studied 17 cases of distal pectoralis major muscle rupture to compare the results of repair in acute and chronic injuries and to compare operative and nonoperative treatment. Thirteen patients underwent surgery (six acute injuries [less than 2 weeks after injury] and seven chronic injuries) and four had nonoperative management. The mean age of the patients at injury was 29, and 10 of the 17 injuries were the result of weight lifting. Follow-up ranged from 18 months to 6 years (mean, 28 months). All patients subjectively rated strength, pain, motion, function with strenuous sporting activities, cosmesis, and overall satisfaction. Objectively, patients were examined for range of motion, deformity, atrophy, and strength. Isokinetic strength testing was performed in eight patients: six treated operatively (three acute and three chronic) and two treated nonoperatively. Overall subjective ratings were 96% in the acute group, 93% in the chronic group, and only 51% in the nonoperative group. Isokinetic testing showed that patients operated on for acute injuries had the highest adduction strength (102% of the opposite side) compared with patients with chronic injuries (94%) or nonoperative treatment (71%). There were no statistically significant subjective or objective differences in outcome between the patients treated operatively for acute or chronic injuries, but these patients fared significantly better than patients treated nonoperatively.

Leadership progression in schools of allied health.

The purpose of this study was to determine the number of future vacancies in the lead administrator positions (i.e., dean or director) in schools and units of allied health academic programs and the potential pool of candidates for the positions. The survey was mailed to the deans or directors of the 100 institutional members of the Association of Schools of Allied Health Professions (ASAHP). The response rate was 80%. Of the respondents, 58% reported intentions to vacate their positions in the next decade; another 28% reported being unsure of their plans. Retirement was listed as the primary reason (76%). The respondents listed 239 qualified candidates for their positions, or 5.2 candidates per vacancy. The ASAHP's initiatives in leadership development appear to have prepared allied health education for leader succession.

Confidential enquiry into deaths due to prematurity.

The aim of this study was to audit the management of neonatal respiratory distress syndrome (RDS) in a geographically defined population using a retrospective peer review of case notes. The subjects were 49 infants of 24-36 wk gestation with a birthweight >499 g, and dying as a consequence of prematurity at <1 y of age in Wales during 1996. Forty-four infants (90%) were delivered in a unit with staff experienced in the management of preterm birth. Of the 30 infants <30 weeks' gestation, 29 (97%) received neonatal intensive care on a (sub)regional unit. Predelivery corticosteroids were indicated in 34 cases and administered in 31 (91%). Resuscitation at birth was indicated in 47 infants and conducted satisfactorily in 42 (89%). Temperature on admission to the neonatal unit was not recorded in 7 infants; in the other 42 it was >35.5 degrees C in 21 (50%). Early surfactant therapy was administered to 31/34 (91%) infants still intubated 120 min after birth, but was given within 30 min to only 8 (24%). Mechanical ventilation was assessed in 41 infants and considered to be good in 23 (56%). Cardiovascular therapy was evaluated in 40 infants requiring active support and considered to be good in 31 (78%). We concluded that neonatal RDS was generally well managed, thermal care during resuscitation was poor, surfactant should be administered more promptly, and deficiencies in the management of ventilation were common and related mainly to poor anticipation and a slow response to problems.

Clinical use of FFP: results of a retrospective process and outcome audit.

An audit has been carried out on the usage of 216 units of fresh frozen plasma (FFP) issued to 41 patients. This involved the systems of FFP issue, the appropriateness of prescription as well as the recorded benefits. Sixty-six per cent of the initial requests for FFP appeared to satisfy criteria for appropriate use. Review of the case notes resulted in some changes to earlier decisions and a slight increase to 73% of those accepted as valid. Only 94% of the FFP issued could be proved to have been given to identified patients and only 88% of case notes showed the reason for treatment. Pre- and post-treatment coagulation results were available for all patients. In 15% of cases, pretreatment results were not significantly abnormal, and consequently no post-treatment improvement found. Coagulation improvement was documented in 78% of cases, and clinical statements on patient progress noted in 40%. In 80% of cases, the patient received other blood products carrying a potential virus risk. Six of the remaining eight patients were treated to stabilize oral anticoagulation. For these patients, virus-inactivated prothrombin concentrates could have been used, resulting in almost the same reduction in virus transmission risk for the group of 41 patients as could be obtained by using virus-inactivated FFP.

The fate of the syndesmosis in type C ankle fractures: a cadaveric study.

