[Study of the efficacy and tolerance of imipenem-cilastatin used as monotherapy for the adjuvant treatment to surgery of peritonitis. Results of a French multicenter study including 257 patients].

The antibiotic treatment of peritonitis classically resorts to the association of two and even three molecules. In order to test the efficacy of a single-drug therapy with Tienam* imipenem/cilastatin) as an adjunctive treatment associated to surgery for perforation peritonitis, an open, non-comparative study of 257 patients was carried out in 28 departments. Imipenem is the first beta-lactam antibiotic of the carbapenem family. This antibiotic seems to be particularly useful for the treatment of mixed polymicrobial infections such as peritoneal infections, owing to its activity spectrum covering Gram-positive and Gram-negative, aerobic and anaerobic germs, including strands with multiple resistances (Enterobacter, Pseudomonas aeruginosa, Serratia marcescens, Acinetobacter, Enterococcus and Bacteroides fragilis). A total of 212 patients were assessed with a treatment averaging 7 days. The five most frequently isolated bacteria were Escherichia coli, streptococci, Bacteroides, Proteus and Klebsiella. The healing or improvement rate was 95.3% (202/212). Seven cross-infections occurred during of after the treatment. Tolerance is good in 96% of all cases. Adverse effects were infrequent and mild: the hepatic and hematological alterations never required the interruption of the treatment and they were reversible; the treatment was interrupted in one patient only because of omental tremulation.


[Uretero-vaginal fistulas: diagnosis and operative tactics. Apropos of 19 personal cases].

Personal experience of the treatment of 19 uretero-vaginal fistulae, observed from september 1987 to june 1991 on 17 patients in Africa is described and analysed. Occurring after gynecological or obstetrical surgery, the main cause is hysterectomy (82.3%). Elements for diagnosis were: the appearance of a urine leak, which in most cases came rapidly, echography, and most important, intravenous urography (IVU). Surgical management in all of the cases was mainly aimed at conservation. One end-to-end anastomosis and 18 cuff reimplantations were performed, combined in 2 cases with a sub-mucus tunnel (Politano), in 14 cases combined with a tubular Boari bladder flap (wherein 1 case was bilateral), 3 combined with a bladder psoas hitch and 2 with an isolated ileal graft (ileo-uretero-cystoplasty). One case of vesicouterine fistula and 4 associated vesicovaginal fistulae benefited from a simultaneous surgical operation. In this study of 17 patients treated, except for one patient deceased 14 months following a neoplastic recurrence, the results were excellent. 16 patients were cured. Follow-up extended to more than a year and have shown the perfect conservation of the excretory ducts in all of the cases studied. The cuffed ureterovesical reimplantation combined with a tubular bladder plasty definitively seem to be a most reliable management technique for all ureter injury encountered. While allowing the preservation of the kidney located just below, it has, in particular, prevented ureter stenosis. If the use of simpler methods (psoas bladder hitch) may be sufficient for some cases, the use of more complex methods (ileo-uretero-cystoplasty) for other cases, may be indispensable.


[Gastric schwannoma. A case diagnosed by puncture biopsy].

One case of schwannoma of the stomach diagnosed with ultrasound-guided biopsy puncture is reported. This diagnosis is usually not established with radiographic and endoscopic examinations. A preoperative diagnosis allows partly predicting the type of exeresis to be performed. On the other hand, guided biopsy puncture seldom allows establishing a prognosis, for which the criteria are based on the analysis of the whole tumor and the possible discovery of synchronous or metachronous metastases.


[Anorectal malignant melanomas. Apropos of 2 new cases].

Clinical and therapeutic characteristics of anorectal melanoma have been studied about 2 new cases. The initial symptoms were often misdiagnosed with hemorrhoids disease. This cancer carries a bad prognosis but the best treatment seems to be abdominoperineal resection (APR) when the thickness of the melanoma is under 3 mm. Over this limit, APR alone will not cure this disease. Curative treatment will probably involve a combined therapy with local and systemic therapies.


Retention of C60 and C70 fullerenes on reversed-phase high-performance liquid chromatographic stationary phases.

The separation of C60 and C70 fullerenes on four different polysiloxane stationary phases was examined. It was determined that polar solvents can be used as mobile phases effectively for the separation of fullerene molecules. Unlike previously published work, a polymeric octadecyl siloxane (ODS) stationary phase provided higher separation factors for C70/C60 than did monomeric ODS stationary phases or phenyl substituted stationary phases. For example, for a methanol-diethyl ether (50:50, v/v) mobile phase and C60, k' approximately 5.0 separation factors, alpha = 3.3, were achieved with polymeric ODS compared to alpha = 2.2, with a monomeric ODS stationary phase. A linear solvation energy relationship (LSER) was used to model the importance of solvent interactions and stationary phase interaction to solute retention.


Studies on an abnormally sharpened elution peak observed in counter-current chromatography.

Counter-current chromatography (CCC) of the bromoacetylation product of 3,3',5-triiodo-L-thyronine (T3) produced an unusually sharp peak for the desired product, N-bromoacetyl T3 (BrAcT3). A series of experiments revealed that bromoacetic acid, probably present as a side reaction product in the sample solution, was responsible. This compound repressed the ionization of the carboxyl group of BrAcT3 forcing it into the less polar stationary phase until the bromoacetic acid had eluted completely from the apparatus. At this point, the sudden increase of pH and consequent ionization of the BrAcT3 allowed the ammonium salt of the latter to enter the more polar moving phase where it eluted rapidly from the column as a sharp peak. The same phenomenon was observed in the CCC fractionation of a series of indole auxins where addition of trifluoroacetic acid to the sample caused peak sharpening by the same process. The phenomenon recalls pH gradient elution and isoelectric focussing except that the substance responsible for the pH range here is added along with the sample in one bolus forming a sharp pH gradient at its trailing edge. As with gradient elution, the technique is of practical interest since it permits collection of the eluting compounds with increased detectability in fewer fractions. The technique can also enhance separation of compounds whose partition coefficients differ with a change in pH.


[Role of surgery in the treatment of dissections of the extracranial internal carotid artery. Apropos of a case, review of the literature].

The authors report about one operated case of spontaneous dissection of the extracranial internal carotid artery close to the bifurcation. The persistence of a floating thrombus in a 60% stenosis after a six-week treatment with heparin led to establishing the indication for surgery. The surgical indication remains exceptional, considering the natural history of dissections and the frequency of repatency of the arterial lumen. This type of surgery is mainly for sequellae such as stenosis, thrombi or saccular aneurysms, whose emboligenic potential leads to operating (exeresis and graft on the internal carotid artery) if the anatomical location of the lesion makes it possible.


[Parietal endometriosis on a cesarean scar. Apropos of two cases].

Parietal endometriosis is a rare disease, for which the pathogenesis is still ill-known and the diagnosis frequently difficult. The author reports about two cases of endometriosis on cesarean scars and, in the light of the literature, sums up the elements of the diagnosis as well as the therapeutic course of action.


Evaluation of peptide-peptide interactions using reversed-phase high-performance liquid chromatography.

The separation of peptides during RP-HPLC depends mainly upon differential hydrophobic interactions of the individual peptides being separated with the C18 group of the stationary phase. We have examined the behavior of dimeric disulfide-linked model peptides during RP-HPLC in order to study self-induced conformational effects. A set of 18 analogues of the amphipathic alpha-helical sequence Ac-LKLLKKLLKKLKKLLKKL-NH2 was used for this study. These analogues differed only by the successive replacement of each position with a cysteine. Strong peptide-peptide interactions, occurring through interchain hydrophobic forces, resulted in a presenting face to the C18 group, consisting primarily of lysine residues and, in turn, in early retention times. Three homo-dimers were also found to be strongly alpha-helical in water as determined by circular dichroism spectroscopy.


[Acute dissection of the infrarenal aorta and horseshoe kidney. Apropos of a case and review of the literature].

We report about one case of acute dissection of the infrarenal abdominal aorta associated with a horseshoe kidney. A few points in the history of this 47-year-old patient deserve being underscored: the absence of an "etiological" factor of aortic dissection, the presence of five renal arteries, illustrating the complex vascularity of a horseshoe kidney, the specific surgical problems arising from both a lesion of the aortic junction and a horseshoe kidney. On the basis of the literature, we underline the incidence of dissection of the infrarenal aorta (1 to 3%), that of horseshoe kidney (0.15%) and that of pathology of the aortic junction in patients with a horseshoe kidney, which seems to be accidental.


Separation of oxidized human growth hormone variants by reversed-phase high-performance liquid chromatography. Effect of mobile phase pH and organic modifier.

Human growth hormone (hGH), a polypeptide of 191 amino acids, contains three methionine residues, two of which are susceptible to oxidation by both chemical and photochemical means (Met14 and Met125). To date, no method has existed for resolving the various mono- and di-oxidation products. We report on the resolution of these oxidized variants and native hGH at weakly (pH 3.5) acidic pH. Although all of the oxidized species can be resolved at pH 3.5, use of low pH and neutral pH mobile phases confer some advantages. For example, the Met14 oxidized variant (MetSO-14) and native hGH are best resolved at neutral pH and the mono-oxidized variants (MetSO-125 and MetSO-14) are best resolved at low pH. The effect of organic modifier on the separation of the oxidized variants was also evaluated. 1-Propanol was more effective than acetonitrile in the separation of MetSO-14 and native hGH while acetonitrile was more effective than 1-propanol in the separation of MetSO-125 and MetSO-14. In summary, mobile phase pH and organic modifier were shown to be important parameters in the separation of oxidized hGH variants.


[Surgical treatment of supraumbilical eventrations].

Among postoperative incisional hernias, mid-epigastric eventrations have peculiar features for physiopathological reasons that are summed up in general and specifically in the first paragraph of this paper; they are characterized by the quick retraction of the lateral belt, with the chondrocostal margin of the thorax participating as the upper limit of the cleft, and by the rapidly irreducible diastasis--hence the importance of an early decision to operate. The authors propose three regular procedures with which they are experienced: repair with a large retromuscular nonabsorbable synthetic tulle prosthesis for extensive epigastric eventrations, fillup aponeuroplasty using the sheath of the rectus abdominis associated with a premuscular patch in case of diastasis or of multiple superimposed orifices and suture associated with a small retromuscular auxiliary patch to treat small incisional hernias. The article, mainly dealing with the technical details of the three procedures and of their variants, is concluded by a brief report of the personal results obtained with a series of 616 postoperative eventrations, including 91 mid-epigastric ones, controlled after an average time lapse of 5.5 years.


