Fluconazole and ketoconazole in the treatment of oral and esophageal candidiasis in AIDS patients.

In our study 77 AIDS patients suffering from oral and/or esophageal candidiasis were evaluated: 38 received fluconazole, 39 ketoconazole. We analyzed the rates of clinical and mycological responses, relapses and toxicities. In vitro susceptibility tests for both antifungal drugs were performed by evaluating their Minimal Inhibitory Concentrations (MICs). The azole drugs investigated show a good activity in the treatment of oropharyngeal and esophageal candidiasis also in advanced stages of HIV infection. Clinical cure or improvement were achieved in 29 (76.3%) and 31 (79.4%) of the patients treated with fluconazole or ketoconazole respectively. Clinical or laboratory adverse experiences related to fluconazole were seen in 7 (21.2%) patients while ketoconazole provoked adverse experiences in 9 (26.4%) patients. In vitro susceptibility tests, if repeated more than once, both in primary infection and relapses, could be important to demonstrate a probable sensitivity change or resistance of the tested strains.


Gamma-interferon enhances the cytotoxic activity of interleukin-2-induced peripheral blood lymphocyte (LAK) cells, tumor infiltrating lymphocytes (TIL), and effusion associated lymphocytes.

The effect of gamma-interferon (IFN-gamma) on the induction of interleukin-2 (IL-2) activated killer cell activity was studied: (I) in peripheral blood lymphocytes (LAK cells) from cancer patients and healthy donors, (II) in lymphocytes infiltrating solid tumors (TIL) from melanoma and breast cancer patients, and (III) in pleural effusion associated lymphocytes (EAL) from patients with lung adenocarcinoma. The coculture of LAK, TIL and pleural effusion mononuclear cells (MNC) with several doses of IFN-gamma (10, 50, 250, and 1250 U/ml) and a low dose of IL-2 (10 U/ml) for 5 days resulted in a synergistic effect on the cytotoxicity of these cells against several tumor cell lines. Furthermore there was a potentiation in the proliferation of MNC after a 5-day culture. The induction of lymphocyte cytotoxicity by a combination of IFN-gamma with low doses of IL-2 may be helpful in designing more effective cancer immunotherapeutic protocols with LAK, TIL or EAL.


Evaluation of toxicity in 22 patients treated with subcutaneous interleukin-2, alpha-interferon with and without chemotherapy.

Biological response modifiers (BRMs) have greatly modified the immunotherapy of tumors. Interleukin-2 (IL-2) has brought about metastasis regression in some cases of malignant tumors, however, when given systemically, it results in high toxicity. More recently, the subcutaneous administration of IL-2 (combined with alpha-interferon, alpha-IFN) seems to be capable of offering the same chances of therapeutic response, but this time with a lower level of toxicity. The Authors report an evaluation of toxicity in 22 patients treated with a combination of IL-2 + alpha-IFN i.m. with or without chemotherapy. The side-effects present in the majority of cases were: fever, diarrhea and asthenia. Approximately 50% of the patients had nausea/vomiting, mucositis, skin rashes, and slight leukopenia. The following side-effects were noted to a much lesser degree, thrombocytopenia, alterations in hepatic and dizziness and cystitis. Only one patient reached 4th degree toxicity, with mucositis, asthenia and skin rash. All the other patients received the treatment without suspensions for toxicity. Biological evaluations will enable us to determine in the future, the cases which can benefit from therapeutic intensification and thus it would seem opportune at this time to use therapy with acceptable toxicity.


Radiotherapy and cisplatin in metastatic squamous cell carcinoma of an unknown primary tumor localized to the neck. A phase II study.

13 male and 8 female patients with metastatic squamous cell carcinoma (SCC) of an unknown primary tumor localized to the neck were treated with radiotherapy (RT) and cisplatin (CDDP). There were 12 (58%) and 9 (42%) patients, while no patient had N1 disease. All patients underwent biopsy. RT was given to all possible sites of the primary tumor (nasopharynx, pyriform sinus, and the base of the tongue). The RT dosage planned for the whole neck or supraclavicular area was 45 Gy, increasing to 60-70 Gy on the metastatic site. CDDP was given at a dose of 30 mg/m2, once weekly during the RT course. We observed 15 (72%) complete responses (CR) and 3 (14%) partial responses, while 3 (14%) patients did not respond to therapy. 12 (58%) patients are with no evidence of disease (NED) currently. The median survival time was 34+ months (range, 18+ to 50+ months). We observed two groups of toxicities: gastrointestinal and kidney toxicity. The majority of patients experienced grade 3 (RTOG) toxicity and no patient experienced grade 4 toxicity. This treatment appears to be effective and suitable for patients with metastatic SCC of an unknown primary tumor localized to the neck.


Adhesion between the resin shell and composite resin.

Adhesiveness between the resin shell and composite resin was examined. As the resin shell, SR-PE-ISOCETTE, made from thermosetting crown and bridge resin, was used. The shear bond strengths between the resin shell and photocurable composite resin bonded by various methods were measured after 1-day of immersion in water at 37 degrees C. Super-bond C & B treatment to the resin shell effectively improved the adhesiveness, giving a bond strength of about 14 MPa. Clearfil new bond, Clearfil porcelain bond, Unifast and MMA/TBBO treatment gave almost the same bond strengths of about 7-9 MPa. Silane coupling agents were not effective for improving the bond strength. It was revealed that 4-META was necessary for obtaining good adhesion between SR-PE-ISOCETTE and composite resin.


Hydroxyproline and total protein levels in gingiva and gingival crevicular fluid in periodontally healthy human subjects.

Age is known to be one of the factors which affect the rate of collagen and protein turnover in the connective tissues of the periodontium. The aim of the present study was to determine the levels of hydroxyproline (Hyp) and total protein in both the gingiva and gingival crevicular fluid (GCF) of periodontally healthy human subjects of two different age groups. The subjects of the young group were selected from among patients scheduled for extraction of upper and lower first or second premolars for orthodontic reasons. The second (older) group included individuals whose teeth were to be extracted for endodontic reasons. GCF was obtained before gingival sampling. The tissues surrounding the sockets were harvested immediately after extraction of the indicated teeth. All samples were analyzed biochemically. No significant difference was found in gingival and GCF levels of Hyp (which is unique to collagen) between the groups. Total protein levels in gingiva were significantly higher in the young group than in the older group. GCF total protein levels showed no significant difference between the groups. The higher gingival protein levels in the younger group seem to conform to previous findings.


Investigation of surface corrosion in amalgam.

In this study, surface corrosion of carved and polished specimens of conventional and high-copper amalgams was investigated. The specimens were studied to detect surface corrosion after immersion in artificial saliva for 48 h or 1 year, and later investigated by SEM. Corrosion was greatest in 1-year-immersed carved conventional amalgam specimens. The surface was very rough with the contours of the particles visible and deep holes opening at the surface. High-copper amalgam specimens showed less corrosion than conventional amalgam specimens.


Mutagenicity of analgesics, their derivatives, and anti-inflammatory drugs with S-9 mix of several animal species.

An investigation was undertaken to determine whether analgesics and their derivatives (13 compounds), and anti-inflammatory drugs (4 compounds) had mutagenicity. Rec-assay was used to clarify specific DNA-damaging properties, and the Ames test was used to find back-mutations, using S-9 fractions obtained from the liver of 4 animal species pretreated with polychlorobiphenyl. In the Rec-assay, salicylic acid (2 mg), aspirin (5 mg), benzoic acid (4 mg), sulpyrine (0.4 mg), indomethacin (0.1 mg), oxyphenbutazone (0.1 mg) and diclofenac sodium (0.1 mg) showed a DNA-damaging tendency. In the Ames test, mutagenicity of methyl salicylate was demonstrated using the Salmonella typhimurium TA98 strain upon addition of hamster S-9 mixture. Weak mutagenicity was also found using the TA100 strain with rat S-9 mixture for salicylic acid, sulpyrine, indomethacin and oxyphenbutazone, and with hamster S-9 mixture for methyl salicylate, acetaminophen and phenacetine.


Synthesis of radiopaque cyclophosphazene monomers, properties of bulk polymers and their application to composite resin.

A series of studies was conducted on the synthesis of polyfunctional cyclophosphazene monomers having radiopacity and a polymerization group in the same molecule, and their properties and applicability to composite resin were examined. Using octachlorocyclotetraphosphazene, P4N4Cl8 (4PNC), monomers were synthesized by replacing the 1-4 of chlorine (Cl) with p-bromophenol (BrC6H4OH, BrPh), and replacing the residual number of Cl, 7-4, with 2-hydroxyethyl methacrylate [CH2:C(CH3)COOCH2CH2OH](HEMA), so as to obtain four kinds of transparent monomer having radiopacity and a polymerization group in the same molecule. We then analyzed these monomers and examined their physical properties after bulk-polymerization. Next, we prepared an organic composite filler using 4PN-(BrPh)3-(EMA)5 monomer, which showed comparatively good radiopacity, to produce a new experimental radiopaque composite resin. Although radiopacity improved in accordance with the increase in the number of BrPh molecules replaced, the mechanical properties of the polymer became poorer. Similarly it was proved that the radiopacity of composite resin made with 4PN-(BrPh)3-(EMA)5 monomer was equivalent or even superior, compared with the radiopacity of the front tooth. Consequently, it was shown that these synthesized monomers can be applied to visible light-cured radiopaque composite resin.


Blood flow to human gingiva measured by the 133Xe clearance technique.

Blood flow to the maxillary and mandibular gingivae was determined in 9 subjects under both normal conditions and in inflammation using the 133Xe clearance technique. A total of 36 sites (18 healthy and 18 inflamed) were selected for 133Xe injection. The clearance of radioactivity was monitored by a gamma camera. The calculated mean blood flows were 51.1 +/- 11.4 and 48.7 +/- 6.7 ml/100 g/min to the normal maxillary and mandibular gingivae, respectively. In inflamed gingiva, the corresponding mean blood flows were 55.0 +/- 13.0 and 54.7 +/- 11.7 ml/100 g/min, respectively. A statistical comparison of the healthy and diseased sites was done according to the paired t and Student's t tests. The difference between the sites was not significant (p > 0.05) in the maxilla, but significant (p < 0.05) in the mandible. There was no significant difference (p > 0.05) when the total healthy and diseased sites were compared.


A case of adenocarcinoma arising in the upper lip.

