Interaction of epidermal growth factor, Ca2+, and matrix metalloproteinase-9 in primary keratinocyte migration

Elevations of epidermal growth factor (EGF) and Ca²⁺ concentrations in the wound site are associated with reepithelialization during wound healing. In addition, Ca²⁺ and EGF can both induce increases in matrix metalloproteinase‐9 (MMP‐9) synthesis. However, little is known about the interplay of these events in regulating the migration properties of primary keratinocytes on collagen I, the most abundant extracellular matrix component in the skin. We found that EGF stimulated both chemokinetic and chemotactic migration of primary keratinocytes on collagen I; however, MMP‐9 was required for EGF‐stimulated chemotaxis but not EGF‐stimulated chemokinesis. Calcium at 0.5 mM stimulated chemokinetic migration of keratinocytes. Together, Ca²⁺ and EGF stimulated higher levels of chemokinesis than either stimulus alone. Furthermore, Ca²⁺ could restore the ability of keratinocytes from MMP‐9 null mice to undergo EGF‐stimulated chemotaxis. The phosphatidylinositol‐3 kinase inhibitor LY294002 inhibited both EGF‐ and Ca²⁺‐stimulated chemokinetic migration. In contrast, the MEK inhibitor PD98059 blocked Ca²⁺‐ but not EGF‐stimulated chemokinetic migration of keratinocytes. A combination of PD98059 and LY294002 was required to inhibit Ca²⁺ enhancement of EGF‐stimulated migration completely. Calcium‐stimulated chemokinesis was completely blocked by either the protein kinase C‐α inhibitor Gö6976 or the src/fyn inhibitor PP2. Using primary keratinocytes, our results showed how the combined action of Ca²⁺, EGF, and MMP‐9 regulated the contributions of extracellular‐regulated kinase and phosphatidylinositol‐3 kinase toward chemokinetic and chemotactic migration of keratinocytes.     

Congenital disorder of glycosylation type 1a: three siblings with a mild neurological phenotype.

We report 3 siblings (1 male and 2 female) recently diagnosed with congenital disorder of glycosylation type Ia (CDG-Ia) in their mid-20s. They experience mild mental retardation but manage to function independently in society. Their professions are library assistant, professional artistic painter and secretarial work. All three siblings have cerebellar hypoplasia and ataxia, but are able to ambulate easily. Two of the siblings have required strabismus surgical repairs. All have antithrombin III deficiency, osteoporosis, and mild dysmorphic features. Hypergonadotrophic hypogonadism was a feature of the two female siblings. A type 1 sialotransferrin pattern and phosphomannomutase (PMM) deficiency have been demonstrated. They are compound heterozygotes for R141H and L32R mutations in the PMM2 gene. While there is clinical heterogeneity in CDG-Ia, we believe that our patients are among the mildest of intellectually affected CDG-Ia patients reported to date.     

Postoperative evisceration: A résumé of the literature and report of five cases

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1. A résumé of literature shows that the cause of wound disruptions may be classified under the following headings: (a) Increased intra-abdominal tension; (b) faulty technic; (c) metabolic disturbances, and (d) allergy.     

Endocrinology: Predictive value of serum oestradiol concentrations and oocyte number in severe ovarian hyperstimulation syndrome

Ovarian hyperstimulation syndrome (OHSS) is a serious complicationof gonadotrophin usage but it is difficult to accurately predictits occurrence. Previous investigators have identified the combinationof high oestradiol concentrations and oocyte number as beingpredictive in 80% of cases. In this study we sought to identifythe incidence of severe OHSS in patients with high oestradiolconcentrations and large numbers of oocytes and to evaluatethe importance of pregnancy in the development of OHSS. Between1990 and 1993, we studied 139 cycles using two assisted reproductivetechniques [oocyte donor, n =72; in-vitro fertilization (IVF),n = 67] in which either oestradiol (>4000 pg/ml), oocytenumber (>25), or both were elevated. OHSS was diagnosed bystandard criteria. There were no cases of severe OHSS in theoocyte donor group and six in the IVF group. Among 10 patientswith oestradiol concentration >6000 pg/ml and >30 oocytes,only one had OHSS (10%). The relative risk of OHSS with pregnancywas 12 (confidence interval 2.18–66.14). We conclude thatthe risk of OHSS even at high levels of stimulation is lowerthan previously believed. Secondly, donors have a very low riskof OHSS, probably because of the absence of pregnancy. As such,cryopreservation of all oocytes in IVF cycles is a reasonablealternative to cycle cancellation or use of adjunctive medication.     

Postirradiation malignant fibrous histiocytoma expressing cytokeratin. Implications for the immunodiagnosis of sarcomas

A malignant fibrous histiocytoma of the sacrum complicating the course of radiation therapy for endometrial carcinoma is presented. Although the tumor fulfilled the clinical, radiologic, and histologic criteria for a postirradiation malignant fibrous histiocytoma of bone, it also expressed cytokeratin. That this immunoreactivity reflected keratin synthesis by the tumor and not an unusual pattern of cross-reactivity with another intermediate filament such as vimentin is strongly suggested by the reproducibility of the immunoreactivity utilizing both polyclonal and monoclonal antibodies and extinction of the immunoreactivity following absorption of the primary antiserum with keratin proteins. This is the first reported instance of keratin expression by a malignant fibrous histiocytoma; it indicates that sarcomas apart from synovial sarcoma and epithelioid sarcoma may sometimes express this protein.     

