Local recurrence rate in a national Danish patient cohort after curative treatment for rectal cancer.

AIM: Several trials have shown that preoperative (chemo)radiotherapy (CRT) reduces local recurrence rates (LRRs) in rectal cancer (RC). The use of CRT varies greatly between countries. It is unknown whether the restrictive use of CRT in Denmark results in a higher LRR relative to other countries. The aim was to evaluate the LRR in a national Danish consecutive cohort of patients with RC. METHODS: All data from patients with RC in Denmark in 2009-2010 who were operated on with curative intent were retrieved from the Danish Colorectal Cancer Group database. Patients with metastases at the time of diagnosis, patients with synchronous colon cancer, and patients, in whom only local surgical procedures were performed, were excluded. In total, 1633 patients met the inclusion criteria. Clinical follow-up was at least five years with a cut-off date of 31 December 2015. RESULTS: Clinical follow-up was 5.4 years (median) with an interquartile range of 4.5-6.1 years. Of all included patients, 479 (29%) were treated with preoperative long-course CRT. Local recurrence was found in 68 patients, resulting in an LRR of 4.2%, and 182 (11%) patients developed distant metastases. Five-year overall survival was 74% (95% CI: 71.64-75.91). CONCLUSIONS: Five-year follow-up of curatively treated patients with RC in Denmark revealed a low LRR. This figure is identical to those reported in other Nordic countries, despite Denmark's considerably stricter guidelines for CRT. The obtained results justify the currently adopted restrictive use of preoperative CRT in Denmark.

Adjuvant FOLFOX +/- cetuximab in full RAS and BRAF wildtype stage III colon cancer patients.

Background: RAS mutations have been shown to confer resistance to anti- epidermal growth factor receptor (EGFR) treatment. We analysed the results of the PETACC8 trial (cetuximab + FOLFOX vs FOLFOX) in full RAS and BRAF wildtype (WT) patients (pts) with resected stage III colon cancer. Patients and methods: Exons 2, 3 and 4 of KRAS and NRAS, and BRAF exons 11 and 15, were sequenced using the Ampliseq colon-lung cancer panel version 2, in PETACC8 trial pts who consented to translational research. The impact of cetuximab on time to recurrence (TTR), disease-free survival (DFS) and overall survival (OS) was investigated in pts with tumours harbouring RAS and BRAF WT, and RAS mutations. The prognostic value of each individual mutation was also tested. Results: Among the 2559 pts analysed, 745 pts (29%) were known to have KRAS exon 2 mutations and 163 pts (6.4%) the BRAF V600E mutation. Of the remaining 1651 pts, 1054 were assessed by NGS, showing that a further 227 pts (21%) had KRAS exon 2, 3, 4 or NRAS exon 2, 3, 4 mutations, and that 46 pts (4.4%) had a newly diagnosed BRAF mutation. Cetuximab added to FOLFOX did not significantly improve TTR, DFS or OS in pts with RAS WT or RAS and BRAF WT tumours (HR 0.77-1.03, all P > 0.05). Cetuximab addition was not either significantly deleterious in RAS mutant pts or in pts with rare RAS or BRAF mutations. In the overall trial population, NRAS and KRAS codon 61 mutations were the only rare mutations with the same pejorative prognostic value as KRAS exon 2 or BRAF V600E mutations. Conclusion: Though not significant, the clinically relevant 0.76 adjusted HR observed for DFS in favour of adding cetuximab to FOLFOX, in full RAS and BRAF WT stage III colon cancer pts, may justify a new randomized controlled trial testing EGFR inhibitors in this setting. Clinical trial number: This is an ancillary study of the PETACC8 trial: EUDRACT 2005-003463-23.

The effect of exercise training on hormone-sensitive lipase in rat intra-abdominal adipose tissue and muscle.