A case of adenocarcinoma arising in the lip of a 20-year-old Japanese man is reported. After electro-irradiation therapy with a dose of 30 Gy, one third of the upper lip, including part of the cheek, was excised. Immediate reconstruction using transpositional flaps of the buccal skin and mucosa, and a functional neck dissection were performed. Nineteen months after surgery, there was no local recurrence or distant metastasis, and desirable results were obtained both functionally and cosmetically.


Use of two miniplates for intermaxillary skeletal fixation in the treatment of jaw deformity and fracture.

Special techniques of skeletal intermaxillary fixation are described, which may be used in edentulous patients or those with many missing teeth or multiple fractures of the jaw. Two such cases are described in which the usual fixation techniques could not provide sufficient stabilization because of linguoversion and mesioversion or lack of teeth, resulting in inability to maintain a vertical interocclusal relationship. Two long eight-hole Champy miniplates were therefore used distally to the canines on both sides. In the first case, they provided fixation following a sagittal ramus osteotomy to advance the mandible, and in the second case they were used in the treatment of a mandibular fracture.


Natural antibody against Thomsen-Friedenreich antigen in bovine milk.

The presence of natural antibody against Thomsen-Friedenreich (TF) antigen in fresh bovine milk was demonstrated by an enzyme-linked immunosorbent assay (ELISA). The amount of the antibody against TF antigen was decreased after heat treatment, and the antibody was not detectable by ELISA in the milk after pasteurization. A small amount of the antibody was detected in fetal bovine serum by ELISA, suggesting the transfer of passive immunity to the calf.


Wear of denture teeth by use of metal plates. Part 3: Abrasive wear of posterior teeth and wear of opposing metal plates.

An in vitro evaluation of abrasive wear resistance of high-strength denture (HS) teeth and wear of metal plates (Pd alloy) on the opposing side was conducted. A total of 8 types of teeth were used in the experiments including 3 types of HS teeth, 3 types of conventional plastic denture (PL) teeth, porcelain teeth and metal teeth (Pd alloy). Sliding-induced wear tests were conducted by sliding these teeth over the metal plates. Abrasive wear resistance of the teeth was evaluated in terms of wear depth and weight loss. A comparison of wear depth showed that the abrasive wear resistance of HS teeth was 4.7 times that of PL teeth, 0.7 times that of porcelain teeth and 8.3 times that of metal teeth. Weight loss showed that the abrasive wear resistance of HS teeth was 3.3 times that of PL teeth, 0.2 times that of porcelain teeth and 11.4 times that of metal teeth. The weight loss of the metal plates was minimal when they slid over HS teeth, but increased in the order PL teeth, porcelain teeth and metal teeth.


Periodontal health parameters in patients with chronic renal failure and renal transplants receiving immunosuppressive therapy.

The periodontal status of 54 renal transplant recipients and 52 patients with chronic renal failure receiving hemodialysis was evaluated and compared with that of systemically healthy subjects matched for age, sex, social status and the number of teeth present. The renal transplant recipients had been receiving immunosuppressive (IS) drug therapy since the time of transplantation. Both of the renal patient groups had significantly higher plaque index scores than the respective controls. By contrast, the renal transplant recipients showed significantly lower periodontal scores and pocket depths. However, there was no significant difference between the hemodialysis group and the corresponding healthy controls with regard to mean periodontal index score and pocket depth. No significant differences could be found among the three groups with regard to mean sulcular bleeding index score or gingival index score. Within the IS group, no relationship was found between the duration of drug therapy and the various periodontal parameters. The observed variations among the groups studied appear to suggest modulation of periodontal condition by both general health status in patients with chronic renal failure and the IS agents used in renal transplant recipients.


Functional regulator therapy in treatment of skeletal open-bite.

A study was performed on the functional regulator, Fränkel appliance (FR4) in order to test its efficiency in the treatment of patients with skeletal open-bite. Pretreatment and post-treatment cephalometric evaluation was done on 11 patients and 10 untreated patients with skeletal open-bite. The results showed that the FR4 appliance was mainly effective on changes in dentoalveolar structures and produced no significant skeletal changes. The degree of anterior open-bite was decreased significantly in the treatment group in comparison with the controls (p < 0.01), due to vertical eruption of upper and lower incisors and retraction of maxillary incisors.


A process for translating and testing a quantitative measure for cross-cultural nursing research.

A study was done to translate an English language, original measure of human behavior into Mandarin Chinese. A process used to translate from one language to the other is explained. Internal consistency of both versions of the measures is tested and equivalence across the two versions of the measure was supported.


Jewish women and nursing: an overview of early history.

This paper seeks to fill a gap in nursing historiography by presenting an overview of the historical presence of Jewish women in nursing. The topic is viewed within the context of women's history and of nursing history. The authors identify several illustrious Jewish women whose contributions to nursing have earned them a place in the annals of the profession. It is hoped that this article will inspire studies about Jewish women in nursing today.


Ethical practice in acute care nursing: are we there yet?

Ethical practice is a necessary component of nursing in today's complex clinical arena. This paper reviews the current status of ethics teaching in nursing education and the role of nurses in ethical decision making in acute care hospitals.


Nurses' empathy and patients' satisfaction with nursing care.

Nurses' self-reported levels of empathy were studied in relation to patients' perceptions of satisfaction with nursing care received. Data were obtained from a volunteer sample of registered nurses and patients using two standardized, paper and pencil questionnaires: Empathy Construct Rating Scale and LaMonica/Oberst Patient Satisfaction Scale. No significant relationship was manifested between the variables under study. It was concluded that empathy training programs for nurses may not be necessary. In addition, although patients are generally satisfied with nursing care received in acute care settings, the data do not support a relationship between nurses' empathy levels and patients' satisfaction. Suggestions for further study are offered.


Experimental infection with Scedosporium inflatum.

The experimental pathogenicity of Scedosporium inflatum (three isolates) and Scedosporium apiospermum (one strain) was determined following intraperitoneal and intravenous injection into immunosuppressed and normal mice. Immunosuppressed animals were treated with cortisone acetate. The results show that the strains studied displayed positive tropism to kidney and brain. In the histopathological study of the first organ, we initially observed abscesses at the glomerular level and later in the renal pelvis. In the brain, we detected large areas with necrosis, which produced important neurological disorders resulting in convulsive movements and a stiff neck. The isolates of S. inflatum were more virulent (45% mortality) than S. apiospermum (16% mortality). The inoculation method did not significantly affect the mortality rate of the mice by either fungus. In infections caused by S. inflatum the percentage of immunosuppressed mice which died was higher in comparison to that of the untreated group. On the other hand no differences were observed in the mortality of either group animals inoculated with S. apiospermum.


Growth response of several Candida albicans strains to inhibitory concentrations of heavy metals.

Prolonged exposure of several Candida albicans strains to inhibitory concentrations of Cd, Cu, or Zn resulted in the appearance of resistant colonies at frequencies and with kinetics significantly different than expected based solely upon the predicted spontaneous mutation rate. Characteristics of the response included: (i) a delay usually of 4-10 days in the emergence of the first resistant colonies; (ii) continued accumulation of resistant colonies for a minimum of 21 days after initial exposure to selection; and (iii) final mutation frequencies ranging from 7.0 x 10(-6) to 9.8 x 10(-4). Further examination of the response of one of the strains to Cd, demonstrated that pretreatment with either ultraviolet irradiation or hydroxyurea resulted in approximately a 10-fold increase in the number of resistant colonies detected. While the distribution and identity of colony phenotypes was altered for all strains after exposure to the heavy metals, no specific morphologies could be correlated to development of resistance.


Enhanced phagocytosis and intracellular killing of Candida albicans by GM-CSF-activated human neutrophils.

Little is known about effector cell modulation regarding phagocytosis and candidacidal activities of human neutrophils in response to granulocyte-macrophage colony stimulating factor (GM-CSF). In neutrophil monolayer assays, pre-treatment of cells with ultrapure GM-CSF at 40 Units ml-1 for a minimum of 1 h showed a significant enhancement of phagocytosis of Candida albicans (phagocytic index of 2.6 compared with 1.6 for unactivated neutrophils) after a 20 min ingestion period (P < 0.001). By counting viable colonies 50% of intracellular yeast cells were killed by non-activated neutrophils following internalization for 2 h. Neutrophils activated for 2 h with 40 Units ml-1 of GM-CSF killed 90% of intracellular blastoconidia (P < 0.02). These results demonstrate that in in vitro assays GM-CSF enhances phagocytosis and intracellular killing of C. albicans.


Iron assimilation in Cryptococcus neoformans.

We studied the effects of iron chelators and of a thallium salt on growth of Cryptococcus neoformans in defined medium. An oxidant-sensitive mutant strain was found to require exogenous ferric iron for growth. Using this strain, we found that the synthetic iron chelator, N-hydroxyethylenediamine triacetate (HEDTA), in several saturation states, stimulated growth as well as the comparably saturated siderophore deferoxamine. This non-specific result makes the existence of a cryptococcal ferrihydroxamate receptor doubtful. The catechols, caffeic acid, L-3, 4-dihydroxyphenylalanine, epinephrine, gallic acid, 3-hydroxytyramine (dopamine) and norepinephrine, were tested for growth stimulation in iron deprivation, under conditions in which deferoxamine was stimulatory. Catechols were found to be either neutral or inhibitory. The ferrous iron chelator, bathophenanthroline disulfonate (BPDS), inhibited growth strongly in the absence of exogenous iron, suggesting that ferric ion must be reduced before it can be internalized. Direct evidence of extracellular reduction was provided by accumulation of red-coloured ferrous-BPDS complex. The inhibition caused by BPDS was relieved by ferric HEDTA, even in the presence of 10-fold increased BPDS, suggesting a second, low-affinity, non-reductive iron uptake pathway. This inference was further supported by the observation that toxicity of the non-reducible ferric analogue, thallium (III), is relieved by iron repletion.


Interaction of terbinafine with human serum and serum proteins.

The allylamine antimycotic terbinafine acts by inhibition of ergosterol biosynthesis at the level of squalene epoxidase. Using this mechanism in Candida parapsilosis cells, a functional assay was developed to investigate the effects of serum and serum proteins on the antifungal action of terbinafine and related drugs in vitro. Inhibition of ergosterol biosynthesis by terbinafine was antagonized by human serum in a dose-dependent non-saturable manner. The results were not affected by varying the period of pre-incubation of serum with the drug or with the fungal cells, or by performing the test in other species of Candida, Aspergillus and Trichophyton. Qualitatively similar effects were observed with the related allylamine compounds naftifine and SDZ 87-469, the extent of antagonism correlating with their lipophilicity. The effect appeared to be caused by non-specific binding of the drug to major serum components, including albumin and the lipoproteins (both LDL and HDL). Reduced bioavailability resulting from binding by serum may at least partly account for the low efficacy of terbinafine in experimental models of systemic infection, in contrast to its high efficacy in infections of the skin, nails and hair.