Detection of substituted benzenes in water at the pg/ml level using solid-phase microextraction and gas chromatography-ion trap mass spectrometry.

Solid-phase microextraction (SPME) is combined with gas chromatography-ion trap mass spectrometry (GC-IT-MS) for the analysis of benzene, toluene, ethyl benzene and xylene isomers (BTEX) in water. SPME is a recent technique for extracting organics from an aqueous matrix into a stationary phase immobilized on a fused-silica fiber. The analytes are thermally desorbed directly in the injector of a gas chromatograph. The wide linear dynamic range (five orders of magnitude) and pg sensitivity of the ion trap mass spectrometer in its full scan mode is an ideal detector for identifying and quantifying the analytes extracted with an SPME device. The combined method SPME-GC-IT-MS, using fibers coated with a 100-microns polydimethylsiloxane coating, showed a limit of quantitation (LOQ) of 50 pg/ml benzene in water. This corresponds to 5 pg of benzene absorbed onto the fiber. The limit of detection (LOD) was 15 pg/ml benzene. For o-xylene spiked at 50 pg/ml in water 50 pg were absorbed by the fiber indicating an LOQ and LOD 10 times better than for benzene. The detection limits obtained exceed the requirements of both the United States Environmental Protection Agency method 524.2 and the Ontario Municipal/Industrial Strategy for Abatement program, which range from 30 to 80 pg/ml and 500 to 1100 pg/ml, respectively. The linearity of the method extended over five orders of magnitude. Relative standard deviation ranged from 2.7 to 5.2% for 15 ng/ml BTEX in water and from 5.5 to 7.5% for 50 pg/ml BTEX in water. SPME-GC-IT-MS was used to evaluate the contamination level in laboratory, potable and wastewater sources.


Comparative study of capillary zone electrophoresis and high-performance liquid chromatography in the analysis of oligonucleotides and DNA.

Capillary zone electrophoresis and high-performance liquid chromatography were compared with regard to the separation of oligonucleotides and double-stranded DNA. Both anion-exchange and reversed-phase high-performance liquid chromatography on non-porous particles are considered to be superior to capillary electrophoresis in terms of speed and selectivity in the analysis of oligonucleotides up to 30 bases in length. Moreover, reversed-phase chromatography allows the simultaneous purification of detritylated oligonucleotides with recoveries > 90%. Compared with anion-exchange chromatography, there is no need for a subsequent desaltation step because the volatile buffer system can be readily evaporated. With regard to dsDNA, however, the resolving power of capillary electrophoresis cannot be matched by anion-exchange chromatography at present. Moreover, the combined use of hydroxyethylcellulose and ethidium bromide not only yielded a separation efficiency equal to that achieved by means of gel-filled capillaries but also avoids some of their limitations such as the destruction of the gel matrix at high current densities and the bias involved in electrokinetic injection.


Determination of benzalkonium chloride in eye care products by high-performance liquid chromatography and solid-phase extraction or on-line column switching.

Benzalkonium chloride (BAK) is a mixture of alkylbenzyldimethylammonium chlorides, which is commonly used as a bacteriostat. In this work, the three major homologues of BAK are quantitated in the over-the-counter eye care products Murine and Murine Plus using high-performance liquid chromatography (HPLC). The analytes are separated from various product excipients and concentrated by either solid-phase extraction onto Sep-Pak C18 cartridges or by an on-line column-switching technique using 1-cm reversed-phase precolumns. Absolute recoveries of BAK homologues by the solid-phase extraction technique ranged from 97.2 to 98.7% for standards and from 98.0 to 98.4% for samples. Absolute recovery of the BAK homologues by the column-switching technique was 101.3% for standards and ranged from 99.9 to 103.7% for samples. Relative recoveries were quantitative by both techniques. Assay precision (R.S.D. values) were +/- 2.2% to +/- 2.6% and +/- 0.4% to +/- 0.8% by solid-phase extraction and column-switching techniques, respectively. The method provides advantages of high sample throughput, excellent column life and automation.


Simultaneous determination of retinol and tocopherols by high-performance liquid chromatography.

A high-performance liquid chromatographic (HPLC) method to determine retinol and all four tocopherols (alpha-, beta-, gamma- and delta-) simultaneously was established using a reversed-phase column (YMC-PACK A-302 S-5 120A ODS). The HPLC conditions were mobile phase 65% isopropanol, sample solvent 99.5% methanol and temperature 30 degrees C. Retinol and tocopherols were measured in rat liver.


Determination of nicotinamide and pyridoxine in an elemental diet by column-switching high-performance liquid chromatography with UV detection.

The determination of nicotinamide and pyridoxine in an elemental diet containing 46 compounds was performed by column-switching high-performance liquid chromatography with UV detection at 260 and 290 nm, respectively. The method is simple, rapid, sensitive and reproducible. The calibration graphs for the two vitamins were linear in the ranges 0-0.2 and 0-0.015 micrograms, respectively. The recoveries of both vitamins by the standard addition method were over 95%. There was good agreement between the concentrations indicated and found for both vitamins.


Elimination of the chloride interference on the determination of arsenic using hydride generation inductively coupled plasma mass spectrometry.

In the determination of arsenic, attention has recently focused on the speciation of As(III) and As(V). Reversed-phase HPLC can be used to efficiently separate these two arsenic species. When inductively coupled plasma mass spectrometry is used for arsenic detection, an isobaric interference at m/z 75 is caused by the presence of chloride in the sample. These experiments describe the use of hydride generation in conjunction with a polypropylene-membrane gas-liquid separator to completely eliminate the transport of chloride to the plasma. A detection limit of 0.46 ppb for As(III) was achieved with this system. The chromatographic resolution of the system was not compromised by the addition of the gas-liquid separator. A determination of the arsenic content of a NIST urine sample was performed to demonstrate the effectiveness of the chloride elimination.


Determination of vitamin C and organic acids in various fruits by HPLC.

Liquid chromatographic methodology for determination of vitamin C and organic acids in different fruits (whortleberry, blackberry, red currant, black currant, raspberry, babaco, feijoa, kiwano, passion fruit, red and yellow tamarillos, medlar, and persimmon) cultivated in Galicia, Spain are developed. Both methods use a C18 column and an RP-18 precolumn for the stationary phase. High-performance-liquid-chromatographic-(HPLC-) grade water is brought to pH 2.2 with sulphuric acid for the mobile phase. The flow rate is 0.4 mL/min, and UV detection is at 254 nm for vitamin C and 214 nm for organic acids. Coefficients of variation of 1.84, 1.20, 1.00, and 2.60% are obtained for the vitamin C, quinic acid, malic acid and citric acid, respectively.


Determination of methadone and its metabolites by high performance liquid chromatography following solid-phase extraction in rat plasma.

This paper describes a rapid, quantitative liquid chromatographic analysis and extraction of methadone and its two major metabolites from rat plasma, using difenoxin as the internal standard. Using a C18 column, resolution of all sample components and the internal standard is achieved with a mobile phase of 25:75 acetonitrile-0.08% diethylamine in 1000 mL water, pH 2.3, at a flow rate of 1.5 mL/min. The injection volume is 100 microL. Standards are linear over the range 25-100 ng, with a lower limit of detection for methadone of 0.25 ng. Within- and between-run coefficients of variation (CV) are 1.24% and 2.94%, respectively. Extraction of methadone and its metabolites from rat plasma uses a solid-phase extraction technique that is highly efficient. Extraction efficiencies of 90.3%, 99.6%, 85.9% and 93.8% were achieved for methadone, its primary and secondary metabolites, and difenoxin, respectively.


Production and characteristics of strain common antibodies against a synthetic polypeptide corresponding to the C-terminal region of potato virus Y coat protein.

Comparing the predicted amino acid sequence between two Japanese potato virus Y (PVY) strains, necrotic strain and ordinary strain, it was found that the C-terminal regions (H2N-HTTEDVSPSMHTLLGVKNM-COOH) of the coat proteins in the two strains were completely conserved. The conserved amino acid sequence was also found in the C-terminal region coat protein of PVY-36, a strain which did not react with monoclonal antibodies specific to the necrotic and the ordinary strain respectively. Antibodies were produced against a synthetic polypeptide PVY-C19 consisting of 19 amino acids, which correspond to the C-terminal region of the coat protein, using 4 coupling combinations of polypeptide PVY-C19 to protein carriers. Carrier-free polypeptides and those coupled to ovalbumin with ECDI (ethyl-dimethylaminopropyl carbodiimide) produced high titer of antibodies and detected PVY strains from PVY-infected plants by Western blot analysis and by ELISA.


A tetrazolium-based colorimetric assay for quantification of HIV-1-induced cytopathogenicity in monocyte-macrophages exposed to macrophage-colony-stimulating factor.

A sensitive assay was developed for in vitro evaluation of anti-HIV agents in monocyte-macrophage cells (M/M) (a crucial target of HIV in the body). Monocyte-macrophage cells are usually poorly sensitive to the cytopathic effect induced by HIV. However, when fresh adherent monocyte-macrophage cells are cultured at relatively high density in the presence of macrophage-colony stimulating factor (M-CSF), they undergo cytolysis and die in 2-3 weeks. HIV-mediated cell-killing can thus be assessed with a method based on the reduction of the yellow colored 3-(4-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) by metabolically active cells to a blue formazan, which can be measured spectrophotometrically. HIV-mediated cytopathic effect of M-CSF-exposed monocyte-macrophage cells was consistently achieved in all experiments performed under the conditions described herein. Anti-HIV activity of zidovudine (AZT) was also comparatively evaluated in M-CSF- and normal monocyte-macrophage cells both using the MTT assay and by measuring HIV-p24 antigen production in supernatants of monocyte-macrophage cells cultures, and similar results obtained with both methods. These results support the use of this colorimetric assay for broad screening of anti-HIV agents in monocyte-macrophage cells.


Molecular epidemiology of respiratory syncytial virus: rapid identification of subgroup A lineages.

Methods for the rapid analysis of samples of respiratory syncytial (RS) virus are described using the polymerase chain reaction (PCR) followed by restriction mapping. Isolates (either clinical samples or tissue culture grown virus) can readily be divided into subgroups and then further classified into lineages. These methods enable examination of large numbers of isolates by molecular techniques, thereby facilitating research into the molecular epidemiology of the virus.