1. Adrenaline-stimulated lipolysis in adipose tissue may increase with training. The rate-limiting step in adipose tissue lipolysis is catalysed by the enzyme hormone-sensitive lipase (HSL). We studied the effect of exercise training on the activity of the total and the activated form of HSL, referred to as HSL (DG) and HSL (TG), respectively, and on the concentration of HSL protein in retroperitoneal (RE) and mesenteric (ME) adipose tissue, and in the extensor digitorum longus (EDL) and soleus muscles in rats. 2. Rats (weighing 96 +/- 1 g, mean +/- S.E.M.) were either swim trained (T, 18 weeks, n = 12) or sedentary (S, n = 12). Then RE and ME adipose tissue and the EDL and soleus muscles were incubated for 20 min with 4.4 microM adrenaline. 3. HSL enzyme activities in adipose tissue were higher in T compared with S rats. Furthermore, in RE adipose tissue, training also doubled HSL protein concentration (P < 0.05). In ME adipose tissue, the HSL protein levels did not differ significantly between T and S rats. In muscle, HSL (TG) activity as well as HSL (TG)/HSL (DG) were lower in T rats, whereas HSL (DG) activity did not differ between groups. Furthermore, HSL protein concentration in muscle did not differ between T and S rats (P > 0.05). 4. In conclusion, training increased the amount of HSL and the sensitivity of HSL to stimulation by adrenaline in intra-abdominal adipose tissue, the extent of the change differing between anatomical locations. In contrast, in skeletal muscle the amount of HSL was unchanged and its sensitivity to stimulation by adrenaline reduced after training.

Persistent DNA damage inhibits S-phase and G2 progression, and results in apoptosis.

We used genetically related Chinese hamster ovary cell lines proficient or deficient in DNA repair to determine the direct role of UV-induced DNA photoproducts in inhibition of DNA replication and in induction of G2 arrest and apoptosis. UV irradiation of S-phase-synchronized cells causes delays in completion of the S-phase sometimes followed by an extended G2 arrest and apoptosis. The effects of UV irradiation during the S-phase on subsequent cell cycle progression are magnified in repair-deficient cells, indicating that these effects are initiated by persistent DNA damage and not by direct UV activation of signal transduction pathways. Moreover, among the lesions introduced by UV irradiation, persistence of (6-4) photoproducts inhibits DNA synthesis much more than persistence of cyclobutane pyrimidine dimers (which appear to be efficiently bypassed by the DNA replication apparatus). Apoptosis begins approximately 24 h after UV irradiation of S-phase-synchronized cells, occurs to a greater extent in repair-deficient cells, and correlates well with the inability to escape from an extended late S-phase-G2 arrest. We also find that nucleotide excision repair activity (including its coupling to transcription) is similar in the S-phase to what we have previously measured in G1 and G2.

Effect of in vivo injection of cholera and pertussis toxin on glucose transport in rat skeletal muscle.

Cholera toxin (CTX) and pertussis toxin (PTX) were examined for their ability to inhibit glucose transport in perfused skeletal muscle. Twenty-five hours after an intravenous injection of CTX, basal transport was decreased approximately 30%, and insulin- and contraction-stimulated transport was reduced at least 86 and 49%, respectively, in both the soleus and red and white gastrocnemius muscles. In contrast, PTX treatment was much less efficient. Impairment of glucose transport appeared to develop 10-15 h after CTX administration, which coincided with development of hyperglycemia despite hyperinsulinimia, increased plasma free fatty acid levels, increased adenosine 3',5'-cyclic monophosphate (cAMP) concentrations in muscle, but no difference in plasma catecholamines. Twenty-five hours after CTX treatment, GLUT-4 protein in both soleus and red gastrocnemius muscles was decreased, whereas no change in GLUT-1 protein content was found. In contrast, GLUT-4 mRNA was unchanged, but transcripts for GLUT-1 were increased > or = 150% in all three muscles from CTX-treated rats. The findings suggest that CTX via increased cAMP impairs basal as well as insulin- and contraction-stimulated muscle glucose transport, at least in part from a decrease in intramuscular GLUT-4 protein.

Increased gene specific repair of cisplatin induced interstrand crosslinks in cisplatin resistant cell lines, and studies on carrier ligand specificity.

Development of resistance to cisplatin in previously treatment-responsive malignancies is a major obstacle to successful treatment. Enhanced DNA repair as well as enhanced replicative bypass of DNA adducts have been suggested to play a role in the development of resistance to cisplatin. However, the relative contribution of these mechanisms is unknown. Second generation platinum compounds containing the 1,2-diaminocyclohexane (dach) carrier ligand have been of particular interest in the studies of resistance mechanisms since they have been effective in treatment of cells resistant to cisplatin. We have investigated the formation and repair of interstrand crosslinks (ICL) in the mouse leukemia cell line L1210/0 and its carrier ligand specific resistant derivatives L1210/DDP and L1210/DACH after treatment with ethylenediamine (en)-Pt and diaminocyclohexane (dach)-Pt compounds. ICL in the overall genome were examined using a modification of the alkaline elution assay. A Southern blot technique was employed for the study of ICL in specific regions of the genome. In the overall genome we found decreased formation of ICL with either -en or -dach carrier ligands in the two resistant cell lines without carrier ligand specificity. Some carrier ligand specificity of ICL formation was observed in the dihydrofolate reductase (DHFR) gene, but it did not correlate with the carrier ligand specificity of resistance. At the level of the overall genome there was no difference in repair of ICL between the sensitive and the two resistant cell lines. When measured in the DHFR gene, however, there was enhanced repair of ICL in the two resistant cell lines compared with the sensitive cell line. The enhanced repair at the level of the gene did not display any carrier ligand specificity.