Contact sensing in Candida albicans: a possible aid to epithelial penetration.

Hyphal development in the dimorphic pathogenic fungus Candida albicans is thought to facilitate the primary invasion of surface epithelia during superficial infections. When mycelia were grown on Nuclepore membrane filters that were placed over serum-containing agar, the hyphae grew over the membrane surface and through the pores thereby crossing to the other side of the membrane. Hyphae that did not contact the lip of a pore did not enter it. The response was likely to be due to contact guidance (thigmotropism) and not chemotropism towards the nutrients since hyphae growing on the underside of the membrane also entered the pores then grew away from the underlying nutrient agar. The response therefore seems to be due to sensation of the substrate topography, and tropic movement in relation to changes in contour. This behaviour may enable the hyphae to penetrate epithelia at microscopic wound sites, membrane invaginations and other foci where the integrity of the epithelium is weak.


Fungemia observations of peripheral tissue clearance in humans.

Patients with fungemia, mainly due to Candida albicans, had cultures repeated from arterial and venous sites to determine yeast cell clearance during fungemia. Of the 48 patients, 37 had repeat positive cultures (36 arterial and venous samples; one venous culture). Additionally, 24 patients had arterial and venous samples cultured quantitatively. An average of 9.1 colony forming units (CFU) ml-1 was isolated from arterial samples and 5.5 CFU ml-1 from venous samples (60% of arterial, P < 0.01). This suggest that arterial fungal densities exceed venous densities and that peripheral tissues clear 40% of yeasts.


Quantitation and morphotyping of Candida albicans from healthy mouths and from mouths affected by erythematous candidosis.

Imprint culture and a mouthwash method were used to determine if quantitative differences exist between isolates of Candida albicans from individuals with healthy oral mucosa and from patients with erythematous candidosis (EC). The C. albicans isolated were differentiated by morphotyping. No quantitative difference in yeast isolations was observed with either technique irrespective of tobacco smoking status, the presence of a prosthesis, or EC. Multiple morphotypes were isolated from smokers with upper dentures and from smokers and non-smokers with EC, whilst a single morphotype was isolated from non-smokers with a healthy oral mucosa.


Activation of human complement system Paracoccidioides brasiliensis and its deposition on the yeast form cell surface.

The yeast form of Paracoccidioides brasiliensis strain Pb18 was able to activate C3 of normal human serum diluted in phosphate-buffered saline or EGTA-MgCl2 in vitro. C3 convertase was also permissive when Pb18 cells were pre-treated with a pool of immune serum from patients with paracoccidioidomycosis and incubated in serum diluted in EDTA-CaCl2. The components C3, and fragments C3c, C3d, C3g, factor H, factor B, C4 and C5b-9 were demonstrated on the Pb18 cell surface by immunofluorescence although no effect was seen on fungal viability.


Quantitative preservation of viability of Aspergillus fumigatus.

Quantitative preservation of the viability of two isolates of Aspergillus fumigatus was studied over a 15-month period of storage. Significant loss of viability occurred in isolates preserved at -70 degrees C in both phosphate-buffered saline with Tween (PBST) and 0.1% gelatin, immediately, and between 6 and 15 months. Storage in 10% and 25% dimethyl sulphoxide at -70 degrees C was successful up to 8 weeks with gradual loss of viability later. PBST at 4 degrees C or room temperature, or 10% glycerol at -70 degrees C maintained 100% viability of the cultures up to 6 months and 15 months, respectively. To preserve 100% viability, long-term storage of A. fumigatus is best done in 10% glycerol in PBST at -70 degrees C compared with the other methods tested.


Oculomotor nerve palsies in children.

Fifty-four patients with oculomotor nerve palsy who presented over a 21-year period at our institution were reviewed retrospectively. There were 38 isolated third nerve lesions, and 16 with additional cranial nerve involvement. Eleven cases were congenital in origin, and 43 were acquired. Of the acquired group, 31 were traumatic, 7 infection-related, 3 attributed to migraine or other vascular causes, and 2 neoplastic. Average follow up was 36 months. The congenital lesions were predominantly right-sided; amblyopia, although common, responded well to treatment. Trauma and bacterial meningitis accounted for more cases of isolated oculomotor nerve palsy than seen in the previous literature. In distinct contrast to the adult population, no cases of diabetes, posterior communicating artery aneurysms, metastatic tumors, or pituitary lesions were found.


The ocular manifestations of the Sturge-Weber syndrome.

Sturge-Weber syndrome (SWS) is a rare neuro-oculocutaneous disorder. The ocular component manifests as glaucoma and vascular malformations of the conjunctiva, episclera, choroid, and retina. The authors reviewed the records of and recalled for examination 51 consecutive patients with a diagnosis of SWS seen at The Hospital for Sick Children, Toronto, Ontario, Canada, from 1980 to 1991. Of the 51 patients, 36 (71%) had glaucoma, 26 experienced onset before 24 months of age and the remainder after 66 months of age, 35 (69%) had conjunctival or episcleral hemangiomas, and 28 (55%) had choroidal hemangiomas, which were bilateral in 12 patients. Other ocular manifestations (retinal vascular tortuosity, iris heterochromia, retinal detachment, and strabismus) also occurred. Thirty-four of 51 (67%) glaucomatous eyes had a final visual acuity of 20/40 or better, or central, steady, and maintained fixation in each eye.


An alternative approach to the surgical management of exotropia--the unilateral lateral rectus recession.

Fifty-five patients with moderate angle exotropia of 15 to 20 prism diopters were surgically treated with a unilateral lateral rectus recession of 7.0, 7.5, or 8.0 mm. The mean age at surgery was 14.5 years. The mean preoperative deviation was 18.0 delta. The mean lateral rectus recession was 7.6 mm. At the initial postoperative follow up, all patients were either a small-angle exotropia or esotropia, or orthophoric. Twenty-eight of the 55 patients (51%) were orthophoric at their most recent follow up. Twenty-four patients (44%) were undercorrected, with 22 of these having residual exodeviations less than 8 delta. Three patients (5%) were overcorrected.


Pattern of childhood blindness and partial sight among Jordanians in two generations.

A study of 260 Jordanians who became blind or visually impaired (according to World Health Organization standards) before the age of 15 years showed the dominant effects of genetically determined causes in two generations. Genetic causes were responsible for the visual impairment in 122 (77.7%) of 157 subjects in the group born after 1970 and for 69 (67%) of 103 in the group born before 1970. There was a statistically significant change in the overall pattern (genetic and acquired causes) of blindness between the two generations, and there was also a significant change in the pattern of acquired blindness alone. A decrease in corneal infections leading to blindness or visual disability in the younger generation was accompanied by an increase of trauma in the same age group. Parental consanguinity in those with genetically determined causes of visual impairment was high compared with those with nongenetic causes (79% vs 33.3%, P < .05). The autosomal recessive mode of inheritance was the most common pattern encountered (53.9%).


Severe visual deficits in infancy in northern Israel: an epidemiological perspective.

The characteristics of 193 legally blind children ranging in ages from birth to 4 years were analyzed. The overall incidence was 1/1000 live births; however, the ethnic specific incidence varies. All children were diagnosed before the age of 20 months and the most frequent alerting sign was lack of visual tracking. In 33.3%, the deficit was first suspected by a family member. A genetic etiology accounted for 38% of the cohort. The relative risk for an associated handicap was significant as well as the rate of hospitalizations for apparently unassociated diseases. It appears that both prevention and early detection could be achieved by a risk index.


Peters' anomaly: a clinicopathologic study.

Two infants were born with bilateral Peters' anomaly. The first baby was a girl, born prematurely at 35 weeks of gestation and who died 8 days later. The second infant was a boy, born at 38 weeks of gestation, who had severe conotruncal abnormality of the heart. Both babies had distinctive facial dysmorphism and severe central nervous system abnormalities including partial or complete absence of the corpus callosum and cerebral calcifications. Biochemical and genetic investigations showed no abnormalities in either child and there was no family history of genetic disorders. Neither case showed evidence of an intrauterine infection. Postmortem ocular findings in the first infant included bilateral herniation of the ruptured cataractous lens into the posterior corneal defect, iridocorneal adhesions, persistent hyperplastic primary vitreous, and total retinal detachment. The left eye of the second infant was eviscerated at 11 months of age because of recurrent, spontaneous perforation. Pathologic ocular findings included large fragments of lens material adherent to the posterior corneal stroma through a large central defect in Descemet's membrane and endothelium, fibrovascular proliferation of the adjacent corneal stroma, and iridocorneal adhesions.


Single-dose kinetics of primidone in human subjects: effect of phenytoin on formation and elimination of active metabolites of primidone, phenobarbital and phenylethylmalonamide.

Effect of repetitive administration of phenytoin (PHT) on the single-dose pharmacokinetics of primidone (PRM) was investigated in 3 healthy male subjects. The peak concentration of unchanged PRM was achieved at 12 and 8 h after the administration of PRM in the absence and the presence of PHT, respectively. The elimination half-life of PRM was decreased from 19.4 +/- 2.2 (mean +/- S.E.) to 10.2 +/- 5.1 h (p < 0.05) and the total body clearance was increased from 24.6 +/- 3.1 to 45.1 +/- 5.1 ml/h/kg (p < 0.01) in the presence of PHT. No significant change was observed for the apparent volume of distribution between the two treatments. In the absence of PHT, the measurable amount (> or = 0.1 mumol/l) of phenobarbital (PB) and phenylethylmalonamide (PEMA) did not appear in the serum until 5.3 and 1.3 h after the PRM administration, and the peak concentrations of PB and PEMA were achieved at 52 and 36 h, but the concentrations of both metabolites were very low (PB 1.3 mumol/l; PEMA 1.7 mumol/l). In the presence of PHT, within 0.8 and 0.5 h after the administration of PRM, the derived PB and PEMA appeared in the serum. About a 6-fold increase in the peak concentrations of both the metabolites were observed (PB 8.2 mumol/l; PEMA 11.0 mumol/l). No significant changes were observed for the elimination half-lives of both PB and PEMA in the absence and presence of PHT.(ABSTRACT TRUNCATED AT 250 WORDS)


Activation of hepatic microsomal glutathione S-transferase of rats by a glutathione depletor, diethylmaleate.