Effects of age on the Rey-Osterrieth and Taylor complex figures: test-retest data using an intentional learning paradigm.

The degree to which the Rey-Osterrieth and Taylor complex figures provide equivalent measures of visual memory, and the effects of age on figure comparability were examined in two experiments. Both experiments employed a multiple-trial, intentional learning procedure wherein each figure was administered twice in a counterbalanced sequence to subjects aged 20 to 80 years. In Experiment 1, a constant 60-s exposure duration was used; in Experiment 2, a self-pacing procedure was employed where the exposure duration was individually determined. The results from both experiments showed that the Taylor figure was easier to learn than the Rey-Osterrieth figure, indicating that the two figures are not equivalent for testing memory. These results were supported by subjective judgements on the relative difficulty to learn and remember each figure. Finally, younger (20-59 years) subjects performed at a higher level than older (60-80 years) subjects on both figures. Recommendations and possible alternatives are suggested regarding the use of the figures in both constructional and visuo-spatial memory test-retest situations.


Specificity in the correlation of verbal memory and hippocampal neuron loss: dissociation of memory, language, and verbal intellectual ability.

Fifty-nine patients with temporal-lobe epilepsy (28 left, 31 right) completed the Boston Naming Test (BNT), verbal subtests of the Wechsler Adult Intelligence Scale-Revised, and the Logical Memory Subtest of the Wechsler Memory Scale (WMS) before surgery. Performances by patients with left temporal seizure foci were significantly more impaired than those of patients with right seizure foci on the WMS Logical Memory subtest and the BNT. After surgical removal of the mesial temporal lobe structures, two blinded observers established volumetric cell densities for hippocampal subfields CA1, CA2, CA3, the hilar area, and the granule cell layer of area dentata. Statistically significant correlations existed only between percent retention scores and hippocampal neuron loss in CA3 and the hilar area for patients with left temporal seizure foci. None of the other dependent measures was significantly correlated with hippocampal neuron density in any subfield. These results support the hypothesis that certain verbal memory impairments are attributable to hippocampal damage specifically, and not to temporal lobe damage in general.


Assessing the reliability of clinical scales when the data have both nominal and ordinal features: proposed guidelines for neuropsychological assessments.

The purpose of this article is to present, for the first time, a comprehensive methodology for assessing the reliability of a clinical scale that is frequently utilized in neuropsychological research and in biomedical studies, more generally. The dichotomous-ordinal scale is characterized by a single category of "absence" and two or more ordinalized categories of "presence" of a symptom trait, state, or behavior, and it also has special properties that need to be understood in order for its reliability to be appropriately assessed. Using the Brief Psychiatric Rating Scale (BPRS) as a clinical example, we cover the principles of expressing scale reliability in terms of a dichotomy ("absence" - "presence" of a given BPRS symptom); as a trichotomy ("none"; "mild to moderate" symptomatology; and "severe" symptomatology); and as the full 7-category dichotomous-ordinal scale: "none," "very mild," "mild," "moderate," "moderately severe," "severe," and "extremely severe." Criteria are presented that can be used to evaluate which of these three formats produces the most reliable results. Finally, we address, with a second sample, the important issue of replication, or whether the original reliability findings generalize to other independent populations.


The subcortical dysfunction hypothesis of memory deficits in depression: neuropsychological validation in a subgroup of patients.

The subcortical dysfunction hypothesis of verbal learning and memory deficits in depression was evaluated by comparing the memory test profiles of unipolar depressives (n = 40) and bipolar depressives (n = 9) with those of patients with a prototypical subcortical dementia (Huntington's disease, HD), patients with a prototypical cortical dementia (Alzheimer's disease, AD), and normal controls. In a discriminant function analysis that well-differentiated the HD, AD, and normal subjects, it was found that 28.6% of the depressed patients were classified as HD patients (DEP-HD subjects), 49.0% were classified as normals (DEP-N subjects), none were classified as AD patients, and 22.4% were not well-classified. The DEP-HD group closely resembled the HD group on additional indices of verbal learning and memory, and differed from the DEP-N group, which strongly resembled the normal control group. DEP-N patients also performed significantly better than DEP-HD patients on a number of other neuropsychological tests (e.g., WAIS-R Digit Symbol, category fluency, Trail Making Test Part B). The findings provide support for the subcortical dysfunction hypothesis, but only for a subgroup of depressed patients. Implications for differentiating depressive "pseudodementia" from AD are discussed.


Electrophysiological evidence of lateralized disturbances in children with learning disabilities.

This study used an electrophysiological measurement operation to investigate lateralized processing deficits associated with academic learning-disability subtypes. Fast frequency EEG activity in the 36-44 hertz (Hz) band was recorded from reading-disabled (RLD), arithmetic-disabled (ALD), and nondisabled control children engaged in verbal and nonverbal cognitive tasks. The control group, but neither LD group, exhibited a task-dependent shift in lateralization of 40 Hz EEG; the RLD subjects generated proportionately less left-hemisphere 40 Hz activity than control or ALD subjects during the verbal task; and the ALD subjects generated proportionately less right-hemisphere activity than control or RLD subjects during the nonverbal task. These results indicate that lateralized processing deficits are associated with different types of disabilities, and provide external validation of learning-disability classifications based on academic performance patterns.


Effects of severe closed-head injury on three stages of information processing.

The present study investigated the loci of the information-processing delay that characteristically follows severe closed-head injury (CHI). Sternberg's additive-factors logic was used to determine the effects of severe CHI on the central information-processing stages of stimulus encoding, memory comparison, and decision-making/response-selection. The task variables used to define the stages operationally were stimulus quality, memory set size, and stimulus-response compatibility. Twenty subjects who had sustained a severe CHI more than 18 months earlier and 20 matched control subjects completed a stimulus encoding by response selection task in Experiment 1, and a Sternberg high-speed memory scanning task in Experiment 2. The CHI group performed the stimulus encoding and decision-making/response-selection stages of processing significantly slower than did the control group. However, no significant group differences were found on the memory comparison stage, suggesting that memory comparison processes may be relatively intact in long-term patients with severe head trauma. The results are discussed in relation to a global and a late-specificity hypothesis of central processing deficits following severe CHI. The possibility that cognitive processes demanding less attention may be more resilient to injury is also considered.


Sex-related differences in the cognitive consequences of early left-hemisphere lesions.

Epileptic patients who had undergone the carotid amytal test were assessed on a variety of measures of verbal and nonverbal ability. All patients had left-hemisphere dysfunction early in life, before 1 year of age. In males, such damage results in generalized cognitive retardation regardless of the status of the cerebral speech pattern. In females, intellectual retardation is linked specifically to a shift in speech processes. This sex-related difference in behavioral outcome may reflect interruption at different maturational stages and/or the influences of the immediate hormonal milieu.


Neuropsychological functioning in nonmentally retarded autistic individuals.

To investigate several neurobiological theories we evaluated the neuropsychological functioning of 15 non-mentally retarded autistic adolescents and young adults and 15 controls matched on age, gender, IQ, and race. The autistic subjects were found to perform less well than controls on measures of abstraction involving cognitive flexibility, verbal reasoning, complex memory, and complex language comprehension in the absence of significant differences on measures of attention, associative memory, and the rule-learning aspects of abstraction. These findings are most consistent with a generalized abnormality in complex information processing and would not support theories purporting fundamental deficits in attention or information acquisition.


Programming of single movements in Parkinson's disease: comparison with Huntington's disease.

The preparation of individual finger movements was examined in Parkinson's disease (PD), in comparison with a similar study of Huntington's disease (HD). Motor programming was varied by increasing the amount of information available in advance of each movement. PD patients had particular difficulty when there was no cue light in advance of the movement, and when two upcoming movements were cued ahead of the current movement. Such difficulties suggest that PD patients may have difficulty in performing movements without sensory cuing, and in maintaining and organising a future sequence of movements. HD patients had been previously shown to have similar deficits. Commonalities in these once contrasted disorders probably arise from disruption of common mechanisms.


Is verbal recognition memory really different in Huntington's and Alzheimer's disease.

Verbal recall and recognition were examined in Huntington's disease (HD) and Alzheimer's disease (AD) patients. Subgroups of HD and AD patients were matched for overall severity of dementia. Subjects were administered the Hopkins Verbal Learning Test, a list-learning task with three free-recall trials followed immediately by one yes/no recognition trial with semantically related and unrelated distractors. The matched AD and HD groups did not differ in the number of words recalled, although the HD patients showed slightly greater improvement over trials. Recognition performance was evaluated with measures of accuracy and response bias that are independent of each other. The matched groups did not differ in overall recognition accuracy, but the AD patients tended to have a more liberal ("yea-saying") response bias than did the HD patients. In addition, only the AD patients were differentially enticed to false-positive responding by semantically related distractors. The results suggest that the rule for making decisions when uncertain, rather than memory strength per se, distinguishes the recognition memory performance of AD and HD patients.


Release from proactive interference: determinants of performance and neuropsychological correlates.

The Wickens (1970) modification of the Brown-Peterson short-term memory task has been used to investigate release from proactive interference (PI) in a number of memory-impaired groups. It has been suggested that failure to release from PI is observed only in patients with compromise of both memory and 'frontal-lobe' functions. The present study examined performance on this paradigm in patients with schizophrenia (SC), a neuropsychiatric disorder which typically includes both frontal and mnemonic impairments. Patients with SC were found to exhibit significantly less release from PI than normal controls. It was determined through correlational analyses that average Trial 1 performance on this task could predict performance on all subsequent trials, indicating that 'release' from PI may measure the same psychological process as the Brown-Peterson task, which does not include a release condition. Trial 1 performance in the SC group was correlated with a wide range of neuropsychological measures, but after the effect of full scale IQ was partialled out, only correlations with measures of memory and measures of frontal-lobe function remained significant. The results support previous formulations of the neuropsychological concomitants of release from PI, but suggest that failure to release on this paradigm may be secondary to a significant compromise of the ability to perform the Brown-Peterson task. It is proposed that the experimental design constraints necessary to elicit a failure to release from PI in any patient group may limit the utility of this measure, and that Brown-Peterson performance may be a more reliable index of the neuropsychological functions involved.


Set-shifting and spatial orientation in patients with Parkinson's disease.