Ankle fractures that involve a fracture of the fibula above the syndesmosis (AO type C) associated with a medial lesion are always said to indicate rupture of the inferior tibiofibular syndesmosis. This study shows that fresh cadaver ankles subjected to a combination of abduction and direct lateral force over the shaft of the fibula consistently produce displaced bimalleolar ankle fractures without disruption of the inferior tibiofibular syndesmosis. The results of this study suggest that the presence of an AO type C ankle fracture does not necessarily indicate diastasis of the inferior tibiofibular joint and, therefore, internal fixation of the syndesmosis of the fracture may not be indicated.

Providing rehabilitative services in rural communities: report of a conference.

Rural communities have a disproportionate need for rehabilitative services, partly attributable to an aging population and higher incidence of occupational injuries. Despite increased need, many rural communities find rehabilitative services unavailable due to personnel shortages, maldistribution of health care personnel, and related recruitment and retention issues. The National Rural Health Association and the Division of Associated, Dental, and Public Health Professions of the Health Resources and Services Administration co-sponsored a conference to explore issues related to ensuring that rural communities have access to vital rehabilitation services provided by allied health professionals. The status of rehabilitative care in rural settings and the barriers to improvement in services delivery were described by consumers, providers, educators, and public and private agency representatives. Recommendations directed to state and federal authorities, educational institutions, and professional organizations centered around increasing the supply of appropriately trained allied health providers. Improving retention of rehabilitative personnel in rural areas could be achieved by specific changes to the practice climate.

A tungsten-supplemented diet delivered by transplacental and breast-feeding routes lowers intestinal xanthine oxidase activity and affords cytoprotection in ischemia-reperfusion injury to the small intestine.

Ischemia-reperfusion injury has been implicated as playing a major role in the development of necrotizing enterocolitis, a major cause of morbidity and mortality in the newborn. A tungsten-supplemented molybdenum-free diet can reduce xanthine oxidase (XO) enzyme activity in the intestine, which in turn reduces the generation of oxygen radicals after an ischemia-reperfusion insult. This study evaluated the ability of this diet to be effective by indirect means, ie, transplacental and breast-feeding routes. XO activity of the intestine was measured in three groups of CD-1 white rats: I, weanlings fed the tungsten diet or standard chow for 1 week; II, 1-day-old rat pups whose mothers were maintained on the tungsten or standard chow for 7 to 10 days prior to term; and III, rat pups at 1 and 3 weeks after birth whose lactating mothers were maintained on the tungsten or standard chow. Some animals from group III also underwent either a 30- or 60-minute episode of occlusion of the superior mesenteric artery (SMA) to evaluate the protective effects of the diet. XO activity was significantly reduced in all groups receiving the tungsten diet (P less than .0001). Blinded histopathologic studies of the entire small bowel showed significantly less villar necrosis (P less than .05) and fibrosis (P less than .0001) in the tungsten-treated group than in the controls. In the 60-minute occlusion study all tungsten-group animals survived, whereas 7 of 12 in the control group died of intestinal infarction within 24 hours (P less than .001).(ABSTRACT TRUNCATED AT 250 WORDS)

Chronic lymphatic leukaemia: an investigation of HLA antigen frequencies and white cell differential counts in patients, relatives and controls.

Histocompatibility antigen (HLA) frequencies in chronic lymphatic leukaemia (CLL) patients and control subjects were compared with respect to disease susceptibility and prognosis. Additionally, HLA and full blood count data were compared in relatives of 25 patients and 31 controls. We found no association of HLA with susceptibility although the presence of HLA B12, alone or in combination with HLA A2, indicated better prognosis. Relatives HLA identical with the patients showed no evidence of white cell disorder when compared with haplo- or non-identical relatives, or controls. As a group, however, relatives of patients had fewer lymphocytes than relatives of controls.

A comparison of DNA-RFLP typing with serology and mixed lymphocyte reaction in the selection of matched unrelated bone marrow donors.

Eleven leukaemic patients and 43 potential unrelated marrow donors were typed serologically, tested in mixed lymphocyte reaction (MLR) and typed by restriction fragment length polymorphism (RFLP) analysis. RFLP typing data were compared with DR serology and MLR results. Eleven of the 54 individuals showed discrepancies between DR serology and RFLP DR assignment. RFLP DR/DQ mismatch always correlated with positive MLR, but RFLP identity was present in both MLR negative and MLR positive pairs. RFLP typing cannot reliably predict a negative MLR response, but we suggest that it should be used in the selection of unrelated marrow donors to exclude mismatched donors from testing in the MLR. This will facilitate donor searches by reducing the number of MLR performed.