The effect of glutathione depletor diethylmaleate on rat hepatic glutathione S-transferase and glutathione peroxidase was studied in vivo and in vitro. When diethylmaleate (600 mg/kg) was given i.p. to rats, liver glutathione was depleted within 2 h and recovered to the control level 5 h after diethylmaleate treatment. Both glutathione S-transferase and peroxidase activities in microsomes, not in cytosol, were markedly increased during glutathione depletion and only glutathione S-transferase activity remained at high levels after recovery of the glutathione content. The increase in microsomal glutathione S-transferase and peroxidase activities with concomitant exhaustion of glutathione was also observed by perfusion of the isolated liver with diethylmaleate (10 mM). When liver microsomes were incubated with diethylmaleate in vitro at 37 degrees C, glutathione S-transferase, but not peroxidase, activity was increased; the increase was not reversed by dithiothreitol. These results indicate that diethylmaleate activates microsomal glutathione S-transferase by direct reaction to the enzyme during glutathione depletion and suggest that glutathione S-transferase activity and glutathione peroxidase activity in the microsomal enzyme may be differently regulated.


Mechanisms of intestinal absorption of the antibiotic, fosfomycin, in brush-border membrane vesicles in rabbits and humans.

In order to clarify the mechanism of intestinal absorption of an antibiotic, fosfomycin (FOM), the uptakes of FOM by rabbit and human small intestinal brush-border membrane vesicles (BBMV) were studied. The initial uptake of FOM by BBMV at 15 s was saturable at a higher concentration of FOM. The kinetic parameters at 37 degrees C of the saturable uptake expressed by the Michaelis-Menten equation were Kt = 5.17 mM and Jmax = 3.88 nmol/15 s/mg protein for rabbits, and Kt = 4.03 mM and Jmax = 1.90 nmol/15 s/mg protein for humans. The most efficient uptake was observed in the presence of both inward-directed Na(+)- and H(+)-gradients in both mammals. The uptake of FOM was inhibited by inorganic phosphate, FOM glycol which is a degradation product of FOM in the gastric juice and specific inhibitors of phosphate transport such as arsenate and phosphonoacetic acid. These findings confirmed that FOM absorption from rabbit and human small intestines is associated with the phosphate transport system. These transport phenomena of FOM are in close agreement with those obtained previously in rat BBMV studies. Judging from the results obtained for three mammalian species, rat, rabbit and human, it was concluded that carrier-mediated transport via the phosphate transport system is a very important pathway of intestinal absorption of FOM.


Clastogenicity of aporphine alkaloids in vitro.

The chromosomal aberration test using a Chinese hamster lung cell line (CHL) was carried out on 19 aporphine alkaloids including apomorphine with and without rat liver homogenates (S9) mix. Eighteen of 19 alkaloids tested induced chromosomal aberration in the presence or absence of S9 mix. Among the alkaloids tested, anolobine, liriodenine and 4,5-dioxodehydrocrebanine induced chromosomal aberrations at relatively low concentrations and as low as 2.5, 5 and 3.13 micrograms/ml, respectively. Dicentrine, anolobine and 4,5-dioxodehydrocrebanine induced chromosomal aberrations with high frequencies. Apomorphine induced 10% aberrant cells at 12.5 micrograms/ml in the direct method and 12% at 100 micrograms/ml with S9 mix in the S9 method. Liriodenine which was the most potent mutagen for TA100 with S9 mix and roemerine which was the most potent for TA98 with S9 mix in Ames test were also clastogenic with and without S9 mix.


Electrical stimulation-evoked release of endogenous taurine from slices of the hippocampus, cerebral cortex and cerebellum of the rat.

Release of endogenous taurine by electrical stimulation of slices of the hippocampus, cerebral cortex, cerebellum and medulla oblongata of the rat was studied and compared with that of alanine and/or gamma-aminobutyric acid (GABA). Electrical stimulation caused a calcium-dependent release of taurine from slices of the hippocampus, cerebral cortex and cerebellum but not from slices of the medulla oblongata. The stimulus-evoked release of taurine in the hippocampus was rapid in onset and declined to baseline fast, which was essentially similar to the time course pattern of the stimulus-evoked release of GABA. In addition, there were distinct regional differences in the relative amounts of taurine released. Electrical stimulation did not release alanine from any regions examined. These results support the hypothesis that taurine plays a neurotransmitter role in the hippocampus, cerebral cortex and cerebellum of the rat.


Evaluation of a new penetration enhancer 1-[2-(decylthio)ethyl]azacyclopentan-2-one (HPE-101).

A new compound, 1-[2-(decylthio)ethyl]azacyclopentan-2-one (HPE-101) was synthesized, and its skin penetration enhancing activity was examined by using 14C-indomethacin as a penetrant. A solution of HPE-101 and indomethacin was applied to a cloth pad affixed onto an adhesive tape to give a HPE-101 patch, and the patch was applied to hairless mouse skin. The amount of percutaneously absorbed indomethacin was determined by measuring the radioactivity excreted in urine for 24 h after application. 1) Azone and decylmethyl sulfoxide, enhanced markedly the percutaneous absorption of indomethacin when the propylene glycol-ethanol (9:1 v/v) mixture was used as the solvent. 2) Among various penetration enhancers dissolved in the indomethacin solutions and applied to screen for penetration enhancing activity, HPE-101 was found to be the most prominent. 3) Solvents containing more than 3% (w/w) of HPE-101 produced a plateau level of the penetration enhancing activity. 4) Daily application of 1% (w/w) solutions of HPE-101 or Azone increased the daily excretion of indomethacin significantly above the level excreted on the previous day. However, repeated daily application beyond 3 d gave a steady state excretion of indomethacin. 5) The mouse skin was pretreated with 3% (w/w) solutions of HPE-101 or Azone for 24 h on the 1st day, and the indomethacin solution was applied for 24 h on the 3rd day and 7th day to examine the recovery of skin barrier function. Enhanced excretion of indomethacin was still noted on the 3rd day, but enhancement was not observed on the 7th day.


Enantioselective oral bioavailability of 0-isovaleryl propranolol as a potential prodrug of propranolol.

The enantioselective oral bioavailability of propranolol (PL) from 0-isovaleryl-PL was determined and compared with parent PL in beagle dogs. The bioavailability of the individual enantiomer from the prodrug increased about 2 fold. The AUC ratio between the S(-)- and R(+)-isomer posed at 0.89 which was statistically not different from that obtained after administration of PL alone. These features indicate that 0-isovaleryl-PL promises to be a potential prodrug of PL from the pharmacokinetic and pharmacodynamic point of view.


Overestimation of the lipoprotein fractional catabolic rate (FCR) measured in short duration experiments.

The aim of the study was to compare two methods classically used in rats to determine the fractional catabolic rate (FCR) of labeled high or low density lipoproteins: constant infusion and single pulse. The FC of [14C]-sucrose HDL (High density lipoprotein) was studied. For the short term experiment (8 hours), both methods gave similar FCR determined 8 hours after HDL constant infusion (9.4%.h-1 +/- 0.6) or single pulse (8.5%.h-1 +/- 0.4), values significantly higher than those measured 24 hr after the single pulse (6.2%.h-1 +/- 0.3). The identification and simulation of the model representing HDL movements between an intravascular and extravascular pool, after single pulse and constant infusion methods, demonstrated that FCR of lipoproteins cannot be precisely measured with techniques involving excessively short observation periods.


An oral melatonin replacement regimen that re-establishes the normal circadian levels of urinary 6-sulphatoxymelatonin in functionally pinealectomized rats.

Wistar rats maintained on a 12-hr daily photoperiod (LD 12:12 cycle) exhibited a diurnal rhythm in urinary 6-sulphatoxymelatonin (aMT6s) concentrations with peak levels in the scotophase. Light-induced functional pinealectomy (FPX) abolished the nocturnal rise in aMT6s, lowering it to photophase levels. The objective of the study was to formulate an oral melatonin replacement regimen that would restore a normal rhythmic output of urinary aMT6s in functionally pinealectomised rats. Three regimens of sequential doses of melatonin were tested. Of these, the regimen with melatonin concentrations of 4 ng, 12 ng, 65 ng, and 4 ng per ml of drinking water given to rats during the 1st, 2nd, 3rd, and 4th 3-hr periods, respectively, of the 12-hr FPX phase, was found to generate a urinary aMT6s level that closely resembled the natural level and rhythm exhibited under an LD 12:12 cycle. This dose is considered appropriate to restore certain melatonin-mediated physiological functions in Wistar rats subjected to FPX.


Entrainment of the circadian rhythm in the rat pineal N-acetyltransferase activity by melatonin is photoperiod dependent.

Entraining effect of melatonin on the circadian rhythm in rat pineal N-acetyltransferase (NAT) activity was studied under various photoperiods. Melatonin administration prior to dark onset for 5 successive days phase-advanced the evening NAT rise under the light:dark (LD) cycle of either LD 10:14 or LD 8:16, but not under LD 12:12. It is assumed that under the latter regime, the end of a light period exhibited a phase-delaying effect on the NAT rise. The light exposure appeared to be a stronger Zeitgeber than melatonin itself. Data show that melatonin applied in the late light period advances the evening NAT rise under a short photoperiod only; under a longer photoperiod, the phase-advancing effect of melatonin may conflict with a phase-delaying effect of the end of a light period, and the effect of light exposure overrides that of melatonin.


Inhibitory influence of late afternoon melatonin injections and the counter-inhibitory action of melatonin-containing pellets on thyroid growth process in male Wistar rats: comparison with effects of other indole substances.