Individuals with Parkinson's disease were compared to normal control subjects on a series of widely used neuropsychological measures. The two groups were matched for gender, handedness, age, education, and occupation. The neuropsychological tests were chosen to measure two specific functions: (a) spatial orientation (i.e., measures of personal orientation, extrapersonal orientation, right/left orientation, and mental rotation), and (b) the ability to shift mental set (e.g., generating responses from alternating categories). The tests chosen to measure spatial orientation had no set-shifting component, and the tests chosen to measure set-shifting had no spatial orientation component. Multivariate statistical analyses revealed a significant difference between the subjects with Parkinson's disease and the control subjects on the measures of set-shifting ability. In contrast, no significant difference between the groups was observed on the measures of spatial orientation. These results are discussed in terms of the current speculation in the literature regarding the relationship between set-shifting deficits and a disruption of dopaminergic fibers to the prefrontal cortex in Parkinson's disease.


Attentional deficits following closed-head injury.

Aimed to assess, in the light of current attentional theories, the nature of the attentional deficit in a group of severely traumatically head-injured subjects, relative to a group of orthopaedic rehabilitation patients, and to establish which neuropsychological measures best reflected the deficit. Three separate studies were conducted in order to meet these aims. The first study focused on selective attention; the second, on vigilance or sustained attention; the third, on the Supervisory Attentional System. Results provided no evidence for the presence of deficits of focused attention, sustained attention, or supervisory attentional control, but ample evidence for the presence of a deficit in speed of information processing. Those neuropsychological measures shown to be the best measures of this deficit included the Symbol Digit Modalities Test, simple and choice reaction-time tasks, colour naming and word reading scores on the Stroop, and the Paced Auditory Serial Addition Test.


Memory search for faces and digits in patients with unilateral brain lesions.

To clarify whether the impairment of right-brain-damaged (RBD) patients in face recognition is related to perceptual or mnestic processing stages, we tested unilaterally lesioned patients and controls in a Sternberg-type memory search task. Subjects had to memorize sets of 1, 2, or 3 faces (or, in a control condition, digits) and were then to recognize these memorized stimuli among new ones by speeded choice reactions. In this task, deficits in stimulus encoding and memory search should show up in increased intercepts and slopes, respectively, of the RT function over memory set size. A face-specific impairment of the RBD patient group, consisting in longer reaction times and higher error rates, was confirmed but could not be unequivocally attributed to either stimulus encoding or memory search. However, inspection of individual data suggested that (1) some RBD patients are virtually unimpaired in face recognition and (2) if impairment after right hemisphere damage is present, it may selectively affect either stimulus encoding or memory search.


Performance of patients with early HIV-1 infection on the Stroop Task.

HIV-seropositive and seronegative control subjects performed a standard paper-and-pencil version and an experimental reaction time version of the Stroop Color-Word Naming Task. Results indicated that both symptomatic and asymptomatic HIV-positive subjects showed an exaggerated Stroop effect compared to controls, but this increase was only apparent on the RT version of the task. Analysis of components of the effect indicated that HIV-positive subjects showed increased inhibition compared to controls but normal facilitation. These results suggest that HIV-related cognitive slowing has an attentional component, most likely involving controlled processes. In addition, these results emphasize the utility and sensitivity of RT measures in the study of early HIV-1 infection.


Pathological findings in SIDS.

The original 1969 definition of SIDS as "unexpected by history" and "unexplained after thorough postmortem examination" is under review in the light of two decades of experience. Suggested modifications include restricting the age to less than 1 year, stipulating that the necropsy includes appropriate histology and laboratory tests, and requiring a review of the clinical history and examination of the death scene. The use of a protocol is recommended both by professional and parent groups. Although the diagnosis of SIDS is to some extent one of exclusion, there are several typical findings which are of value in diagnosis and suggest new avenues for research. External examination is important to exclude trauma and signs of suffocation. A recent study has confirmed that petechiae on the face are rare in SIDS and if found raise the question of deliberate or accidental suffocation. Frothy fluid escaping from the nose and mouth is seen in about half of infants who die from SIDS. Postmortem hypostatic staining as an indicator of position has assumed increased importance since prone sleeping has been shown to be a major risk factor for SIDS. Evidence of sweat in clothing suggests overwrapping. Internal examination shows subserosal petechial haemorrhages in the thymus in most cases. These may be related to age and are commoner in babies dying of SIDS than in controls. Relative sparing of the cervical extension of the thymus is strong evidence for negative intrathoracic pressure, perhaps due to upper or lower airway obstruction. Other typical findings are liquid heart blood, prominent lymph nodes, and an empty bladder (which frustrates some biochemical tests in about half of cases). The lungs are usually well inflated, arguing against surfactant deficiency as a significant cause of SIDS. Microscopic evidence of pulmonary oedema and congestion is found in infant deaths for many reasons and is not discriminatory for SIDS. Minor inflammation and infection of the respiratory tract is common in SIDS and may be important by contributing to overheating, apnoea, or sensitisation to bacterial toxins. Mild fatty change in the liver is very common in infant deaths. Panlobular microvesicular fatty change is rare and may require special stains for its recognition. It indicates the necessity of searching for inherited biochemical disorders. Although these are rare in true SIDS, they are an important cause of unexpected death in infancy. Of Naeye's "tissue markers of hypoxia'', extramedullary haemopoiesis in the liver and brainstem gliosis have been confirmed. Persistence of fetal haemoglobin and raised hypoxanthine values in vitreous humour are further pointers to periods of premortem hypoxia. Painstaking neuropathology has shown delayed myelination and maturation of dendritic spines. Changes in the brain may explain the link between antenatal factors such as smoking and SIDS. A second cot death in a family requires expert examination. Minor injuries or unexplained apnoeic spells may be important retrospective clues to non-accidental injury. Investigations mus exclude inherited disorders before the death is ascribed to SIDS. Parents demand that the pathologist takes care of their baby before, during, and after the necropsy, carries out the procedure to a high standard, checks reconstruction of the body, facilitates access, and is responsible for communicating the results of the examination. The "SIDS postmortem" presents both a practical and an intellectual challenge.


Development of thermoregulation in infancy: possible implications for SIDS.

Over the first three months of life the infant's metabolic rate rises, which, together with the rise in ratio of mass to surface area, means that the net heat loss per unit surface area is 50% higher in a 3 month old infant than in a neonate. This, together with the thicker layer of subcutaneous fat and more effective peripheral vasomotor response to cold in a 3 month old infant, means that thermal balance is shifted in favour of heat conservation. The head is the site of 40% of heat production and of up to 85% of heat loss in an infant in bed: covers rising up over the head could therefore result in acute thermal imbalance with a rise in brain temperature not necessarily accompanied by a rise in body temperature. In animal studies relatively small changes in hypothalamic temperature have profound effects on the control of respiration. Alternatively, a rise in metabolic rate (from an acute infection, for example) could result in a significant change in thermal balance. There is anecdotal evidence that heat stress may be associated with sudden infant death or with severe hypoventilation. In the Avon studies infants with SIDS, particularly those over 70 days of age, were more heavily wrapped and were more likely to have had the heating on all night than control infants matched for age, date, and neighbourhood. There was no significant excess of viral infections in the infants with SIDS, but those who had virus infections were much more heavily wrapped than control infants with similar infections, suggesting that the combination of heavy wrapping and virus infection may be more important than either factor alone. There is, therefore, some physiological evidence that infants of 2 to 3 months of age may be more vulnerable to heat stress than younger infants, and limited evidence, from clinical studies, that this may occur and be associated with some sudden deaths. The precise contribution of thermal stress and the mechanism by which it could cause death remain unclear.


Susceptibility to infection in relation to SIDS.

Because there is little evidence that invasive bacterial diseases contribute to cot deaths, most studies on infectious causes of SIDS have focused on viruses or toxin producing bacteria. Although epidemiological studies found marginally significant associations between influenza virus and SIDS, respiratory syncytial virus (RSV) was isolated from 90% of older infants with SIDS. There are conflicting reports that some toxigenic bacteria (Clostridium botulinum, Clostridium difficle, enterotoxigenic Escherichia coli and Staphylococcus aureus) might be implicated in cot deaths. S aureus are common micro-organisms and their toxins are very powerful. As the pyrogenic toxic shock syndrome toxin of S aureus can kill a previously healthy adult, it might easily kill a small infant. Based on our studies on susceptibility of infants to other infections, we suggest the following might be factors leading to colonisation of infants by toxin producing S aureus: The Lewis blood group antigen appears to act as a receptor for some micro-organisms. Epithelial cells expressing high concentrations of Lewis bound appreciably more toxin producing S aureus than cells expressing low concentrations of the antigen. Lewis is expressed in secretions of nearly 90% of infants aged 3 months, the peak age for SIDS. RSV infects about 50% of infants by the first year of life and it is often isolated from infants with SIDS. Studies in our laboratory indicate that RSV infected HEp-2 cells bind more toxin producing S aureus than uninfected controls.


Viral infection and alpha interferon in SIDS.

Conventional approaches to virus detection fail to provide convincing evidence in support of a viral aetiology for SIDS. Virus positivity of about 20% in cases of SIDS is typical of most studies and is similar to that found in control groups. The application of direct immunofluorescence assays (DFA) has increased virus detection rates to 30-40%. Constraints imposed by technology, postmortem interval, choice of samples for analysis and the necessary limitation of virus types to be sought may all result in under-diagnosis of virus positivity. Alpha interferon (IFN alpha), produced by cells in an early response to exposure to many viruses, has been shown to increase in concentration in the cerebrospinal fluid of patients with viral meningitis. In cases of SIDS significant increases in IFN alpha concentrations have been shown in nasopharyngeal aspirates from virus positive cases and from apparently virus negative cases. The application of conventional techniques of DFA and IFN alpha measurement therefore identifies a much larger percentage of SIDS cases as having been exposed to virus. Disturbance of respiratory regulation has been suggested as an aetiological mechanism in SIDS. Apnoeic episodes are frequently described and are known to be associated with certain viral infections, particularly respiratory syncytial virus. The abnormal presence of IFN alpha in neurones of the medulla of the brain stem in a proportion of SIDS cases were identified by immunohistochemistry. This might suggest a link between viral infection and disturbance of respiratory regulation. The higher rates of virus exposure which can now be detected and the localisation of IFN-alpha in medullary neurones suggest that it is premature to discount the viral hypothesis as an explanation for at least a proportion of SIDS cases.


Viral respiratory infection and SIDS.