DNA repair in a UV resistant Chinese hamster ovary cell line.

We have established an ultraviolet (UV) resistant Chinese hamster ovary (CHO) cell line B11UVres by repetitive UV exposure of the CHO cell line B11. We have characterized the resistant cell line with respect to growth, sensitivity to various DNA damaging agents, and the repair of UV induced DNA lesions. When examining sensitivity to UV in clonogenic survival studies, we find that the ID50 is increased 2.3-fold in the resistant cell line B11UVres compared to the parental cell line B11. Although the doubling time of the resistant cell line is greater than that of the parental cell line, there is no difference in the rate of replication after UV irradiation. When measuring repair of UV induced DNA lesions in the overall genome we find no significant difference between the two cell lines. However, at early times after UV, there is a significant increase in the rate of repair of cyclobutane pyramidine dimers (CPDs) in the transcribed strand of the dihydrofolate reductase (DHFR) gene in the B11UVres cells compared to the B11 cells. There is a small increase of steady state transcription of the DHFR gene in the UV resistant cells, but hardly enough to account for the repair increase. The UV resistant cell line B11UVres is not cross-resistant to the cross-linking agents mitomycin C or cisplatin, but shows increased sensitivity to these compounds.

Insulin-stimulated muscle glucose clearance in patients with NIDDM. Effects of one-legged physical training.

Physical training increases insulin action in skeletal muscle in healthy men. In non-insulin-dependent diabetes mellitus (NIDDM), only minor improvements in whole-body insulin action are seen. We studied the effect of training on insulin-mediated glucose clearance rates (GCRs) in the whole body and in leg muscle in seven patients with NIDDM and in eight healthy control subjects. One-legged training was performed for 10 weeks. GCR in whole body and in both legs were measured before, the day after, and 6 days after training by hyperinsulinemic (28, 88, and 480 mU x min(-1) x m(-2)), isoglycemic clamps combined with the leg balance technique. On the 5th day of detraining, one bout of exercise was performed with the nontraining leg. Muscle biopsies were obtained before and after training. Whole-body GCRs were always lower (P < 0.05) in NIDDM patients compared with control subjects and increased (P < 0.05) in response to training. In untrained muscle, GCR was lower (P < 0.05) in NIDDM patients (13 +/- 4, 91 +/- 9, and 148 +/- 12 ml/min) compared with control subjects (56 +/- 12, 126 +/- 14, and 180 +/- 14 ml/min). It Increased (P < 0.05) in both groups in response to training (43 +/- 10, 144 +/- 17, and 205 +/- 24 [NIDDM patients] and 84 +/- 10, 212 +/- 20, and 249 +/- 16 ml/min [control subjects]). Acute exercise did not increase leg GCR. In NIDDM patients, the effect of training was lost after 6 days, while the effect lasted longer in control subjects. Training increased (P < 0.05) muscle lactate production and glucose storage as well as glycogen synthase (GS) mRNA in both groups. We conclude that training increases insulin action in skeletal muscle in control subjects and NIDDM patients, and in NIDDM patients normal values may be obtained. The increase in trained muscle cannot fully account for the increase in whole-body GCR. Improvements in GCR involve enhancement of insulin-mediated increase in muscle blood flow and the ability to extract glucose. They are accompanied by enhanced nonoxidative glucose disposal and increases in GS mRNA. The improvements in insulin action are short-lived.

A UV-responsive G2 checkpoint in rodent cells.