Previous studies performed in our laboratory indicated that melatonin, when administered in late afternoon (1600-1800) as s.c. injections for 10 days, exerted an inhibitory effect on thyroid growth in mice and Sprague-Dawley rats. The goal of the present study was to examine the effects of melatonin and other indole substances (5-methoxytryptophol, N-acetylserotonin, 6-methoxytryptamine), administered for 10 days, for either 4, 8, or 10 weeks, on thyroid growth processes in adult male Wistar rats. We have also compared the action of melatonin administered in late afternoon as s.c. injections with effects of the melatonin-released chronically from s.c. implanted beeswax pellets containing 1 mg of the hormone. Additionally, the effects of melatonin injections in animals with the pineal gland removed and in thyroid stimulating hormone (TSH)-injected rats have been studied. We examined the mean mitotic activity rates (MMARs) of thyroid follicular cells (TFC) and the wet thyroid weights. We concluded that melatonin, of the examined substances, is the most potent inhibitor of thyroid growth; the hormone reduced the MMAR of TFC and the thyroid weight at all time-points. 5-Methoxytryptophol, like melatonin, exerted the inhibitory influence on the mitotic activity; however, it did not affect thyroid weight. The influence of other indole substances was much less pronounced. It was shown that melatonin-pellets prevented the inhibitory effect of late afternoon melatonin injections on thyroid growth processes. This observation is consistent with results of other authors concerning the counter-antithyroid effect of melatonin on thyroid hormone secretion. Pinealectomy revealed the stimulatory effect on thyroid growth processes, while melatonin treatment reversed the effect of the surgery.(ABSTRACT TRUNCATED AT 250 WORDS)


Serum prolactin and luteinizing hormone levels and the activities of hypothalamic monoamine oxidase A and B and phenylethanolamine-N-methyl transferase are changed during sexual maturation in male rats treated neonatally with melatonin.

Male rat pups were given a single dose of melatonin on day 5 of age. On days 30, 45, and 60, prolactin (PRL), luteinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone (T) were measured in serum and monoamine oxidase A (MAO A) activity, monoamine oxidase B (MAO B), and phenylethanolamine-N-methyl transferase (PNMT) activity were measured in the hypothalamus. Melatonin administration increased serum PRL levels at all ages studied. Serum LH levels were decreased in the melatonin treated group on day 30, but levels were elevated on days 45 and 60 of age as compared to controls. LH response to luteinizing hormone-releasing hormone (LHRH) only increased in melatonin treated animals at 30 days of age. Serum T levels decreased with melatonin treatment at 30 days of age, but increased on days 45 and 60 of age. T response to human chorionic gonadotropin (hCG) was blunted by melatonin treatment at 30 days of life. Hypothalamic MAO A activity increased, after neonatal melatonin administration, at 30 and 45 days of age and decreased at 60 days of life. Early neonatal melatonin administration increased MAO B and PNMT activities on day 45. These findings suggest that neonatal melatonin administration induces an earlier sexual maturation in male rats, possibly related to PRL, LH, MAO, and PNMT increases.


The pineal gland of the trumpet-tailed rat (Octodon degus).

The structure and ultrastructure of the pineal gland of the degu or trumpet-tailed rat (Octodon degus), a rodent inhabiting tropical-equatorial areas, was examined under light and electron microscopy. On the basis of its form, size, and location, the pineal gland of the degu is classified as a proximal or "A" type. The connective tissue appeared poorly developed and the gland contained non-fenestrated capillaries. A single population of typical pinealocytes was found. In addition, a small number of glial cells and cells with electron dense bodies appeared scattered throughout the gland. Cells with dense granules were found isolated or forming small groups always in close proximity to blood vessels. Numerous sympathetic nerve fibers with small dense-core vesicles were found. Also, some myelinated nerve fibers were observed. The physiological significance of the presence of large electron-dense granules in some pineal cells and their particular location around the blood vessels in discussed.


Melatonin concentration in the umbilical artery and vein in human preterm and term neonates and neonates with acute fetal distress.

In order to assess the existence of a rhythmic secretion of melatonin (aMT) in newborns and whether this rhythm is affected by neonatal stress, we studied 112 newborns classified in three groups: normal babies delivered at term, preterm infants born before the 38th week, and babies with fetal distress. Melatonin was measured by RIA in the umbilical artery and vein at the time of birth. Melatonin levels in umbilical arterial and venous blood showed a diurnal rhythm in all groups. Melatonin levels in umbilical cord artery and vein were closely related. Nocturnal melatonin levels were increased in newborns with acute fetal distress in comparison with normal term and preterm neonates. These results suggest that (1) a rhythm of aMT secretion exists in newborns, although it cannot be determined whether this rhythm is of maternal or fetal origin and (2) neonatal stress (acute fetal distress) increases aMT production during the night in comparison with normal term and preterm neonates.


Models for describing absorption rate and estimating extent of bioavailability: application to cefetamet pivoxil.

Five absorption rate models have been compared for describing cefetamet data in 34 adults after oral administration of cefetamet pivoxil with food alone or in combination with either an antacid or an H2 antagonist. A sequential zero- then first-order input process provided the most flexible description of the absorption rate of cefetamet. If the first-order rate constant is linked to the zero-order input parameters the model can be interpreted as the consequence of solubility-limited absorption. While a sequential input is theoretically reasonable to assume, the first-order process appeared to be independent of the zero-order input. A population-based approach was applied to estimate the effect of dose and gastric pH increase on absorption and disposition. There appeared to be a dose-associated change in several parameters. The most marked change was an increase in volume of distribution of cefetamet. Treatments expected to increase gastric pH slowed the first-order component of the absorption process. Three models for estimating the extent of bioavailability have been compared using observations from 18 adults and 13 children receiving iv cefetamet and oral cefetamet pivoxil on two separate occasions. The most consistent estimates of the disposition parameters and the extent of bioavailability were achieved with the sequential zero- and first-order model under the assumption that steady state volume of distribution and nonrenal clearance were the same after iv and oral treatment.


Variational analysis of the transdermal delivery rate from two prototypical ethanol-water nitroglycerin TTS devices and Transderm-Nitro 10 in the normal population.

The performance of two prototypical ethanol-water flux-enhanced transdermal therapeutic systems were compared to the performance of commercial Transderm-Nitro 10. This was a single-center, open-label, three-treatment, randomized crossover study in six healthy subjects who completed the study. Concurrent with each transdermal treatment, an infusion of the stable isotope [15N]3-nitroglycerin was administered. The use of double isotope methodology was incorporated into this study to minimize the variation introduced by fixed-effect error on the evaluation of transdermal flux. The objectives of this study were to isolate experimentally and characterize the average flux enhancement of each prototype, to determine the temporal profile of delivery, and to evaluate the components of variance of drug delivery from each transdermal system. The results of this study showed that the two flux-enhanced transdermal systems with different fill volumes both produced flux enhancement factors of 2 to 3 relative to Transderm-Nitro 10. Prototype B demonstrated a 57% reduction in intersubject variation relative to Transderm-Nitro 10 indicative of enhanced control of drug permeation across a subject population. Prototype A, while reducing intersubject variations, was less than optimal. Both prototypes demonstrated comparable intrasubject variation relative to Transderm-Nitro 10, indicating similar stability for within-subject transdermal drug delivery. The flux enhancement and variational properties of Prototype B were consistent with those intended based on mechanistic considerations of mutual nitroglycerin and ethanol-coupled transdermal delivery.


Salbutamol disposition and dynamics in conscious rabbits: influence of the route of administration and of the dose.

This study assessed the influence of dose and route of administration on salbutamol kinetics and hypokaliemic effect. Salbutamol plasma kinetics were studied in a first group of 6 rabbits who received 60, 800, and 60 micrograms/kg by the intravenous (iv), oral (po), and intratracheal (it) routes, respectively, at 1-week intervals. A second group of 6 rabbits received 120, 2400, and 120 micrograms/kg of salbutamol by the same three routes. Multiple blood samples were withdrawn to assay salbutamol and potassium. Following iv salbutamol (60 micrograms/kg), total plasma clearance was 82 +/- 5 ml/min per kg, apparent volume of distribution was 5.0 +/- 0.5 l/kg, and terminal half-life was 41 +/- 2 min. Similar values were estimated when 120 micrograms/kg of salbutamol was administered iv or was given po or it. The bioavailability of po and it salbutamol was approximately 1 and 20%, respectively. For the first group, the maximal decrease in plasma potassium elicited by salbutamol was 0.80 +/- 0.19, 0.48 +/- 0.22, and 0.78 +/- 0.46 mmol/l, and for the second group, maximal decrement was 1.31 +/- 0.37, 0.70 +/- 0.24, and 0.84 +/- 0.17 mmol/l for the iv, po, and it routes, respectively. Compared to salbutamol peak plasma concentrations, maximal decrease in plasma potassium appeared between 60 and 108 min later for the iv route, 90 and 25 min later for po and it routes, and for this reason, the hypokaliemic effect was not associated to salbutamol plasma concentrations. The hypokaliemic effect was dependent upon the route, e.g., po > it > iv.(ABSTRACT TRUNCATED AT 250 WORDS)


Fundamental pharmacokinetic limits on the utility of using a sinusoidal drug delivery system to enhance therapy.

Clinically, it is known that some disease states respond to drug treatment in a cyclic manner. This has resulted in qualitatively, or empirically, determined cyclically varying drug treatment studies which have been shown to improve therapeutic response in some cases. A theory is developed, for drugs that can be described by pure catenary pharmacokinetic models, which enables one to quantitatively determine at what time a cyclic infusion of drug should be initiated, what the frequency of infusion should be, and what the amplitude of the infusion should be to obtain maximum therapeutic benefit at steady state. Also, the theory allows one to determine quantitatively a priori if a drug's pharmacokinetics precludes the possibility of any real advantage to be gained by cyclically infusing the drug. To implement the theory, it is assumed that the drug obeys linear pharmacokinetics and that the desired pharmacological response is rapid and approximately proportional to a pharmacokinetic compartmental concentration. In particular, a linear system analysis approach is applied to drugs obeying linear pharmacokinetics. It is found that at steady state the amplitude of the sinusoidally varying component of drug's compartmental concentration can be expressed as the amplitude of the rate of infusion times the magnitude of the compartment's transfer function. In addition, an expression for the shift in phase (lag time) of the compartmental drug concentration, relative to the input infusion, is obtained. For a one-compartment model, or for a compartment containing the site of infusion, the amplitude of the sinusoidally varying component ultimately declines in direct proportion to the period (T) of oscillation and the lag time increases from 0 to -0.25T as the period decreases. At a short enough cyclic infusion period, the lag time increments by an additional value of -0.25T, and the attenuation in sinusoidal amplitude decreases by an additional factor of T, for each compartment sequentially connected down the chain from the compartment receiving the infusion. This theory is then applied to the drugs, 5-fluorouracil, KS1/4-DAVLB, theophylline, and adriamycin to see if sinusoidal modulation of the infusion rate would be of therapeutic benefit. The theoretical predictions are then compared to clinically determined empirical results and shown to be consistent. In general, it is shown that the micro rate constants describing the drug's pharmacokinetics must be large (i.e., the system must be able to respond rapidly) for sinusoidal infusion to be of value.