One of the many factors which have been implicated in the aetiology of SIDS is infection of the respiratory tract, particularly viral infection. This applies particularly to those infants who die from SIDS who are more than 3 months old. The evidence for this belief is based on both epidemiological and pathological factors. Among the epidemiological factors are the pronounced seasonal variation of SIDS (it being commoner in winter); the increased incidence of pre-existing illness, particularly upper respiratory infections, in the two weeks before death; and the increased occurrence of SIDS during epidemics of viral infection in the community. Not all of these factors are universally accepted, however, particularly when appropriate controls are investigated. The necropsy evidence includes the presence of lymphoid inflammatory infiltrates in the respiratory tract, particularly the upper respiratory tract. While these are present in many cases of SIDS, they are not present in all. Postmortem isolation of respiratory viruses has also given conflicting results: some authors show an apparent increase compared with controls, while others do not. No specific virus has been implicated. Part of the reason for these conflicting epidemiological and pathological results is failure to use proper controls. An additional explanation may be the technical difficulties involved in isolating viruses. Apart from the problems resulting from postmortem effects, culture, immunofluorescence, and ELISA tests are known to give significant false negative rates. Accordingly, newer, potentially more sensitive and robust techniques, such as molecular hybridisation, are being applied to cases of SIDS to determine whether viral infection is more common than is currently recognised. Whatever the outcome of these investigations, it is highly unlikely that viral infection per se is the cause of SIDS. One or more additional factors are also involved which may include an abnormal immune response, generation of thermal stress, precipitation of respiratory obstruction, bacterial overgrowth with toxin release, or suppression of the arousal response.


Metabolic deficiencies and SIDS.

The role of inherited metabolic defects in SIDS is controversial: some workers think that they may account for the cause of death in about 10% of cases. Many maintain that this is a gross overestimate, but it cannot be denied that the sudden onset and rapid deterioration known to occur in some metabolic disorders during the first year of life can mimic SIDS. This may remain undetected unless postmortem material is examined in specialist centres with individual metabolic disorders in mind. Defects in energy metabolism and the maintenance of glucose homeostasis frequently show this pattern of presentation precipitated by minor clinical infection. These disorders include the glycogen storage disorders, gluconeogenic enzyme defects, and the defects of fatty acid oxidation. Several reports have appeared since 1984 linking fatty acid oxidation defects with SIDS. Estimates of their prevalence vary, due partly to methodological heterogeneity and partly to the limited size of individual studies which have not permitted adequate statistical analysis. Nevertheless, the lack of adequate information has not precluded a great deal of debate. Over the past seven years a group in Sheffield has studied the occurrence of these defects in SIDS using three distinct approaches: retrospective analysis of SIDS cases, prospective analysis of SIDS cases, prospective analysis of urine obtained from siblings of SIDS cases during the first week of life. The result of these studies would suggest that the contribution to SIDS made by medium chain acyl CoA dehydrogenase deficiency may be in the region of 1%. Additional related metabolic disorders may account for a further as yet undefined small percentage. The eventual resolution of some of these uncertainties may be provided by harmonizing the results of existing studies and by DNA analysis of materials obtained at necropsy in SIDS cases.


Immunopathology of SIDS.

Immunopathological studies of SIDS share the problems of all necropsy based studies of this syndrome: the extent of autolytic changes in the material under study; and the lack of appropriate controls. Despite these problems, several studies have been performed on serum, bronchoalveolar lavage, and pulmonary tissue. Many of these studies have been inspired by the modified anaphylaxis hypothesis, based on the experiments of Coombs and coworkers. Lightly anaesthetised guinea-pigs, which had been sensitised to cows' milk protein, were shown to die after intratracheal challenge. Studies of serum IgE concentrations in SIDS initially indicated raised specific IgE for Dermatophagoides pteronyssinus, Aspergillus fumigatus, and bovine beta-lactoglobulin, but subsequent studies have not sustained these findings. Raised immunoglobulin concentrations in bronchoalveolar lavage fluid have been found in association with SIDS but this probably reflects plasma leakage rather than local secretion. Immunocytochemical analysis of lavage cells performed by the same group revealed no major difference between SIDS cases and controls, although these were limited to four cases. To date, there have been no comprehensive studies of the inflammatory cell content of the pulmonary parenchyma in SIDS. In our own studies, we have examined the mast cell and eosinophil populations in the lungs of 49 cases of infants with SIDS and in 33 infants dying of non-pulmonary causes in the first 18 months of life. We found no difference in mast cell numbers between the groups but there was a striking excess of eosinophils in the lungs of infants dying of SIDS. Because eosinophils can secrete oxygen free radicals and cytotoxic cationic proteins, we regard this as evidence of a potential mechanism for the pulmonary oedema that is characteristic of SIDS. A viral infection which might otherwise have been trivial could therefore prove fatal.


An evaluation of the effect of food on the oral bioavailability of sustained-release morphine sulfate tablets (ORAMORPH SR) after multiple doses.

The effect of food on the oral bioavailability of sustained-release morphine sulfate tablets (ORAMORPH SR; Roxane Laboratories, Inc., Columbus, OH; OSR) was examined in an open-label, randomized, two-period crossover study. Healthy male volunteers received a 30-mg OSR tablet orally every 12 hours for seven doses during both the fasted and fed states. Dosing periods were separated by a 14-day washout. Volunteers in the fasted group received all doses either 2 hours before or after meals. Volunteers in the fed group received all doses immediately after meals. All meals were standardized. Serial blood samples were collected for analysis of plasma morphine concentration by radioimmunoassay. Pharmacokinetic parameters were calculated using plasma concentration data collected after the last dose at 72 hours of each dosing period. The two one-sided t analysis indicated confidence intervals between 80% and 120% for maximum peak plasma concentration (Cmax), AUC72-84hr, Cavg, and Cmin. The relative bioavailability of OSR administered after meals was 90.2% of that administered in the fasted state. As compared with the fasted condition, morphine bioavailability was essentially unchanged when multiple oral doses of 30-mg OSR tablets were given after meals.


Salivatory responses to classical and nontraditional parasympatholytic agents in human subjects: critical comments.

Both classical (atropine, scopolamine) and nontraditional (pirenzepine, telenzepine) cholinolytic agents themselves cause no salivation in human subjects. Ordinarily, they block salivation caused by pilocarpine. Conversely, they all stimulate intense salivatory response in the chronically denervated human parotid gland. The author presents critical comments on the concept that cholinolytic agents cause salivation by suppression of the mechanism of presynaptic autoinhibition. An alternative explanation of the initial cholinomimetic effect of cholinolytic agents is suggested.


Effectiveness and duration of intramuscular antimotion sickness medications.

Motion sickness inhibits gastric motility, making the oral route ineffective for medications. The intramuscular route is an effective alternative. The rotating chair was used to produce the M 111 level of motion sickness on the Graybiel Symptom Scale. The intramuscular medications given 30 minutes before rotation were compared with placebo (saline, 1 mL) for effectiveness and duration in increasing the number of tolerated head movements. Average placebo number of head movements was 294. Promethazine 25 mg increased head movements by 78% (P < .05), with a duration of 12 hours. Scopolamine 0.2 mg increased head movements by 91% (P < .05), with a duration of 4 hours. The effect of caffeine 250 mg and ephedrine 25 mg was not significant. When combined with scopolamine, ephedrine produced an 32% additive effect. Scopolamine 0.08 mg, 0.1 mg, and 0.2 mg and also promethazine 12.5 mg and 25 mg were significant (P < .05). Promethazine appears to be the drug of choice for intramuscular use because of a longer duration and a high level of effectiveness. Scopolamine was of high effectiveness, but had a duration of 4 hours. It was eight times as potent by the intramuscular as by the oral route.


Pharmacokinetics of nadolol in children with supraventricular tachycardia.

The pharmacokinetics of intravenous and oral nadolol, a long-acting beta-adrenoceptor blocking agent, were investigated in six children receiving the drug for treatment of supraventricular tachycardia. In the youngest patient (age 3 months), no distribution phase was seen. In children younger than 22 months of age, nadolol is more rapidly eliminated (t1/2 = 4.3 hours or less) than in older children, in whom elimination is more similar to that in adults (t1/2 approximately 7.3-15.7 hours). After intravenous administration, nadolol displayed two-compartment pharmacokinetics with a distribution phase (t1/2 = 0.2-1.1 hours) followed by elimination. Large changes in nadolol pharmacokinetics may occur during the first year of life. Nadolol should be used cautiously in infants.


Elucidating the relationship between acetazolamide plasma protein binding and renal clearance using an albumin infusion.

The effect of plasma protein binding changes on drug clearance is an important concept in clinical pharmacology. In a hypoalbuminemic patient receiving acetazolamide, albumin infusion (50 g) increased acetazolamide plasma protein binding towards normal as the serum albumin concentration rose (r = 0.91, P < .001). The ratio of acetazolamide renal plasma clearance to creatinine clearance decreased as serum albumin levels increased (r = 0.78, P < .05) and the unbound drug fraction fell (r = 0.88, P < .01), but clearance ratios based on unbound plasma acetazolamide levels did not change. Albumin infusion resulted in a nonparallel decline over time between plasma and unbound plasma acetazolamide concentrations. These data demonstrate that, over the range of observed serum albumin concentrations, acetazolamide renal plasma clearance is sensitive to changes in plasma protein binding. Furthermore, our findings emphasize the importance of measuring unbound drug levels when protein binding changes occur during the course of drug disposition studies. Finally, this methodology allows for the fascile assessment of the effects of plasma protein binding changes on renal drug clearance.


Disposition of cefpodoxime proxetil in hemodialysis patients.

The disposition of cefpodoxime after single, oral 200-mg doses of cefpodoxime proxetil (cefpodoxime equivalents) was investigated in an open-label study of six patients with end-stage renal disease currently maintained on hemodialysis. Subjects were randomly assigned to one of two treatment groups, which differed in the sequence of the interdialytic and intradialytic periods. Doses were separated by at least 2 weeks. Blood samples were serially collected for 48 hours after each treatment; if obtainable, urine was also collected over this same period. During the intradialytic period, hemodialysis was scheduled to begin approximately 3 hours after dosing, and dialysate was collected before and until the end of dialysis. Average cefpodoxime elimination half-life for the interdialytic period was 18.0 +/- 6.5 hours; apparent total body clearance was 28.6 +/- 13 mL/minute. The half-life during hemodialysis, 2.66 +/- 0.74 hours, was considerably shorter than that after hemodialysis, 19.2 +/- 3.5 hours, in the intradialytic period of the study. Hemodialysis clearance of cefpodoxime was 120 +/- 31 mL/minute, which was 57.1 +/- 13% and 71.7 +/- 25% of the hemodialysis clearance for urea nitrogen and creatinine, respectively. The 2.86 +/- 0.25 hour hemodialysis session removed 22.4 +/- 2.9% of the administered dose, as assessed by cefpodoxime recovery in dialysate. A maximum rebound in cefpodoxime plasma concentration of 0.41 +/- 0.33 mcg/mL was observed, at about one-half hour after the end of hemodialysis. Based on these results, dosage adjustment is not required, but extension of the dosing interval is warranted.(ABSTRACT TRUNCATED AT 250 WORDS)


Clarithromycin pharmacokinetics in healthy young and elderly volunteers.