We have studied the effect of UV irradiation on the cell cycle progression of synchronized Chinese hamster ovary cells. Synchronization of cells in S or G2 phase was accomplished by the development of a novel protocol using mimosine, which blocks cell cycle progression at the G1/S boundary. After removal of mimosine, cells proceed synchronously through the S and G2 phases, allowing manipulation of cells at specific points in either phase. Synchronization of cells in G1 was achieved by release of cells after a period of serum starvation. Cells synchronized by these methods were UV irradiated at defined points in G1, S, and G2, and their subsequent progression through the cell cycle was monitored. UV irradiation of G1-synchronized cells caused a dose-dependent delay in entry into S phase. Irradiation of S-phase-synchronized cells inhibited progression through S phase and then resulted in accumulation of cells for a prolonged interval in G2. Apoptosis of a subpopulation of cells during this extended period was noted. UV irradiation of G2-synchronized cells caused a shorter G2 arrest. The arrest itself and its duration were dependent upon the timing (within G2 phase) of the irradiation and the UV dose, respectively. We have thus defined a previously undescribed (in mammalian cells) UV-responsive checkpoint in G2 phase. The implications of these findings with respect to DNA metabolism are discussed.

Gene-specific and strand-specific DNA repair in the G1 and G2 phases of the cell cycle.

We have analyzed the fine structure of DNA repair in Chinese hamster ovary (CHO) cells within the G1 and G2 phases of the cell cycle. Repair of inactive regions of the genome has been suggested to increase in the G2 phase of the cell cycle compared with other phases. However, detailed studies of DNA repair in the G2 phase of the cell cycle have been hampered by technical limitations. We have used a novel synchronization protocol (D. K. Orren, L. N. Petersen, and V. A. Bohr, Mol. Cell. Biol. 15:3722-3730, 1995) which permitted detailed studies of the fine structure of DNA repair in G2. CHO cells were synchronized and UV irradiated in G1 or early G2. The rate and extent of removal of cyclobutane pyrimidine dimers from an inactive region of the genome and from both strands of the actively transcribed dihydrofolate reductase (DHFR) gene were examined within each phase. The repair of the transcribed strand of the DHFR gene was efficient in both G1 and G2, with no major differences between the two cell cycle phases. Neither the nontranscribed strand of the DHFR gene nor an inactive region of the genome was repaired in G1 or G2. CHO cells irradiated early in G2 were more resistant to UV irradiation than cells irradiated in late G1. Since we found no major difference in repair rates in G1 and G2, we suggest that G2 resistance can be attributed to the increased time (G2 and G1) available for repair before cells commit to DNA synthesis.

Stability of GLUT-1 and GLUT-4 expression in perfused rat muscle stimulated by insulin and exercise.

In vivo exercise and insulin may change the concentrations of GLUT-4 protein and mRNA in muscle. We studied in vitro whether adaptations in glucose transporter expression are initiated during a single prolonged period of contractions or during insulin stimulation. Rat hindquarters were perfused at 7 mM glucose for 2 h with or without insulin (> 20,000 microU/ml) while the sciatic nerve of one leg was stimulated to produce repeated tetanic contractions. During electrical stimulation, contraction force decreased 93 +/- 1% (SE; n = 26) and muscle glycogen was markedly diminished (P < 0.05). Both contractions and insulin markedly increased glucose transport and uptake (P < 0.05). At the end of contractions, glycogen was higher in the presence of than in the absence of insulin (24 +/- 4 vs. 14 +/- 3 mumol/g for the soleus and 13 +/- 2 vs. 8 +/- 1 mumol/g for the red gastrocnemius, respectively; P < 0.05). In nonstimulated muscle, glucose transporter mRNA and protein concentrations were higher in the soleus than in the white gastrocnemius (GLUT-4 mRNA 184 +/- 18 vs. 131 +/- 36 arbitrary units; GLUT-1 mRNA 173 +/- 29 vs. 114 +/- 26 arbitrary units; GLUT-4 protein 0.96 +/- 0.09 vs. 0.46 +/- 0.03 arbitrary units; GLUT-1 protein 0.41 +/- 0.08 vs. 0.19 +/- 0.05 arbitrary units, respectively; P < 0.05). These concentrations were not changed by contractions or insulin. In conclusion, GLUT-1 and GLUT-4 mRNA and protein levels are higher in slow-twitch oxidative than in fast-twitch glycolytic fibers.(ABSTRACT TRUNCATED AT 250 WORDS)

Physical training increases muscle GLUT4 protein and mRNA in patients with NIDDM.