Bias and variance of extrapolated tails for area-under-the-curve (AUC) and area-under-the-moment-curve (AUMC).

The usual formulas for the extrapolated values of AUC and AUMC from tn to infinity produce estimates that are biased. An empirical correction factor is shown to reduce both bias and variance of estimates. The fitted value Cz at the last time-point tn should normally be used in the formulas, rather than the measured concentration Cn. Nonlinear least squares methods offer no advantage over the fitting of a straight line to ln (C).


Building population pharmacokinetic--pharmacodynamic models. I. Models for covariate effects.

One major task in clinical pharmacology is to determine the pharmacokinetic-pharmacodynamic (PK-PD) parameters of a drug in a patient population. NONMEM is a program commonly used to build population PK-PD models, that is, models that characterize the relationship between a patient's PK-PD parameters and other patient specific covariates such as the patient's (patho) physiological condition, concomitant drug therapy, etc. This paper extends a previously described approach to efficiently find the relationships between the PK-PD parameters and covariates. In a first step, individual estimates of the PK-PD parameters are obtained as empirical Bayes estimates, based on a prior NONMEN fit using no covariates. In a second step, the individual PK-PD parameter estimates are regressed on the covariates using a generalized additive model. In a third and final step, NONMEM is used to optimize and finalize the population model. Four real-data examples are used to demonstrate the effectiveness of the approach. The examples show that the generalized additive model for the individual parameter estimates is a good initial guess for the NONMEM population model. In all four examples, the approach successfully selects the most important covariates and their functional representation. The great advantage of this approach is speed. The time required to derive a population model is markedly reduced because the number of necessary NONMEM runs is reduced. Furthermore, the approach provides a nice graphical representation of the relationships between the PK-PD parameters and covariates.


Smooth nonparametric maximum likelihood estimation for population pharmacokinetics, with application to quinidine.

The seminonparametric (SNP) method, popular in the econometrics literature, is proposed for use in population pharmacokinetic analysis. For data that can be described by the nonlinear mixed effects model, the method produces smooth nonparametric estimates of the entire random effects density and simultaneous estimates of fixed effects by maximum likelihood. A graphical model-building strategy based on the SNP method is described. The methods are illustrated by a population analysis of plasma levels in 136 patients undergoing oral quinidine therapy.


Sample size determination for bioequivalence assessment using a multiplicative model.

In bioequivalence studies Cmax and AUC serve as the primary pharmacokinetic characteristics of rate and extent of absorption. Based on pharmacokinetic relationships and on empirical evidence, the distribution of these characteristics corresponds to a multiplicative model, which implies a logarithmic normal distribution in the case of a parametric analysis. Hence, consideration is given to exact and approximate formulas of sample sizes in the case of a multiplicative model.


Hepatitis B surface antigen screening in a nonindigent population.

The recommendation for universal screening of all pregnant women for hepatitis B surface antigen (HBsAg) is based on data from publicly funded hospitals. We retrospectively reviewed screening results of 2,696 mothers who delivered between May 1989 and April 1990. Our population was 85% privately funded. Screening for HBsAg was positive in 0.07%, negative in 80.4% and not done in 19.6%. All positive screens would have been identified by screening only patients with recognized risk factors. We conclude that the sensitivity of identifiable risk factors to detect HBsAg carriers may be high in some populations. We speculate that universal screening in these populations is not cost efficient.


Effects of induced menopause on Burch colposuspension for urinary stress incontinence.

The clinical and urodynamic short term results after colposuspension for urinary stress incontinence has been studied in a group of young patients in whom menopause was induced surgically and compared with a similarly treated group who did not undergo surgical castration. Clinically, no differences were found in the incidence of diurnal frequency, nocturia, urgency, urge incontinence or stress incontinence between the groups. No urodynamic changes in the cystometric, uroflowmetry and urethral pressure profile measurements were found post-operatively between the two groups. It is concluded that surgically induced menopause in the absence of aging has no effect on the results of colposuspension for urinary stress incontinence in the short term.


Neugebauer-Le Fort operation for vaginal prolapse. A review of 38 cases.

Thirty-eight patients with varying degrees of vaginal wall prolapse were operated on using the Neugebauer-Le Fort technique. Their ages ranged from 59 to 90 years. Grand multiparity (> 4) was relatively uncommon (26%). Symptoms were present for more than two years in over half of the women. Serious medical conditions requiring preoperative attention were present in 55% of patients. If the uterus was present, dilation and curettage (D&C) was performed prior to the operation. Intraoperative complications were virtually absent; however, minor postoperative complications occurred in 30% of the patients. None of these complications were related to surgery or altered discharge plans. There were no deaths. No recurrences of prolapse were reported among 30 patients who were followed.


Laser laparoscopy versus laparotomy in lysis of pelvic adhesions.

Severe adhesions were induced at laparotomy by laser ablation of the surface of one uterine horn and 1 cm2 of pelvic sidewall in 20 rabbits. Three weeks later the rabbits were selected at random for laparoscopy or laparotomy. Adhesions at the horn, sidewall and incidental sites were scored and lysed with laser at similar power densities. Three weeks later animals were killed and adhesions were blindly scored. We found a significant and similar reduction in severe adhesions at uterine horns after either laser laparoscopy or laser laparotomy, better lysis of sidewall and incidental adhesions by laser laparoscopy and formation of de novo adhesions at nonoperative sites after laparotomy but not after laparoscopy. We conclude that (1) de novo adhesions are common after laparotomy; (2) severe uterine horn adhesions can be reduced equally well by both laparoscopy and laparotomy but laparoscopy is superior to laparotomy with less severe peripheral adhesions; (3) outcome of adhesiolysis depends on several variables, including adhesion density and location and approach (laparotomy or laparoscopy), even when the tool (laser) is constant.


Confidentiality in the age of AIDS.

Confidentiality is a fundamental rule of medicine and has been specifically defined in many codes of medical ethics. A changing clinical environment both because of diseases such as AIDS, which were not anticipated when these clinical codes were created, and because of the changing relationship between the physician, the patient, and the payor for the physician's care creates dilemmas concerning the rule of confidentiality.


Variability of serum gonadotropin and dehydroepiandrosterone sulfate concentrations in women with polycystic ovary syndrome.

This study was designed to assess the variability of luteinizing hormone (LH), follicle-stimulating hormone (FSH) and dehydroepiandrosterone sulfate (DHEAS) levels over time in women with polycystic ovary syndrome (PCOS). Serum LH, FHS and DHEAS concentrations were determined for four consecutive monthly intervals in three groups of women: group 1, normal cycling women in the follicular phase (n = 9); group 2, normal cycling women in the luteal phase (n = 10); and group 3, women with PCOS (n = 11). For LH, DHEAS and the LH/FSH ratio, a histogram was constructed based on whether the subjects in each group had 0, 1, 2, 3 or 4 high values. In addition, the coefficient of variation (CV) for the four individual values of each hormone was determined for each subject to quantitatively assess the variability of measurement over time. Histographic analysis revealed that an elevated LH value or an elevated LH/FSH ratio in PCOS was inconsistent. For DHEAS, 9 of 11 PCOS subjects had either 0 (n = 7) or 4 (n = 2) high values, suggesting that such determinations are relatively consistent. We conclude that (1) isolated LH or LH/FSH measurements may not be sufficiently reproducible to be clinically useful despite evidence that LH values may be more stable in PCOS than in normal women and (2) a normal or high DHEAS value in PCOS is more likely to be consistently replicated, although the number of subjects studied limits the power of this conclusion.


Incidental finding of endolymphatic stromal myosis during luteinizing hormone releasing hormone agonist therapy for suspected benign uterine myomata. A case report.

A 39-year-old woman with an enlarging myomatous uterus underwent a three-month course of luteinizing hormone releasing hormone (LHRH) agonist treatment. Despite a 50% reduction in uterine size, pathologic examination after uncomplicated hysterectomy revealed a low-grade endometrial stromal sarcoma. As the use of LHRH agonists for myoma reduction increases, delay in the diagnosis of sarcomatous disease will become more widespread. With current available diagnostic modalities, differentiation between sarcomatous and myomatous growth within the uterus is difficult. The possibility of delay in the diagnosis of unsuspected sarcoma when using LHRH agonists is an inherent and apparently unavoidable complication in some cases.


Pain during sexual response due to bilateral Bartholin's gland adenomas. A case report.

Benign adenomas of the major vestibular gland are very rare. Presented is a case of bilateral vestibular gland adenomas in a woman whose chief complaint was vulvar pain occurring with sexual arousal and orgasm. Surgical removal of the adenomas relieved the symptoms. The development of pain during sexual response in this case appears to be mediated by vascular engorgement.


Prenatal detection and management of quadruple nuchal cord. A case report.

As imaging techniques improve, nuchal cords are often being identified prior to labor. Nuchal cords are encountered in up to 25% of deliveries and are usually not clinically significant. They may, however, have devastating results. Nuchal cords may be associated with abnormal fetal activity and testing, but there is often no clinical warning of a nuchal cord during pregnancy, labor or delivery. We report a case of a quadruple nuchal cord discovered after the mother complained of decreased fetal movement. The clinical course of this patient highlights many of the difficulties encountered in the management of antenatally diagnosed nuchal cords, particularly in the preterm fetus.


Uterine prolapse after laparoscopic uterosacral transection. A case report.

Two cases of severe uterine prolapse are reported following laser uterosacral nerve ablation (LUNA). Both patients had a history of vaginal childbirth and subsequent development of secondary infertility and severe dysmenorrhea. It is suggested that this procedure be performed with caution on vaginally parous patients, and that it be reserved for use in patients who have adequate uterine support. Future studies are needed to determine the long-term incidence of uterine procidentia following this procedure.


A continuous glucose monitoring system based on microdialysis.

The development of a system for continuous glucose measurement is described. A microdialysis fibre is used to continuously withdraw the glucose sample. After passing through the microdialysis fibre the perfusion liquid enters a micro-enzyme reactor which is filled with immobilized glucose oxidase. The enzyme activity, which varies with the glucose concentration, is monitored by an oxygen electrode. The measuring system can be adapted to a desired dynamic range by varying the perfusion rate. The measurement system has been calibrated for two different perfusion rates and shows a linear response to glucose concentrations between 0-3.5 mmol at 12 microliters/min and 0-8 mmol at 25 microliters/min. A probe, which can be configured with different lengths of the dialysing fibre, has also been designed to enable subcutaneous insertion of the microdialysis fibre in clinical studies. Subcutaneous glucose sampling by means of microdialysis is suggested to be used in the design of a glucose monitoring device for clinical use.