The pharmacokinetics of clarithromycin and its active 14(R)-hydroxy metabolite were assessed in 12 healthy young and 12 healthy elderly volunteers after oral administration of a multiple dose regimen of oral clarithromycin (500 mg every 12 hours for 5 doses). Plasma and urine clarithromycin and 14(R)-hydroxyclarithromycin concentrations were determined using high-performance liquid chromatography. The elderly subjects exhibited significantly elevated clarithromycin peak (Cmax) and trough (Cmin) plasma concentrations and area under the plasma concentration-time curve (AUC) compared with young subjects. In addition, the elderly group exhibited a significantly reduced apparent total body clearance (300 +/- 97 versus 476 +/- 112 mL/min, respectively) and renal clearance (CLR) (84 +/- 31 versus 168 +/- 35 mL/min, respectively). Similar results were noted for the 14(R)-hydroxy metabolite, with significantly elevated Cmax, Cmin, and AUC and reduced CLR in the elderly compared with the young group. Because the differences in parent and metabolite pharmacokinetic parameters were small and the increase in circulating drug concentrations was well tolerated (no increase in incidence or severity of adverse events), adjustments in clarithromycin dosing regimens may not be necessary solely on the basis of age.


Lack of effect of pentoxifylline on red blood cell deformability.

The proposed mechanism of action for pentoxifylline's beneficial effect in peripheral vascular disease is an improvement in red blood cell deformability. Likewise, single doses of pentoxifylline in healthy volunteers have been shown to improve whole blood filterability, which was suggested to occur as a result of augmented red blood cell deformability. To further assess this, the authors studied the effects of short-term pentoxifylline administration (400 mg three times daily for 7 days) on red blood cell deformability in ten healthy, methylxanthine-free, nonsmoking volunteers. Blood samples were obtained at baseline and after 1 week of therapy (steady-state). Samples were analyzed for red blood cell deformability by ektacytometry, which showed no significant change in deformability in any subject. Despite the improvement in whole blood filterability associated with both single-dose and short-term administration of pentoxifylline, the current study demonstrates no effect on red blood cell deformability after short-term administration in healthy volunteers.


Comparison of pentoxifylline pharmacokinetics between smokers and nonsmokers.

Pentoxifylline is a synthetic xanthine derivative and is hepatically cleared. The natural dimethylxanthines theobromine and theophylline have been shown to have enhanced metabolism in smokers when compared with nonsmokers. Subsequently, the effect of smoking on pentoxifylline plasma concentrations was investigated. Twenty healthy volunteers (10 smokers and 10 nonsmokers) received pentoxifylline 400 mg as a controlled-release tablet every 8 hours for 17 doses. Several blood samples were collected for 8 hours after the final dose. These samples were assayed for pentoxifylline and its metabolites. The mean values of the smokers were compared with those of the nonsmokers. With respect to pentoxifylline, no statistically significant differences in maximum concentration and time of maximum concentration were observed between the two groups. Although no statistical differences in plasma concentrations and area-under-the-curve at steady state (AUCss) were observed, the oral clearance of pentoxifylline among the smokers (.22 +/- .08 L/minute/kg) was significantly greater (P < .05) than that among the nonsmokers (0.15 +/- 0.06 L/minute/kg) when corrected for body weight. With respect to the pentoxifylline metabolite 1-(5-hydroxy-hexyl)-3,7-dimethylxanthine (MI), the maximum concentration and AUCss of the smokers were significantly decreased when compared with the nonsmokers. The AUCss of the smokers was 1438 +/- 819 ng.hour/mL and of the nonsmokers was 2864 +/- 1375 ng.hour/mL (P < .02). The results of this trial suggest that smoking tends to reduce pentoxifylline plasma concentrations and significantly reduces MI plasma concentrations.


Classifying antiarrhythmic actions: by facts or speculation.

Classification of antiarrhythmic actions is reviewed in the context of the results of the Cardiac Arrhythmia Suppression Trials, CAST 1 and 2. Six criticisms of the classification recently published (The Sicilian Gambit) are discussed in detail. The alternative classification, when stripped of speculative elements, is shown to be similar to the original classification. Claims that the classification failed to predict the efficacy of antiarrhythmic drugs for the selection of appropriate therapy have been tested by an example. The antiarrhythmic actions of cibenzoline were classified in 1980. A detailed review of confirmatory experiments and clinical trials during the past decade shows that predictions made at the time agree with subsequent results. Classification of the effects drugs actually have on functioning cardiac tissues provides a rational basis for finding the preferred treatment for a particular arrhythmia in accordance with the diagnosis.


Optimization of sampling time for cyclosporine monitoring in transplant patients.

Cyclosporine (CsA) dosing is based on CsA plasma or blood concentrations measured 12 to 24 hours after drug administration (trough levels). This study evaluated the relationship between the timing of CsA concentrations and subsequent pharmacokinetic parameters to predict an optimal sampling period. Plasma samples were obtained from 22 patients before their morning dose of CsA and at 2, 4, 6, 8, 10, and 12 hours after the dose on the 7th and on the 21st day after heart transplantation. The plasma samples were assayed by both HPLC and FPIA. The Cmax for CsA was achieved over a period ranging from 2 to 6 hours (mean/median = 4.7/4.0) during the day 7 and the day 21 studies. The mean (+/- SD) half-life was 3.2 (1.0) hours on day 7 and 2.9 (1.1) hours on day 21, (P > 0.05); the mean apparent oral clearance was 276 (117) L/hr on the day 7 and 269 (209) L/hr on day 21, (P > 0.05). When CsA plasma concentration by either FPIA and HPLC was monitored, the drug concentration best correlated with AUC was found to correspond to the plasma samples taken 4 to 8 hours after drug administration. The authors conclude that through blood sampling for therapeutic drug monitoring of CsA is not optimal, and that further studies are necessary to correlate concentration monitoring during the dosing interval with pharmacologic and toxicologic parameters.


The stereoselective pharmacokinetics of etodolac in young and elderly subjects, and after cholecystectomy.

The pharmacokinetics of the enantiomers of etodolac were studied in six young subjects (ages 28 +/- 3.3 years), 6 nonarthritic elderly subjects (ages 73 +/- 6.0 years), and in three cholecystectomy patients after single oral doses of the racemate (200 mg). In all subjects, the plasma concentrations of R-etodolac, which is pharmacologically inactive, greatly exceeded those of the pharmacologically active S-enantiomer. Stereoselectivity was reflected in the pharmacokinetics, with R > S for maximum peak plasma concentration and area under the concentration versus time curve, and S > R for apparent oral clearance and apparent volume of distribution. On average, less than 25% of the dose of each enantiomer was excreted in the urine within 24 hours as alkali-labile conjugates; little or no unchanged drug was recovered. Bile constituted a minor route of elimination of etodolac as conjugated enantiomers. There were no significant differences in the pharmacokinetics of etodolac enantiomers between the young and elderly subjects. The results reflect the importance of considering stereoselectivity in evaluating the pharmacokinetics of etodolac.


Acceptability and efficacy of two associations of paracetamol with a central analgesic (dextropropoxyphene or codeine): comparison in osteoarthritis.

A double-blind randomized parallel group trial was undertaken to compare the acceptability and efficacy of 2 forms of analgesic treatment, DI-Antalvic (Houde Laboratories, Puteaux, France) (30 mg dextropropoxyphene and 400 mg paracetamol per capsule) and Efferalgan-Codeine (UPSA Laboratories, Rueil Malmaison, France) (30 mg codeine and 500 mg paracetamol per tablet) prescribed for 1 week at doses of 6 capsules/day and 6 tablets/day, respectively, in 141 outpatients with active osteoarthritis of the knee or hip. The principal aim of the trial was concerned with acceptability, with efficacy as its secondary aim. The principal trial criterion was defined as overall assessment of acceptability by the patient at the end of the trial (success or failure) or by treatment dropouts because of an adverse effect (failure). Comparability of the groups was confirmed before any treatment regarding the physical characteristics of the patients, characteristics of osteoarthritis, and the initial level of pain and functional consequences of pain. Results show that the analgesic efficacy of the treatment was similar, but that the acceptability of Efferalgan-Codeine was significantly worse than that of DI-Antalvic: 53% failure with Efferalgan-Codeine versus 29% failure with DI-Antalvic (P = .005). Other trials of the same type would seem necessary (comparison of lower doses, other types of pain) before being able to generally extrapolate such findings.


Central nervous system effects of meclizine and dimenhydrinate: evidence of acute tolerance to antihistamines.

Relative daytime drowsiness and performance impairment produced by meclizine and dimenhydrinate was assessed in 24 healthy male volunteers. Subjects received either dimenhydrinate, 100 mg, at 8:00 AM, 12:00 PM, and 4:00 PM; meclizine, 50 mg, at 8:00 AM, with placebo at 12:00 PM and 4:00 PM; or placebo at all three times in this randomized, double-blind, three-way crossover study. Impairment of mental performance was assessed by choice reaction time testing and digit symbol substitution scores. Drowsiness was self-assessed on the Stanford Sleepiness Scale and on a visual analog scale. Both antihistamines produced changes in digit symbol substitution, recognition time, and subjective assessments of sleepiness different from placebo. Expressed as change from baseline, the greatest reductions in digit symbol substitution scores after dimenhydrinate occurred 3 hours after the first dose (6.6 +/- 7) and were not different from the greatest measured change after meclizine (5.8 +/- 8), which occurred 9 hours after the dose was administered. Similar results were obtained with the other psychometric test scores. Self-rated sleepiness after dimenhydrinate was greatest 1 hour after the first dose, and was significantly greater than the largest degree of sleepiness after meclizine, which occurred at 7 hours after the dose. The effects of the first dose of dimenhydrinate on psychometric test scores were compared with the magnitude of the effects produced by subsequent doses. The magnitude of effect of the first dose of dimenhydrinate was significantly greater than the magnitude of effect produced by subsequent doses. The data suggest the possibility that acute tolerance to central nervous system impairment develops with multiple doses of dimenhydrinate.