Mechanisms of conversion of xanthine dehydrogenase to xanthine oxidase in ischemic rat liver and kidney.

Previous studies have proposed and supported a role for the proteolytic, irreversible conversion of xanthine dehydrogenase to xanthine oxidase (XO) in postischemic injury in a wide variety of organs. A second mechanism of conversion, due to sulfhydryl modification and reversible with dithiothreitol (DTT), is potentially important but has not been well investigated. In this study rat liver and kidney were found to produce significant amounts of DTT-reversible XO during normothermic global ischemia. Formation of reversible XO precedes that of irreversible XO by approximately 0.5 h with a strong correlation (r = 0.92) existing between the rate of irreversible XO formation and the concentration of reversible XO. The formation of reversible XO is preceded by a depletion of glutathione with concentrations of glutathione during ischemia correlating (r = 0.85) with the observed concentration of reversible XO. While a large increase in the extent of liver damage occurs concurrently with conversion in an in vivo liver model of liver ischemia, an ischemia-reperfusion regimen (1 h of ischemia plus 0.5 h of reperfusion) that resulted in no conversion caused significant elevations in serum glutamic pyruvic transaminase and serum glutamic-oxaloacetic transaminase. Rats depleted of XO by tungsten dieting release 65% less enzyme after the same insult, suggesting that endogenous XO may also participate in the damage process independent of any conversion.

Purification and characterization of calpain from human polymorphonuclear leukocytes.

Recent studies have demonstrated that a calcium-sensitive protease converts Ca2+/phospholipid-dependent protein kinase C to a Ca2+/phospholipid-independent form during the activation of human neutrophils. In this paper, the results of the purification and characterization of a calcium-dependent cytosolic protease from neutrophils is reported. Calcium-dependent protease has been purified 1062-fold from human neutrophils and behaves as a single species on native polyacrylamide gels. The protease is active in the neutral pH range with no observable activity amide gels. The protease is active in the neutral pH range with no observable activity at pH values greater than 8.0, has an absolute requirement for calcium for expression of activity with half-maximal activity observed at 12 microM free calcium, and has an apparent molecular weight of 110,000 based on gel filtration. The protease requires the presence of dithiothreitol for activity and is inhibited by sulfhydryl inhibitors, leupeptin, and antipain but not by serine protease inhibitors, pepstatin, or orthophenanthroline. The protease is also susceptible to inactivation by autoproteolysis. Based on the similarities of this calcium-dependent protease with calpains from a variety of other mammalian tissues, the protease isolated from human neutrophils appears to be a calpain I.

Free radical-producing enzyme, xanthine oxidase, is undetectable in human hearts.

Samples from four human hearts were analyzed for both their xanthine dehydrogenase and xanthine oxidase content. We used the conventional spectrophotometric assay and a more sensitive fluorometric assay to determine the content of enzyme in these samples. In no case could any activity be detected. We conclude that human hearts must contain less than 2.0 nU/g of activity. This makes it unlikely that xanthine oxidase is a significant source of O2 free radicals in the ischemic human heart or that xanthine oxidase inhibitors will be of therapeutic value in that setting.

Conversion of xanthine dehydrogenase to oxidase in ischemic rat tissues.

In response to global ischemia, tissue xanthine dehydrogenase was converted to xanthine oxidase in all tissues with half-times of conversion at 37 degrees C of approximately 3.6, 6, 7, and 14 h for the liver, kidney, heart, and lung, respectively. The time course of enzyme conversion at 4 degrees C was greatly extended with half-conversion times of 6, 5, 5, and 6 d for the respective tissues. Increases in xanthine oxidase activity were accompanied by the appearance of a distinct new protein species with greater electrophoretic mobility. The oxidase from ischemic rat liver was purified 781-fold and found to migrate with a higher mobility on native gels than the purified native dehydrogenase. Sodium dodecyl sulfate profiles revealed the presence of a single major band of 137 kD for the native dehydrogenase, whereas the oxidase had been partially cleaved generating polypeptides of 127, 91, and 57 kD. Polypeptide patterns for the oxidase resemble those seen following limited in vitro proteolysis of the native dehydrogenase supporting a proteolytic mechanism for the conversion of xanthine dehydrogenase to oxidase in ischemic rat liver.