Multielectrode spiral cuff for selective stimulation of nerve fibres.

In this paper we present the modelling, design, and initial experimental testing of a nerve cuff multielectrode system for selective stimulation of fibres in superficial peripheral nerve trunk regions which is capable of making a selective activation of multiple muscles. The developed multielectrode nerve cuff consists of 14 platinum stimulating electrodes embedded within a self-curling sheet of biocompatible insulation, exhibiting a spiral transverse cross-section. The spiral shape of the system is such that the number of stimulating electrodes which can be utilized depends on the diameter of the stimulated nerve. Nerves with a greater diameter automatically make use of more electrodes than thin ones. The development was based on results obtained by a histological examination of the peripheral nerves which were planned to be stimulated, and on models of excitation of myelinated nerve fibres. The modelling objectives were to determine the electric field that would be generated within a nerve trunk by a specific electrode. Moreover, the extent of initial excitation of the nerve fibres within the superficial region of the dog sciatic nerve elicited by a certain discrete stimulating electrode was predicted. For this purpose a calculation of activating function for six positions where the nerve fibres were supposed to lie within the longitudinally dissected sciatic nerve was performed. In two acute experiments on the sciatic nerve of the dog the objective was to characterize the effectiveness of the multielectrode system in monopolar selective stimulation of the superficial regions, innervating the gastrocnemius and tibialis anterior muscle. A selectivity preliminary tested by measuring the myoelectric activity of the gastrocnemius and tibialis anterior muscle after 2 months showed good results in both animals.


An intra-oral access device.

Using developments from the science of electropalatography, an intra-oral access device is being developed which increases the range and sensitivity of control available to the severely physically disabled individual. The system provides the user with a consistent positional relationship between the tongue and sensor in contrast to extra-oral mounted tongue switches. The system allows the tongue to function within the oral cavity where it has maximum speed, agility and mobility and gives the user a chance to increase accuracy through practice. A major benefit of this system is its versatility. By covering the surface area of the plate with a large number of sensors, the groups of sensors that are programmed to act as switches can take any size, shape, position and number to match the user's needs and abilities. As with any developing system, a number of problems have been encountered in practical use.


Effects of skin temperature on skin-electrode impedance: measurements at high direct current density.

Skin-electrode impedance was determined between two disposable electrodes 5 cm apart on the volar skin of the forearm in 20 patients during cooling on cardiopulmonary bypass. Measurements were made using a constant direct current pulse of 200 microseconds duration, at a current density of 25.6 mA cm-2. The mean inter-electrode resistance was 1.11 k omega, and the mean inter-electrode capacitance was 33.3 nF. In 19 patients there was no change in the inter-electrode resistance or the inter-electrode capacitance with changes in skin temperature from 27.5 to 36.0 degrees C. In one patient the inter-electrode resistance increased from 1.71 k omega at 35 degrees C to 1.94 k omega at 31.0 degrees C, while the inter-electrode capacitance increased from 19.6 to 26.6 nF. We conclude that temperature effects on the impedance of the stimulus electrodes are not responsible for the observed failure of evoked electromyography during clinical monitoring of neuromuscular function.


Perioperative nutrition in cancer patients.

Cancer patients have the highest incidence of protein-calorie malnutrition seen in hospitalized patients, with significant malnutrition occurring in more than 30% of cancer patients undergoing major upper gastrointestinal procedures. Clinically significant malnutrition occurs as a result of diminished nutrient intake, increased nutrient losses, and tumor-induced derangements in host metabolism. In the absence of adequate exogenous nutrients, the body utilizes endogenous substrates to satisfy the ongoing requirements of both host and tumor for energy and protein. In those patients with malignant obstruction of the gastrointestinal tract, the tumor itself may induce diminished nutrient intake. Present day treatment modalities including gastrointestinal resection, chemotherapy, and radiotherapy compound these metabolic derangements, further increasing the risk of postoperative morbidity and death. The presence of malnutrition in cancer patients has prognostic importance. In a review of more than 3000 cancer patients, DeWys and colleagues identified significantly improved survival in those patients without weight loss compared with those had lost 6% of their body weight (Am J Med 69:491-497, 1980). Other investigators have noted increased postoperative morbidity and mortality associated with malnutrition. Early hypotheses suggested that reversal of weight loss would improve survival. The development and refinements of enteral and parenteral nutrition have provided the opportunity for studying the relationship between nutritional supplementation and postoperative prognosis. Nutrition support is therefore often instituted to improve nutritional status and thereby reduce the risks of postoperative complications. This article addresses the beneficial role of preoperative nutrition therapy in cancer patients.


Overcoming difficulties in demonstrating health outcome benefits.

Nutrition interventions with cancer patients may produce benefits beyond those typically evaluated, such as increased appetite, food intake, and weight gain. Other benefits include enhanced mood, improved sense of well-being, and increased socialization because of an increased ability to eat in public or with family. Along with the target benefits of nutrition interventions, these "untargeted" benefits have come to be clustered under the general rubric of health-related quality of life. All medical treatments, including nutrition interventions, can be evaluated in terms of their total effect upon health-related quality of life. However, demonstrating health outcome benefits of nutrition interventions can be very difficult. This difficulty is at two levels: conceptual and practical. Conceptual difficulties can be overcome by refining and clarifying the definition and measurement of health-related quality of life. Practical difficulties are more diverse and must be tackled on a point-by-point basis, depending upon the unique characteristics of the disease being treated, the intervention being tested, and the context of the trial. This paper offers some guidelines and recommendations for overcoming many of the more commonly confronted barriers to successful demonstration of health outcome benefits from clinical nutrition trials with cancer patients.


Optimal design of clinical outcome studies in nutrition and cancer: future directions.

Many studies have assessed the benefits of nutrition support in cancer patients. Except for studies directed at the treatment of severe malnutrition, most clinical trials have failed. Although prospective randomized controlled clinical trials (Phase III) remain the most reliable means of evaluating the efficacy of therapy, the available literature reports only results from small trials (Phase II to III), most of which appear to be contradictory and none of which conclusively answer the question being considered. To address this gap in knowledge, tools such as meta-analysis have been adapted from the field of statistics. Meta-analysis involves pooling results across several studies and provides a more precise estimate of treatment effect than can each individual study. However, clinical trials selected for meta-analysis, although broadly similar, can differ significantly in terms of therapies used and clinical populations studied. Major cancer types with differing effects on food intake and malnutrition (eg, the mechanical obstruction in head and neck cancer vs the cytokine-induced metastases associated with lung, ovarian, colon, and breast cancer) cannot be subject to the same analytic criteria. In this paper, the current state of clinical outcome trials in nutrition and cancer is examined, and the desired design for future studies is proposed. Research priorities include the conduct of Phase II clinical trials that use as outcome measures quality of life, performance status, and survival to identify optimal cancer-specific and patient-specific nutrition support. The next round of Phase III efficacy studies should establish the appropriate use of nutrition support in cancer therapy.


The role of cytokines in cancer cachexia.

There is, at present, considerable interest in the possible role for the proinflammatory cytokines, tumor necrosis factor-alpha, interleukin-1, interleukin-6, and interferon-gamma in the pathogenesis of cancer cachexia. Indirect evidence for such a role is based on the observation that chronic administration of many of these cytokines, either alone or in combination, can reproduce the myriad of host responses seen in experimental and human cancer cachexia. Elevated plasma levels of tumor necrosis factor-alpha, interleukin-2, and interferon-gamma have rarely been detected in patients or experimental animals with cancer, although interleukin-6 levels appear to correlate with tumor progression in animal models. The strongest evidence for a causal role for cytokines has come from rodent studies in which tumor-bearing animals have been passively immunized with antibodies directed against individual cytokines. Several groups have shown modest but significant improvements in food intake and lean tissue retention with antibodies directed against tumor necrosis factor-alpha, interleukin-1, interleukin-6, and interferon-gamma. However, there has been no consistent finding that one cytokine is universally involved in cancer cachexia in histologically distinct tumor models. One ominous finding in several tumor models has been that the endogenous production of cytokines appears to support tumor growth. Such findings raise the intriguing possibility that these cytokines, although contributors to tissue wasting and anorexia, may also serve the tumor as either direct or indirect cell growth factors.(ABSTRACT TRUNCATED AT 250 WORDS)


Cytokines and their role in the pathophysiology of cancer cachexia.

Cancer cachexia describes a syndrome that consists of weight loss, and abnormalities in carbohydrate, protein, and lipid metabolism, which result in a state of persistent net negative energy balance. Patients suffering from cancer cachexia have a significantly shortened survival after cancer treatment. Recent experimental studies have focused on the belief that the mechanisms of cancer cachexia involve the host's production of inflammatory cytokines, which through broad physiologic actions ultimately lead to a chronic state of wasting, malnourishment, and death. Cytokines that have been thought to play a role in the pathophysiology of cachexia include tumor necrosis factor, interleukin-1, interleukin-6, interferon-gamma and differentiation factor. It has become clear that these cytokines have overlapping physiologic activities, which makes it likely that no single substance is the sole cause of cachexia in most cancer patients. Only further investigation may make it possible to more clearly define the role of cytokines in the pathophysiology of cancer cachexia. Specific strategies to reverse the cachectic effects of these substances may then be developed to ultimately improve cancer treatment.


The early cancer anorexia paradigm: changes in plasma free tryptophan and feeding indexes.

Tumor growth is accompanied by an anorexia mediated by humoral factors that appear to influence appetitive mechanisms in the brain. Because tumor resection is followed by resumption of normal food intake, the circulating anorexigenic substance(s) are produced either by the neoplastic tissue or by the host in response to the tumor. Increased levels of plasma free tryptophan and plasma ammonia have been proposed to mediate cancer anorexia. With animal models, it is often difficult to ascertain whether changes in food intake depend upon metabolic changes or the progressively increasing tumor mass per se. The feeding patterns and biochemical changes that occur during tumor growth were evaluated in 96 male Fischer rats that were inoculated with 10(6) methylcholanthrene sarcoma cells or saline (controls). Rats were placed into metabolic cages equipped with an Automated Computerized Rat Eater Meter to continuously determine meal size and meal number. Plasma free tryptophan and ammonia were evaluated 6, 10, 16, 18, 22, and 26 days after tumor inoculation. Anorexia developed by day 17-18, when food intake started to decrease via a decrease in meal size but not meal number and reached 60% of control by day 26. However, long before anorexia developed, free tryptophan was significantly higher 6 days after tumor inoculation, and the greatest increase occurred after 18 days. Ammonia did not differ from control at any time. Data confirm tumor-associated increases in plasma free tryptophan that occurred before the manifestation of anorexia and support a possible role of brain serotonin in cancer anorexia.