Effect of hepatic artery chemotherapy on survival of patients with hepatic metastases from colorectal carcinoma treated with cryotherapy

Thirty-eight patients with unresectable multiple liver metastases from colorectal carcinoma were treated with either hepatic artery chemotherapy (HAC) and cryotherapy (n=27) or cryotherapy alone (n=11). Follow-up survival data were summarized using Cox regression. Allowing for the effect of the pathology of the primary tumor and the preoperative carcinoembryonic antigen (CEA) level, those patients who did not receive HAC after cytoreduction were three times as likely to die as those given HAC (RR 3.3, 95%; CI 1.2–9.3). The estimated median survival of patients treated with cryotherapy alone was 245 days, whereas for those given more than 3 months of HAC plus cytoreduction therapy it was 570 days. It is recommended that all patients who receive cryotherapy for multiple liver metastases from colorectal rectal carcinoma be given subsequent hepatic artery chemotherapy.

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Resumen En el presente estudio, 38 pacientes con metástasis hepáticas múltiples y no resecables de carcinoma colo-rectal fueron tratados con quimioterapia administrada en la arteria hepática (HAC) y crioterapia (n=27) o crioterapia sola (n=11). Los datos del seguimiento fueron resumidos según el método de regresión de Cox. Teniendo en cuenta el efecto de la patología del tumor primario y el nivel preoperatorio de antígeno carcino-embrionario, se halló que aquellos pacientes que no recibieron HAC luego de la citorreducción tuvieron una probabilidad de muerte 3 veces mayor que los que recibieron HAC (RR 3.3, 95% CI 1.2 a 9.3). La sobrevida media estimada de los pacientes tratados con crioterapia sola fue de 245 días, en tanto que aquellos que recibieron HAC por tres meses y terapia de citorreducción fue de 570 días. Se recomienda que todos los pacientes que reciben crioterapia para metástasis hepáticas múltiples de carcinoma colo-rectal reciban luego quimioterapia por vía de la arteria hepática.

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Résumé Trente-huit patients ayant des métastases hépatiques multiples non reséquables d'origine colorectale ont été traités soit par chimiothérapie par voie artérielle (CVA) associée à la cryothérapie (n=27) soit par cryothérapie seule (n=11). Les survies ont été analysées selon la méthode d'analyse du Modèle de Cox. En tenant compte de l'effet de la pathologie de la tumeur primitive et du niveau préopératoire de l'ACE, les patients n'ayant pas eu de de décéder que ceux qui en ont eu (RR 3.3, 95% IC 12 à 9.3). L'estimation de la survie médiane des patients traités par la cytoréduction seule a été de 245 jours, alors que celle des patients traités par les deux avec une CVA d'au moins trois mois, a été de 570 jours. On recommande que tous les patients ayant des métastases multiples du foie à partir des cancers colorectaux aient une CVA par la suite.

     

Assessment of the Severity of Asthma in a Family Practice

The objective of this study was to evaluate clinical history and self-perception of severity as predictors of asthma severity. A short-term longitudinal study was conducted in a family practice in Melbourne, Australia, utilizing peak flow monitoring, medication diary, and self-administered asthma severity questionnaire. Seventy-two asthmatic subjects with a positive bronchodilator or exercise test, aged between 6 and 79 years, were studied. Symptom and treatment items were correlated with peak flow variability and minimal peak expiratory flow rate (PEFR). An asthma severity scale was generated using the partial credit version of Item Response Theory and the participants' severity scores were validated against lung function tests and medication usage. Quantitative modeling procedures were used to investigate the interrelationships of factors associated with peak flow variability. Severity scores demonstrated significant relationships with peak flow variability (partial r = 0.34) and treatment items. Self-perceived severity of asthma in the preceding 2 weeks showed significant association with peak flow variability (partial rho = 0.46) and minimal PEFR (rho = -0.41). The severity module of the Monash Respiratory Questionnaire is a valid and reliable instrument. The most important symptoms appear to be the frequency of use of bronchodilator and frequency of nocturnal attacks. A carefully structured clinical history in conjunction with the peak flow criteria of variability and minimal peak flow rate would be appropriate in the evaluation of asthma severity. Patients' self-perception of the severity of their asthma needs further evaluation.     

Functional MR activation correlated with intraoperative cortical mapping.

PURPOSETo evaluate the spatial specificity of functional MR imaging by comparing it with intraoperative electrocortical mapping.METHODSFunctional MR imaging was performed in 28 patients before awake craniotomy and intraoperative electrocortical mapping. Activation was mapped for finger movement, lip movement, tongue movement, word generation, and counting paradigms. During surgery, finger movement, lip movement, tongue movement, counting, and/or speaking were mapped. The functional images and the photographic recordings of the brain functions mapped during surgery were converted to bit maps and coregistered by a computer program. The distance between the intraoperatively mapped function site and the MR activation site for a comparable function was measured.RESULTSForty-six functions were recorded on MR images and intraoperative maps. In 100% of correlations, the intraoperative site and the MR activation site were within 20 mm; in 87% of correlations they were within 10 mm. For each paradigm, 67% or more of the intraoperative stimulation maps correlated within 10 mm of the MR activation site.CONCLUSIONSFor the tasks used in this study, the activation site on functional MR images correlated well with the site at which intraoperative stimulation identified function.