Patients with non-insulin-dependent diabetes mellitus (NIDDM) exhibit insulin resistance and decreased glucose transport in skeletal muscle. Total content of muscle GLUT4 protein is not affected by NIDDM, whereas GLUT4 mRNA content is reported, variously, to be unaffected or increased. Physical training is recommended in the treatment of NIDDM, but the effect of training on muscle GLUT4 protein and mRNA content is unknown. To clarify the effect of training in NIDDM, seven men with NIDDM (58 +/- 2 years of age [mean +/- SE]) and eight healthy men (59 +/- 1 years of age) (control group) performed one-legged ergometer bicycle training for 9 weeks, 6 days/week, 30 min/day. Biopsies were obtained from the vastus lateralis leg muscle before and after training. GLUT4 protein analyses was performed along with analyses of muscle biopsies from five young (23 +/- 1 years of age) (young group), healthy subjects who participated in a previously published identical study. In response to training, maximal oxygen uptake increased (delta 3.3 +/- 1.8 in NIDDM subjects and 4.5 +/- 1.2 ml.min-1.kg-1 in control subjects [both P < 0.05]). Before training, GLUT4 protein content was similar in NIDDM, control, and young subjects (0.35 +/- 0.02, 0.34 +/- 0.03, and 0.41 +/- 0.03 arbitrary units, respectively), and it increased (P < 0.05) in all groups during training (to 0.43 +/- 0.03, 0.40 +/- 0.03, and 0.57 +/- 0.08 arbitrary units, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Postincubation with aclarubicin reverses topoisomerase II mediated DNA cleavage, strand breaks, and cytotoxicity induced by VP-16.

In previous studies, we found that VP-16 (etoposide) induced cytotoxicity and protein-concealed strand break formation was prevented in a small cell lung cancer (SCLC) cell line, when the cells were incubated with aclarubicin prior to treatment with VP-16. In the present work, we studied the effect of adding aclarubicin to the cell suspension after VP-16. In a clonogenic assay, we found that the cytotoxicity induced by VP-16 in SCLC cells was inhibited when cells were postincubated with aclarubicin. The addition of aclarubicin at any time in relation to VP-16 was able to stop further cytotoxicity induced by the topoisomerase II (topo-II) targeting drug. Aclarubicin was also found to antagonize the cytotoxicity induced by VM-26 (teniposide), and m-AMSA. With the alkaline elution technique we found that postincubating the cells with aclarubicin inhibited VP-16-induced DNA strand break formation. In an in vitro system with purified topo-II and naked DNA we likewise found, that postincubation with aclarubicin prevented VP-16 induced cleavage. In the same in vitro system, also baseline cleavage induced by topo-II was inhibited when aclarubicin was present. Importantly, aclarubicin exerted the antagonism to topo-II targeting drugs both when administered prior to and after the topo-II targeting agents. Thus, our data suggest that sequential rather than simultaneous administration of aclarubicin and topo-II targeting agents may be superior with respect to net-cytotoxicity.(ABSTRACT TRUNCATED AT 250 WORDS)

Repair of ribosomal RNA genes in hamster cells after UV irradiation, or treatment with cisplatin or alkylating agents.

We have measured the DNA damage formation and repair in the ribosomal and the dihydrofolate reductase (DHFR) genes after treatment of hamster cells with different types of DNA damaging agents. In mammalian cells, the ribosomal DNA (rDNA) is transcribed by RNA polymerase I, whereas the DHFR is transcribed by RNA polymerase II, whereas the DHFR is transcribed by RNA polymerase II. Cells were treated with agents that induce different types of lesions, and that are known to be repaired via different pathways. We used UV (254 nm) irradiation, treatment with cisplatin and treatment with the alkylating agents nitrogen mustard (HN2) and methyl methanesulphonate (MMS). UV induced pyrimidine dimers were detected with the enzyme T4 endonuclease V, which creates nicks at the dimer sites; the breaks are then resolved and identified by denaturing electrophoresis and Southern blot. Intrastrand adducts formed by the alkylating agents HN2 and MMS were quantitated by generating strand breaks at abasic sites after neutral depurination. Interstrand crosslinks (ICL) formed by HN2 and cisplatin were detected by a denaturation-reannealing reaction before neutral agarose gel-electrophoresis. We find that the repair of the pyrimidine dimers is significantly less efficient in the RNA polymerase I transcribed rDNA genes than in RNA polymerase II transcribed DHFR gene at 8 and 24 h after irradiation. ICL and intrastrand adducts induced by HN2 are also removed more slowly from the rDNA than from the DHFR gene. In contrast, MMS induced intrastrand adducts and cisplatin induced ICL are repaired equally efficiently in the RNA polymerase I and RNA polymerase II transcribed genes. We conclude that for some types of DNA damage, there is less repair in the ribosomal genes than in the DHFR; but for other DNA lesions there is no difference. The difference in repair efficiency between the rDNA and the DHFR genes may reflect the different RNA polymerase involved in their transcription. It may, however, alternatively, reflect the different nuclear localization of these genes.