Hormonal and metabolic abnormalities in the malnourished cancer patient: effects on host-tumor interaction.

Many common metastatic cancers are associated with marked weight loss at the time of diagnosis. Anorexia clearly plays a major role in weight loss in the cancer patient, but cannot explain all of the weight loss noted. Malnourished patients with localized cancers under metabolic ward conditions fail to gain weight when given apparently adequate calories for anabolism, thus suggesting that these patients are hypermetabolic. Increased whole body protein breakdown, increased lipolysis, and increased gluconeogenesis have been repeatedly demonstrated in malnourished cancer patients. Protein and glucose metabolism are closely linked, and both are regulated by a number of the same hormones and metabolites. For example, when increased glucose production in malnourished cancer patients is inhibited pharmacologically, protein catabolism is proportionally decreased. Studies of glucose, growth hormone, cortisol, and insulin secretion following an oral glucose load in well-nourished cancer patients are consistent with insulin resistance but no other hormonal abnormalities. Malnourished cancer patients have elevated levels of growth hormone that are further stimulated by arginine and insulin infusion. No abnormalities of thyroid function were noted in cancer patients. Current studies are underway to determine the mechanisms and effects of progestational steroids and cytokines on both food intake and intermediary lipid metabolism.


Metabolic response to chemotherapy in colon cancer patients.

The goal of this investigation was to identify the metabolic abnormalities in a group of colon cancer patients before and during 5-fluorouracil chemotherapy. Twenty-two colon cancer patients were prospectively enrolled into a Clinical Research Center for measurement of counter regulatory hormones, fasting hepatic glucose production (HGP), intravenous glucose tolerance test, plasma leucine appearance (LA), and leucine oxidation (LO). Both the cancer group and the normal volunteers were matched for nutrition status (109 +/- 5% of ideal body weight vs 104 +/- 4%, mean +/- SEM, respectively) and history of weight loss (6.3 +/- 2.6 kg vs 4.4 +/- 4.8). Plasma growth hormone was significantly elevated in the colon cancer patients (3.22 +/- 0.62 ng/mL vs 0.73 +/- 0.18, p < .05) despite the fact that insulin-like growth factor-1 levels were not different. Plasma glucose, insulin, cortisol, glucagon, epinephrine, and norepinephrine levels were not significantly different than those of the normal volunteers. Fasting HGP rates were slightly but not significantly elevated in the group of colon cancer patients compared with the normal volunteers (2.09 +/- 0.11 mg/kg per minute vs 1.79 +/- 0.10, p = .10). Plasma LA was not significantly elevated in the colon cancer group (63.3 +/- 3.0 mumol/kg per hour vs 57.7 +/- 4.2; p = .25). Five days of continuous 5-fluorouracil chemotherapy was associated with a significant elevation in both the fasting glucose level (97 +/- 3 mg/dL vs 106 +/- 5, p < .05), and HGP (2.09 +/- 0.11 mg/kg per minute vs 2.27 +/- 0.10; p < .05).(ABSTRACT TRUNCATED AT 250 WORDS)


Stimulation of tumor growth by nutrition support.

Controversy exists regarding the use of nutrition support in the cancer patient. Although nutrition support can clearly improve host nutritional status and restore immunoconfidence, the efficacy of nutrition support to reduce morbidity and mortality associated with antineoplastic therapy is questionable. A potential concern with the use of nutrition support in the tumor-bearing host is stimulation of primary tumor growth and metastasis. Numerous animal studies clearly demonstrate that oral and parenteral nutrition can significantly stimulate tumor cell proliferation and distant metastasis. Although cellular kinetic studies in humans have shown alterations after parenteral nutrition, objective measures of tumor growth, metastasis and tumor protein synthesis have not been affected by parenteral nutrition. This chapter summarizes the research and clinical work regarding the effect of nutrients on tumorigenesis, primary tumor growth, and metastasis in both animal and human tumors.


Nutrition and tumor promotion: in vivo methods for measurement of cellular proliferation and protein metabolism.

The notion that tumors act as "nitrogen traps" has led to the belief that nutrition support of the cancer-bearing patient can enhance tumor growth. Proponents of this theory consider the provision of energy and essential nutrients as well as the influence of hormones and growth factors as responsible for this effect. On the other hand, nutrition administration in the debilitated cancer patient may improve antitumor host defense mechanisms and reduce tumor growth. This paper reviews methodologic issues related to the study of nutrition and cancer growth with emphasis on in vivo methods for measuring tumor protein turnover and cytokinetics. Using this combined approach, we previously demonstrated that dietary fat may significantly regulate tumor growth during chronic feeding as well as with short-term intravenous nutrition support in experimental models. Although the mechanism of this effect remains unclear, we have reasoned that by altering arachidonic acid metabolism and prostaglandin synthesis, omega-3 fatty acids could change tumor protein breakdown rates and inhibit the proliferation potential of these tumors. Acknowledging alternative hypotheses, we now present cytokinetic evidence that intracellular protein degradation may regulate tumor cell proliferation. Additional studies relating dietary fat, tumor protein metabolism and tumor proliferation potential are currently in progress. We propose that the effect of nutrition administration on tumor growth is complex and involves several regulatory systems. Thus, based on available evidence, an a priori tumor-enhancing effect for nutrition support is clearly not warranted. Intracellular protein breakdown and host defense mechanisms, both of which are energy dependent, are important loci at which nutrition and tumor growth regulation could interact.(ABSTRACT TRUNCATED AT 250 WORDS)


Glutamine facilitates chemotherapy while reducing toxicity.

Dose intensification of chemotherapy is thought to increase survival. With recent advances in hemopoietic cell modulators such as granulocyte colony stimulating factor, the limiting toxicity of intensifying chemotherapeutic regimens has become the severity of the associated enterocolitis. In animal models, glutamine protects the host from methotrexate-induced enterocolitis. This study evaluates the effects of a glutamine-supplemented diet on the tumoricidal effectiveness of methotrexate. Sarcoma-bearing Fisher 344 rats (n = 30) were pair-fed an isocaloric elemental diet containing 1% glutamine or an isonitrogenous amount of glycine beginning on day 25 of the study. Rats from each group received two intraperitoneal injections of methotrexate (5 mg/kg) or saline on days 26 and 33 of the study. On day 40, rats were killed, tumor volume and weight were recorded, and tumor glutaminase activity and tumor morphometrics were measured. Blood was taken for arterial glutamine content, complete blood count, and blood culture. The gut was processed for glutaminase activity and synthesis phase of the deoxyribonucleic acid. In rats receiving methotrexate, the tumor volume loss was nearly doubled when glutamine was added to the diet. Significant differences in tumor glutaminase activity and morphometrics were not detected. The toxicity to the host was ameliorated. Significantly increased synthesis phase of deoxyribonucleic acid of the whole jejunum, decreased bacteremia, "sepsis," and mortality were demonstrated. Glutamine supplementation enhances the tumoricidal effectiveness of methotrexate while reducing its morbidity and mortality in this sarcoma rat model.


[Chronic fatigue syndrome--symptoms, signs, laboratory tests, and prognosis].

Chronic fatigue syndrome (CFS) is an undefined clinical problem and is perceived as a complex of multiple symptomatology with an unexplained persistent fatigue. Major symptoms include fatigue lasting for more than 6 months, low-grade fever, moderate lymphadenopathy, muscle and joint pain, and various psychological presentations. Since no specific laboratory tests are available, clinical diagnosis demands that known causes of chronic fatigue should be excluded. The pathogenesis is at present unknown, but it is suspected that CFS is a physical and psychological condition associated with some unrecognized infectious agent. Further study is needed to clarify the precise pathophysiology of this newly recognized entity.


Nutrition in advanced cancer: anorexia as an outcome variable and target of therapy.

The endpoints used as outcome variables in clinical cancer treatment trials, including nutrition intervention studies, should contain items that are meaningful to the patient. Variables to consider are appetite, food intake, physical performance, psychological and social functioning, response to cancer therapies, survival time, nutrition status, associated morbidity, and costs. Ideally, the design and conduct of nutrition trials should be carried out by a multidisciplinary team comprising medical oncologists, physician specialists in nutrition, dietitians, and social scientists. Anorexia has not been a focus of nutrition support trials in the past partly because of the lack of effective strategies to reverse it. Anorexia is one important cause of cancer starvation, and it also causes patient discomfort. This paper describes outcome variables that include patient derived subjective factors such as anorexia, and outlines new strategies to reverse anorexia. Pharmacologic strategies tested to reverse anorexia include corticosteroids, anabolic steroids, cyproheptadine, hydrazine sulfate, cannabinoids, and megestrol acetate. Of these, only the latter has been consistently well tolerated and effective, with significant improvements in appetite and food intake demonstrated in large-scale, randomized, controlled trials involving more than 600 cancer patients. Dose-response studies have demonstrated increasing efficacy with increasing doses of megestrol acetate from 160 to 800 mg/day. Doses in excess of 800 mg/day are not currently recommended. The mechanisms of action of megestrol acetate involve both behavioral and metabolic effects, and its impact on energy expenditure, appetite, body composition, endocrine function, and lipid metabolism is the subject of ongoing research.(ABSTRACT TRUNCATED AT 250 WORDS)


[Definition of the chronic fatigue syndrome and its issues].

This article reviewed Definition of CFS proposed by CDC 1988. There are several issues in Definition for CFS of CDC. It is presented that other chronic clinical conditions have been satisfactorily excluded, including preexisting psychiatric diseases in (2) of major criteria. However, fibromyalgia can not be excluded from the fifth symptom of minor criteria, myalgia, and also depression from the ninth symptom. It is practically difficult to define impairment of average daily activity below 50% of the patient's premorbid activity level for a period of at least 6 months, as shown in (1) of major criteria, and it is not adapted for a first visit patient. Definition for CFS of CDC has been discussed on EBV infection, but not written on postviral fatigue syndrome and myalgic encephalomyelitis. Especially whether epidemic type of CFS is present or not was not discussed. Diagnostic criteria of CFS is necessary for clinical practice.