Psychotropic drugs and injuries among the elderly: a review.

Injuries are a major public health problem among the elderly, and they have substantial medical, social, and economic consequences. There has been a longstanding concern that psychotropic drugs increase the risk of injury, particularly in the elderly, who frequently use psychotropic drugs and are more vulnerable to drug effects that may predispose to injuries. For benzodiazepines and antidepressants, the most commonly used psychotropic drugs outside of institutional settings, an extensive body of data demonstrating psychomotor function impairment establishes a firm basis for concern, which is reinforced by the more limited epidemiologic data. However, because of limitations in both types of data, this issue remains controversial. To resolve this controversy, we suggest three lines of further research: psychomotor function tests more directly relevant to the injury risk of the elderly medication user, epidemiologic studies designed to distinguish drug effects from those of underlying psychopathology, and clinical trials that include injuries as an outcome.


Pharmacokinetics and pharmacodynamics of adinazolam and N-desmethyladinazolam after oral and intravenous dosing in healthy young and elderly volunteers.

The pharmacokinetics and pharmacodynamics of adinazolam and N-desmethyladinazolam were studied in 18 young subjects, from 21 to 36 years of age, and 18 elderly subjects, ranging in age from 65 to 76 years. Nine men and 9 women per age group were studied in a randomized three-way crossover design. Single doses of one 30-mg adinazolam mesylate sustained release tablet, one 30-mg immediate release tablet, and 15 mg of intravenous adinazolam mesylate were administered. Plasma adinazolam and N-desmethyladinazolam were determined by high-performance liquid chromatography, and psychomotor performance tests, including digit-symbol substitution and two card-sorting tasks, were performed. An effect index, defined as the maximal performance decrement divided by N-desmethyladinazolam maximum plasma concentration was calculated as a measure of sensitivity to these effects. Adinazolam oral and systemic clearances were reduced approximately 30% and 25%, respectively, in elderly volunteers. Adinazolam half-life was prolonged approximately 40% in the elderly after oral dosing. N-Desmethyladinazolam plasma concentrations and half-life were increased approximately 40% in elderly volunteers. Psychomotor performance decrements were observed following all treatments; decrements were lowest following sustained release tablets and intravenous adinazolam. Maximal performance decrements in elderly subjects were approximately twice those observed in young subjects. No significant influence of age on the effect index for digit-symbol substitution was evident. Effect indices for card-sorting tests were significantly higher in the elderly. Lower clearances of adinazolam and N-desmethyladinazolam are observed in elderly volunteers, and increased N-desmethyladinazolam levels contribute to increased psychomotor performance decrements in elderly subjects. Results also suggest that elderly subjects may be more sensitive to certain cognitive effects of N-desmethyladinazolam.


Clomipramine, clonazepam, and clonidine treatment of obsessive-compulsive disorder.

Serotonergic reuptake inhibitors have been the primary medications for treatment of obsessive-compulsive disorder (OCD); however, other serotonergic and alpha 2-adrenergic medications also have been reported to reduce obsessive-compulsive symptoms. In this study, we compare three medications with reported efficacy in OCD to a control medication, diphenhydramine, a medication without theoretical or demonstrated treatment benefit. The three active medications were clomipramine, a serotonergic reuptake inhibitor; clonazepam, a benezodiazepine with putative serotonergic properties; and clonidine, an alpha 2-adrenergic agonist. Twenty-eight subjects with DSM-III-R diagnosis of OCD rotated through 6-week trials of each of the four medications in a randomized, double-blind, multiple crossover protocol. Clomipramine and clonazepam were both effective relative to the control medication in reducing OCD symptoms. There was a significant cross-response between these two medications; however 40% of subjects failing clomipramine trials had a clinically significant response to clonazepam treatment. The control medication, diphenhydramine, itself produced a significant decrement in symptoms, whereas clonidine was ineffective in reducing OCD symptoms. Clonazepam improvement was unrelated to changes in anxiety and occurred early in treatment. Clonazepam was significantly more effective than the other medications during the first 3 weeks of treatment. The results confirm the efficacy of clomipramine in the treatment of OCD and suggest that clonazepam might be a useful alternative treatment for patients with this disorder.


Carbamazepine-induced increases in total serum cholesterol: clinical and theoretical implications.

To assess the effect of carbamazepine (CBZ) upon total serum cholesterol, we examined 38 inpatients with affective illness and one with multiple personality disorder who received a course of CBZ monotherapy. CBZ therapy yielded significant increases in total serum cholesterol that became evident during the second week of therapy, persisted throughout therapy, and reversed in the first few weeks after discontinuation of therapy. CBZ-induced increases in total cholesterol appeared independent of initial mood state, diagnostic subtype, baseline cholesterol or thyroid indices; CBZ levels, doses, and level-to-dose ratios; and the degree of change in mood and thyroid indices. CBZ induction of enzymes mediating cholesterol synthesis is a possible mechanism of the increase in total cholesterol observed with CBZ therapy. Although preclinical studies suggest possible influence of cholesterol on neurotransmitter regulation and behavior, clinical studies have yielded conflicting data. There are insufficient data to support a role for cholesterol in the anticonvulsant and psychotropic mechanisms of CBZ. The increase in total serum cholesterol seen with CBZ therapy is likely due to an increase in the high density lipoprotein fraction and is thus not likely to be clinically problematic in relationship to atherosclerosis.


Analysis of the 14;18 translocation in cutaneous lymphomas using the polymerase chain reaction.

A series of 25 cutaneous B-cell lymphoid proliferations was analyzed for the presence of the (14; 18) translocation using the polymerase chain reaction. Junctional sequences of rearranged chromosomes 14 and 18 were amplified in vitro, and t (14; 18) specific sequences were detected in 1 of 14 primary cutaneous B-cell lymphomas, in 3 of 8 primary nodal B-cell lymphomas and in none of 3 B-cell pseudolymphomas. These results indicate that the t (14; 18) may occur in a small subset of primary cutaneous lymphoma. However, the difference in incidence of the t (14; 18) between primary nodal and primary cutaneous lymphomas suggests that different molecular mechanisms are involved in the pathogenesis of these lymphomas.


Cell cycle analysis by flow cytometry of non-exposed, sun-exposed, and tretinoin-treated skin.

The percentage of keratinocytes in the proliferative phase of the cell cycle (S + G2 + M) was measured by DNA flow cytometry in sun-exposed, non-exposed, and tretinoin-treated skin. Before tretinoin treatment, the percentage of keratinocytes actively cycling was higher in sun-exposed than in non-sun-exposed skin (p = .002) and was correlated with clinically assessed photodamage (p = .007). Subsequently, tretinoin-treated sun-exposed skin was compared to the pre-treatment sun-exposed skin. Overall, there was no statistically significant change. However, there was a trend toward a decrease in the percentage of keratinocytes in the S + G2 + M phases immediately after four months of tretinoin use that was limited to the most severely damaged patients. This effect was no longer evident two months after discontinuing treatment. This is the first study, to our knowledge, utilizing flow cytometry to investigate the effects of tretinoin in patients with varying degrees of photodamage.


Alpha-6 (CD 49f) integrin expression in genetic and acquired bullous skin diseases. A comparison of its distribution with bullous pemphigoid antigen.

Bullous pemphigoid (BP) antigen and alpha 6 integrin are hemidesmosome-associated glycoproteins of basal keratinocytes. In this work, the immunoreactivity of antibodies to BP and to alpha 6 in salt- or dispase-split human skin, and in 46 biopsy specimens of various genetic and autoimmune bullous dermatoses taken from various body sites, was studied by double-labeling immunofluorescence. In all specimens, both antigens localized at the same side of the blisters observed, i.e. the roof of the bulla in cases with a junctional or dermolytic cleavage, or the floor of the blister in those with intraepidermal cleavage. Immunostaining for alpha 6 was strong and present in all specimens studied, whereas the one obtained with the BP serum was absent from some specimens. These results show that the BP antigen and the alpha 6 integrin colocalize at the level of cleavage in bullous diseases; however, the more consistent and reproducible reactivity obtained with the anti-alpha 6 antibody suggests that this should be preferentially used in the immunohistochemical investigation of bullous dermatoses.


Mitten deformity in severe generalized recessive dystrophic epidermolysis bullosa: histological, immunofluorescence, and ultrastructural study.

Light and electron microscopy and indirect immunofluorescence techniques were used to study the nature of the mitten deformity in five adult patients with severe generalized recessive dystrophic epidermolysis bullosa undergoing release of hand and finger contractures. Although the mitten appeared largely to be clinically separated from the underlying fixed digits, histology showed mostly normal keratinocytes beneath a thickened stratum corneum. The lower margin of the mitten was formed just below the lamina densa of the basement membrane, at a level similar to that of the usual blister formation in this condition. No anchoring fibrils and only a few distinct dermal structures were noted. A substantial portion of the mitten, however, consisted of necrotic keratinocytes without an intact basement membrane. This finding suggests that the mitten is not suitable for use as an epidermal autograft and confirms the rationale for taking split thickness skin grafts to close skin defects in patients with recessive dystrophic epidermolysis bullosa undergoing plastic surgery.


Image analysis of stage 1 melanoma (1.00-2.50 mm): lymphocytic infiltrates related to metastasis and survival.

Image analysis of histologic sections of 11 patients with clinical Stage 1 melanoma, 1.00 mm-2.50 mm, who developed metastasis, was done to determine the significance of lymphocytic infiltrates relative to metastasis and survival. An age, sex, site, and thickness matched control group of non-metastasizing clinical Stage 1 melanoma revealed no significant difference in the lymphocytic infiltrate parameters from the metastasizing group with the exception of the ratio of lymphocyte infiltrate width to the tumor width (p = 0.003). Increased lymphocytic infiltrates within the tumor and subjacent to its base significantly correlated with delayed time to metastasis (p = 0.014 and p < 0.001, respectively) and longer survival period (p = 0.045 and p < 0.001, respectively). Lymphocytic infiltrate area at the tumor base in relation to tumor area was of prognostic value: the larger the ratio, the greater the time interval from metastasis to death (p = 0.008).


