Cisplatin resistance is associated with reduced interferon-gamma-sensitivity and increased HER-2 expression in cultured ovarian carcinoma cells

In ovarian carcinoma cells, the combination of interferon-gamma (IFN-gamma) and cisplatin (cDDP) has been reported to result in a synergistic amplification of antiproliferative activity. To assess whether IFN-gamma may also prevent the occurrence of cisplatin resistance, the human ovarian carcinoma cell line HTB-77 was treated repeatedly in an intermittent fashion with either cisplatin alone (HTB-77cDDP) or cisplatin plus IFN-gamma (HTB-77cDDP + IFN). After 8 months of treatment, both new lines (HTB-77cDDP or HTB-77cDDP + IFN) were found to be three times more resistant to cisplatin than the wild-type cells (HTB-77wt). IFN-gamma could not prevent the development of cisplatin resistance. Interestingly, both HTB-77cDDP and HTB-77cDDP + IFN cells were also less IFN-gamma sensitive than the parental line. Both cisplatin-resistant lines expressed p185HER-2 and HER-2 mRNA at a higher concentration than the HTB-77wt cells. IFN-gamma was in all three HTB-77 cell lines able to suppress the HER-2 message and its encoded protein. The expression of IFN-gamma-induced antigens, namely CA-125 and class II antigens of the major histocompatibility complex (HLA-DR), was markedly augmented by IFN-gamma in all three lines, whereby the most prominent effect was seen in HTB-77cDDP and HTB-77cDDP + IFN.     

Audit of public sector primary diabetes care in Cape Town, South Africa: high prevalence of complications, uncontrolled hyperglycaemia, and hypertension

This study was undertaken to investigate the prevalence of diabetes complications and level of glycaemic and blood pressure control in Black African patients at the primary care level in the public sector Cape Town, South Africa. A stratified random sample of 300 patients attending the three largest ambulatory diabetes clinics in community health centres in Black African residential areas of Cape Town (100 patients from each) during the last 6 months of 1992 was selected. Each patient had a clinical examination, interview, and 1 year retrospective record review. Eighty-one per cent of the sampled patients were reviewed, 90% were non-insulin-dependent (NIDDM) and 10% were treated with insulin. The mean duration of diabetes was 8 (range 0-28) years. Acceptable glycaemic control was present in 49.4% (95% Confidence Intervals 45.6-53.5) of patients while 38.5% (CI 24.8-52.2) of hypertensive patients had acceptable blood pressure control. The prevalence of any grade of retinopathy was 55.4% (CI 48.90-62.9), proliferative and preproliferative retinopathy 15.6% (CI 8.5-22.8), cataracts 7.9% (CI 4.4-11.4), peripheral neuropathy 27.6% (CI 15.2-39.4), absent foot pulses 8.2% (CI 5.2-12.6), amputations 1.4% (CI 0.4-2.4), persistent proteinuria 5.3% (CI 2.5-8.1) and an elevated albumin-creatinine ratio 36.7% (CI 29.0-44.4). The complications were not documented in the clinic records of the preceding year with the exception of 1 patient with absent foot pulses and the 12 patients with proteinuria. The high prevalence of suboptimal glycaemic and blood pressure control as well as complications of diabetes, largely unrecorded in the preceding years' clinic notes, demonstrates the deficiency of and need for preventative diabetes care at the primary care level. The design, institution, and evaluation of effective intervention programmes are a priority to improve the quality of care provided and the health of diabetic patients.     

The dexamethasone suppression test and treatment outcome in elderly depressed patients participating in a placebo-controlled multicenter trial involving moclobemide and nortriptyline

A 28-year-old woman was referred to us to undergo 131I therapy who had multiple pulmonary metastases from papillary thyroid carcinoma after total thyroidectomy. There was no increased accumulation of a tracer in the pulmonary metastatic foci on whole-body scanning using a 111 MBq diagnostic dose of 131I. However, the pulmonary metastases were gradually decreased in size, and then clearly reduced 8 months after the start of TSH suppression therapy, which was maintained by T3 instead of T4 to bring down the serum TSH level below 0.1 microU/ml. Reduction rates of the foci were 33-76% on chest X-ray. The reduction was confirmed and no new lesions were found on the serial CT scans. Serum thyroglobulin level was lowered 80 to 25 ng/ml by this suppression therapy and progression of disease was not observed under a 54 months' T3 treatment. Thus, TSH suppression therapy might improve survival of patients with differentiated thyroid cancer.     

Increased acute and chronic mitotic activity in rat laryngeal muscles after botulinum toxin injection

OBJECTIVES: To characterize the acute and chronic cellular effects of botulinum toxin (BT) injection into rat laryngeal muscles. A complete characterization of these effects is important because patients with focal dystonias of the head and neck are commonly treated with BT injection. Further, potential muscular changes in the larynx must be carefully delineated owing to the critical phonatory and airway protective functions of these muscles. STUDY DESIGN: The acute and chronic cellular effects of BT injection were studied using 5'-bromo 2'-deoxyuridine (BrdU) following single and repeated BT injection into rat laryngeal muscles. BrdU is incorporated into mitotically active nuclei such that changes in cell proliferative behavior following BT injection can be monitored. RESULTS: Increased mitotic activity was detected in the tissue samples studied following BT injection. Differences in the times of the peak distribution of BrdU-labeled cells in each laryngeal muscle were observed. This may be related to the diffusion effects of BT. Prolonged muscle fiber changes, including splitting, were also observed as the result of repeated BT injection. CONCLUSIONS: The results of this study suggest that BT may induce a proliferative response in muscle tissue.     

The sequential in utero death of heterokaryotic monozygotic twins. A case report and literature review

A case of monozygotic twins in a 19-year-old primigravida is presented. Ultrasound examination at 15 weeks' gestation showed one twin to have a cystic hygroma and hydrops fetalis. The other twin appeared normal. The twins appeared to occupy the same amniotic cavity. Fluid was taken from the cystic hygroma under ultrasound guidance for karyotyping and this showed 45,XO chromosomes. Conservative management was adopted. Serial ultrasound examination showed deteriorating hydrops and at 26 weeks the first twin died. Intensive monitoring of the remaining twin was undertaken with weekly ultrasound, cardiotocography (CTG), and clotting screens. At 29 weeks' gestation the CTG and clotting were normal, but ultrasound revealed that multicystic encephalomalacia had developed in the second twin. A very thin dividing membrane was seen for the first time between the twins. The parents decided to terminate the pregnancy. Prior to an intracardiac potassium chloride injection, a fetal blood sample was taken which revealed 46,XX chromosomes and a normal clotting screen including natural anticoagulant levels. Labour was then induced. Delivery took place 5 h later and the woman made an uneventful recovery. The mechanism for genetic differences between monozygotic twins is discussed and the literature reviewed. A non-disjunction event around the time of splitting of the twins is proposed as the cause. The prognosis for the remaining twin is also discussed, as is the pathogenesis of the cerebral damage.     

Toxicity of fotemustine in rat hepatocytes and mechanism-based protection against it