Occurrence of melanoma in "dysplastic" nevus spilus: report of case and analysis by flow cytometry.

We report a case of melanoma arising in a large nevus spilus. On histologic examination, the nevus spilus had diagnostic features of melanocytic dysplasia. Further characterization by flow cytometry showed DNA-aneuploidy within the melanoma as well as in one of the darker pigmented papules within the nevus spilus. The significance of this finding and a review of melanomas originating in nevi spili are presented.


Cutaneous lymphadenoma with ductal differentiation.

Cutaneous lymphadenoma (CL) is a recently described neoplasm of unknown histogenesis. Histologically, these tumors typically present as well-circumscribed nodules with scant or no epidermal connections. They are composed of multiple rounded lobules of basaloid cells with some degree of peripheral palisading. These epithelial lobules characteristically show a dense lymphoid infiltrate within them. In cases of CL previously described, there was no obvious adnexal differentiation except for isolated cells showing apparent sebaceous differentiation or hints of follicular differentiation. We report two typical cases of CL that were studied histologically and immunohistochemically. In some of the tumor lobules, there were foci of ductal differentiation, with luminal positivity for CEA and EMA. We postulate that some CL represent a form of immature sweat gland tumor with ductal differentiation.


Juvenile colloid milium: clinical, histological and ultrastructural features.

We report the clinical, histological and ultrastructural features of juvenile colloid milium affecting a brother and sister. In this rare condition, translucent papules develop on sun-exposed areas of skin, with onset in childhood. Histologically and ultrastructurally, the papules consist of amyloid-like material derived from epidermal keratonocytes. A review of the literature suggests a possible genetic abnormality that leads to sun-induced degeneration of keratinocytes.


Bubble hair.

An unusual hair dystrophy was studied by means of light and electron microscopy. Hair fibers demonstrated a boomerang deformity containing small and large "bubbles". Electron microscopy revealed a loss of cortical cells and medulla at these sites. Cross-section images showed either a single large cavity or a reticulated, "swiss cheese-like" loss of cells. These two cases represent the second and third reported cases of bubble hair deformity. We present the second light and electron microscopic study of this disorder, including new electron microscopic findings. The cause of bubble hair deformity remains obscure. The involved tufts of wiry hair resolved with gentle hair care. This suggests that trauma to the hair shaft may play a role. It is likely that additional cases of bubble hair remain unrecognized. Investigation of other patients with localized tufts of wiry hair is likely to reveal additional cases.


Vertically growing ectopic nail.

A 64-year-old Japanese woman with an ectopic nail at the palmar tip of the left middle finger is reported. Interestingly, the nail grew vertically to a line horizontal to the surface epidermis. Atypically, it appeared at 60 years of age with no prior injury or trauma to explain inoculation of a nail matrix into the regional skin. Roentgenographically, there were no abnormal findings such as Y-shaped bifurcation of the distal phalanx of the affected finger. There are conflicting opinions concerning whether or not a proximal nail fold is critical for the nail to grow outward instead of upward. Although the present case had a wide proximal nail fold, it did not seem to play its role of compressing and assisting the nail plate to grow outward. Hence, it may be that the absence of a proper nail bed, rather than the absence of a proximal nail fold, promotes upward growth of a nail plate instead of outward growth.


Relationship between oxygen sensitivity and oxygen metabolism of Bifidobacterium species.

Bifidobacteria, which are obligate anaerobes, were studied to determine the relationship between their sensitivity to oxygen and oxygen metabolism. Among the four species tested, Bifidobacterium infantis, Bifidobacterium breve, and Bifidobacterium longum differed from Bifidobacterium adolescentis in sensitivity to oxygen. The former three species showed marked growth under conditions of partial aeration, whereas the growth of B. adolescentis was suppressed by low concentrations of oxygen. Bifidobacteria express reduced NAD-oxidase and -peroxidase activities, which function in a pathway for two-electron reduction of molecular oxygen, producing hydrogen peroxide and, subsequently, water. Activities of reduced NAD-oxidase and -peroxidase were inversely correlated with their sensitivities to oxygen. Bifidobacterium adolescentis exhibited lowered activities of these two enzymes; the activities were 10 to 20% of those observed with B. infantis, B. breve, and B. longum. These observations are compatible with the hypothesis that reduced NAD-oxidase and reduced NAD-peroxidase in Bifidobacterium species play a role in prevention of oxygen toxicity. Superoxide dismutase activity was also detected in Bifidobacterium species. Superoxide dismutase is probably not involved in detoxification of oxygen, because the activity of this enzyme was extremely low, and the sensitivity to oxygen varied independently of superoxide dismutase activity.


Performance of selected milk fat fractions in cold-spreadable butter.

Based on solid fat content profiles, milk fat fractions produced by fractional crystallization procedures employing melted milk fat and milk fat dissolved in acetone were selected for incorporation into soft butter samples. Butter samples made from low melting liquid fractions or a combination of primarily low melting liquid fractions and a small amount of high melting solid fractions exhibited good spreadability at refrigerator temperature (4 degrees C) but were almost melted at room temperature (21 degrees C). Butters made with a high proportion of low melting liquid fraction, a small proportion of high melting solid, and a small proportion of very high melting solid fractions were still spreadable at refrigerator temperature and maintained their physical form at room temperature. Very high melting fractions, which provided key structural functionality in spreadable butter, were obtained from acetone fractionation. Because the use of acetone in processing may hinder or prevent commercialization of these fractions, other means to obtain very high melting fractions from milk fat should be pursued.


Plasmid pattern analysis of Staphylococcus species isolated from bovine mammary secretions.

Plasmid profiles of staphylococci isolated from bovine mammary secretions were heterogeneous as shown by the study of 94 isolates representing six species. Plasmids were identified in 19 of 94 staphylococcal isolates. Number of plasmids per isolate varied from 1 to 4. Size of plasmids ranged from 1.2 to 45 MDa; however, most were between 1.8 and 4.8 MDa. Some isolates with identical plasmid profiles were observed within and between species. Plasmid profiles observed in this study suggest that no specific plasmid pattern occurs within a species. Ability to differentiate isolates was not enhanced when antibiograms were used in conjunction with plasmid profiles. Plasmid pattern analysis does not appear to be an adequate method for discriminating between isolates of a species and would likely provide limited epidemiological information regarding staphylococci of bovine origin.


Susceptibility of Escherichia coli isolated from intramammary infections to phagocytosis by bovine neutrophils.

Thirteen Escherichia coli isolated from naturally occurring IMI were tested for susceptibility to phagocytosis by bovine blood neutrophils. Isolates were opsonized in pooled serum collected from nine healthy lactating cows. Bacteria isolated from IMI first diagnosed within 3 d after calving were more resistant to phagocytosis than were isolates from IMI originating during either the first half of the dry period or later during lactation. Duration of the IMI was negatively correlated with both phagocytic index and percentage of neutrophils phagocytizing within bacterial isolates from IMI originating at calving and during lactation. Phagocytosis was independent of duration of IMI within isolates from IMI originating during the first half of the dry period. Susceptibility to in vitro phagocytosis by neutrophils was not related to O antigen serotype, encapsulation, or growth in dry cow secretion.


Potentiation of antibiotic therapy for bovine mastitis by recombinant bovine interleukin-2.

Adjunct therapy with recombinant bovine interleukin-2 and antibiotics for Staphylococcus aureus IMI was investigated in an attempt to improve the therapy of antibiotics alone. Treatment of established S. aureus IMI with Na-cephapirin or Cefa-Lak produced average cures of 32.0 and 41.8%, respectively. When Na-cephapirin treatment was combined with recombinant bovine interleukin-2 at either 3.3 or 10 mg, the therapeutic efficacy was improved by an average of 20 to 30%. When Cefa-Lak treatment was combined with recombinant bovine interleukin-2 at 10 mg, the therapeutic efficacy was improved on average by 20%. Recombinant bovine interleukin-2, formulated in the excipient of the commercial Cefa-Lak, also improved the therapeutic efficacy by 16% compared with Cefa-Lak alone. Recombinant bovine interleukin-2, formulated in Cefa-Lak, maintained biological activity at room temperature for at least 21 d. After intramammary infusion of recombinant bovine interleukin-2, no biologically active interleukin-2 was detected in milk 48 h (four milkings) after administration. These data suggest that cytokines may be used as adjunct therapy with existing mastitis antibiotics or formulations of existing commercial products to improve the therapeutic efficacy.


The effect of chronic immunostimulation of the nonlactating bovine mammary gland with interleukin-2, pokeweed mitogen, and lipopolysaccharide.

Interleukin-2, pokeweed mitogen, and lipopolysaccharide were evaluated for their ability to accelerate involution and to stimulate local cellular defenses in the nonlactating bovine mammary gland. Twelve cows were divided into three treatment groups of 4 cows each to receive interleukin-2, pokeweed mitogen, or lipopolysaccharide. One day after drying off, 3 mammary quarters of each cow were infused with 100 micrograms of immunostimulant daily for 21 d; the remaining control quarter received PBS. Secretion samples were collected weekly to determine bacteriologic status, total SCC, and differential cell counts. On d 21, cows were killed, and tissues were collected for microscopy. Overall, SCC were higher in immunostimulated quarters, but only those infused with interleukin-2 were significantly elevated over controls. By wk 3, the percentage of neutrophils decreased in interleukin-2 and pokeweed mitogen quarters over pretreatment values, percentage of macrophages increased in interleukin-2 quarters, and percentage of lymphocytes increased in pokeweed mitogen and lipopolysaccharide quarters. Percentage of alveolar lumina was reduced, and connective tissue stroma increased, in all immunostimulated quarters compared with those of controls, suggesting accelerated involution. Involution was greatest in quarters treated with interleukin-2. Leukocyte infiltration was greater in immunostimulated quarters than in control quarters. Similarly, concentrations of Ig-producing plasma cells were greater in immunostimulated quarters than in control quarters. Quarters infused with interleukin-2 exhibited the greatest concentration of plasma cells, followed by quarters treated with pokeweed mitogen and lipopolysaccharide; IgG1 plasma cells predominated, followed by IgG2, IgA, and IgM. Interleukin-2 accelerated involution and stimulated local antibody production more than did the two mitogens, suggesting a potential role for this cytokine as a general immunostimulant at drying off.