Fotemustine is a relatively novel DNA-alkylating 2-chloroethyl-substituted N-nitrosourea (CENU) drug, clinically used for the treatment of disseminated malignant melanoma in different visceral and non-visceral tissues. Thrombocytopenia has been observed in patients treated with fotemustine and liver and renal toxicities as well. In this study, firstly the metabolism of fotemustine was investigated in vitro and secondly the undesired cytotoxicity of fotemustine as well as different ways of protection against it. In rat hepatocytes, chosen as a model system, fotemustine was shown to cause lactate dehydrogenase (LDH) leakage, glutathione (GSH) depletion, GSSG-formation and lipid peroxidation (LPO). A reactive metabolite, DEP-isocyanate, is most likely responsible for these undesired cytotoxic effects. Based on the observed cytotoxicity mechanisms, chemoprotection with several sulfhydryl-containing nucleophiles and antioxidants was investigated. The sulfhydryl nucleophiles; GSH, N-acetyl-L-cysteine (NAC) and glutathione isopropylester (GSH-IP) protected almost completely against fotemustine-induced LDH-leakage and LPO. NAC and GSH protected partly against fotemustine-induced GSH-depletion. The antioxidant, vitamin E protected completely against fotemustine-induced LPO, but only partly against fotemustine-induced LDH-leakage and not against GSH-depletion. Ebselen, a peroxidase-mimetic organoselenium compound, did not show protective effects against the cytotoxicity of fotemustine, possibly because GSH is required for the bioactivation of ebselen. It is concluded that co-administration of sulfhydryl nucleophiles, in particular NAC and GSH-IP, possibly in combination with antioxidants, such as vitamin E, are effective against the toxicity of fotemustine in vitro. It might, therefore, be worthwhile to investigate the cytoprotective potency of these agents against undesired toxicities of fotemustine in vivo as well.     

Compound heterozygous deletion of the PROP-1 gene in children with combined pituitary hormone deficiency

Mutations in the prophet of Pit-1 gene (PROP1) have been shown to be responsible for combined pituitary hormone deficiency (CPHD) with deficiencies of growth hormone (GH), Prolactin (Prl), thyroid-stimulating hormone (TSH) and gonadotropins. We previously reported that homozygosity for a 2bp deletion in exon 2 (296delGA) accounted for CPHD in three patients from two Russian families. Here we report a second mutational hot spot in exon 2. This 2bp 149delGA deletion results in a frame shift that leads to the same serine to stop codon change at codon 109 (S109X). The predicted proteins are each truncated at residue 108 but diverge from the wild type sequence at different points in the homeodomain. Compound heterozygosity for the two mutations (149delGA/296delGA) was detected in 5 of 14 CPHD children from 4 families (36%). This provides the first evidence of heterozygosity for two common deletions as a cause of CPHD in Russian children.     

The dental, craniofacial, and biochemical features of pyknodysostosis: a report of three new cases

1.Near-infrared (IR) spectroscopy is based on the relative transparency of skin, skull and brain to the light in the near-IR region (700-1100 nm) and on the oxygen-dependent tissue absorption changes of haemoglobin.2. We evaluated the most relevant factors (reproducibility, venous return, age and sex) that might affect reliability of near-IR spectroscopy to test CO2 cerebrovascular reactivity.3.Thirty-four healthy volunteers were enrolled in the study. The protocol consisted of a 3-min baseline, a 3-min hypercapnia (5% CO2 in air) and a 2-min recovery. Transcranial Doppler sonography measurements were simultaneously performed. The CO2 reactivity test was repeated on 27 subjects after 1 h to assess reproducibility. CO2 reactivity was also evaluated at different body positions (supine, 35 degrees Trendelenburg and 35 degrees reverse Trendelenburg), and over a gradual increase of the inspired CO2.4. Changes in near-IR spectroscopy and transcranial Doppler sonography parameters were significantly correlated with variations of end-tidal CO2 (P<0.005). A significant correlation between the reactivity indexes of near-IR spectroscopy parameters and flow velocity was also found (P<0.01). A high reproducibility was also found for deoxyhaemoglobin (rI=0.76), oxyhaemoglobin (rI=0.68) and flow velocity (rI=0.60) reactivity indexes. No significant differences between the reactivity indexes of different body positions were found (P>0.05). The reactivity index of oxyhaemoglobin and deoxyhaemoglobin decreased (P<0.05) and increased (P<0.01) with age respectively.5. We found that near-IR spectroscopy is a reliable and reproducible method for the evaluation of cerebrovascular reactivity and might be considered, after appropriate validation, for the assessment of patients with cerebrovascular disease.