[Foot zone therapy and bronchial asthma--a controlled clinical trial]. / Fodzoneterapi og asthma bronchiale--en klinisk kontrolleret undersøgelse.

Thirty patients with proved bronchial asthma receiving treatment with inhaled steroid in dosages of less than 1,000 micrograms daily were subdivided at random into two groups of 15 patients. One group received foot zone therapy and the other merely uniform clinical care but without "placebo foot zone therapy". The "active" group received a total of ten foot zone therapy sessions of one hour at intervals of one week. The asthmatic symptoms, consumption of medicine and the objective pulmonary function parameters were followed-up during the subsequent six months. Decrease in consumption of beta-2-agonists and increase in peak-flow levels were observed in the group which had received foot zone therapy, but the same changes were observed in the control group. The authors do not find that this investigation demonstrates that foot zone therapy is of effect on the disease bronchial asthma. They conclude, however, that the favourable effect in both of the groups are due to increased care and control which occurred in both patient groups.

[Spirapril and nitrendipine in arterial hypertension. A comparison of therapeutic effects and tolerance]. / Spirapril og nitrendipin ved arteriel hypertension. Sammenligning af behandlingseffekt og tolerabilitet.

In a double-blind, randomized parallel-group investigation, a new angiotensin-converting enzyme-inhibitor, spirapril, was compared with a calcium antagonist, nitrendipine, in 266 patients with mild to moderate hypertension (diastolic blood pressure 96-119 mmHg). The object was to reduce the diastolic blood pressure measured 24 hours after intake of medicine to less than or equal to 90 mmHg. After monotherapy for four weeks with either 20 mg nitrendipine once daily or 12 mg spirapril once daily, the dosages were doubled in the patients in whom the desired blood pressure had not been obtained. After treatment for eight weeks, 12.5 mg hydrochlorthiazide daily was employed as a supplement in patients who had not yet obtained satisfactory blood pressures. Both methods of treatment resulted a lower number of patients who responded and lesser decreases in blood pressure than anticipated. No differences were found in the decreases in blood pressure resulting from the two therapeutic methods. The effect of supplementary hydrochlorthiazide to spirapril treatment was as anticipated while the combination with nitrendipine only resulted in a marginally extra decrease in blood pressure. Nitrendipine resulted in significantly more side effects and more patients defected from the investigation on account of side effects in the nitrendipine group (27%) than in the spirapril group (7%). This investigation had documented the abilities of nitrendipine and spirapril to reduce blood pressure and the side effects associated with this but does not predict whether the preparations can be employed to prevent the complications of hypertension which constitute the indications for treatment. Supplementing nitrendipine therapy with hydrochlorthiazide is not recommended.

Effect of the nonsedative H1-receptor antagonist astemizole in perennial allergic and nonallergic rhinitis.

We studied the efficacy and side effects of the H1-antihistamine astemizole in perennial rhinitis. We also defined subgroups of responders and examined the added effect of a steroid spray. Fifty-five adults completed a 10- to 14-week controlled trial. Astemizole reduced the number of sneezes to 41% (p less than 0.001) and the number of nose blowings to 55% (p less than 0.001) of the placebo values. The added use of beclomethasone dipropionate caused a further reduction to 14% (p less than 0.001) and 37% (p less than 0.05), respectively. Nasal blockage was only marginally affected by the antihistamine, but it was reduced to 64% by the steroid spray (p less than 0.001). "Sneezers" responded better to the antihistamine than "blockers," with "nose blowers" in an intermediate position. The effect was equal in allergic and nonallergic patients. Astemizole was completely nonsedative but increased appetite and body weight. An open 1-year study of 17 patients demonstrated that astemizole maintained its efficacy and that further weight gain did not occur. It is concluded that astemizole is a highly effective nonsedative H1-antihistamine suitable for continuous therapy of perennial rhinitis.

Tampon-induced changes in vaginal oxygen and carbon dioxide tensions.

Vaginal oxygen and carbon dioxide tensions were measured continuously in a group of normal young women on the second day of menstruation during a 90-minute period. PO2 averaged 3 mm Hg (+/- 11 SD) and PCO2 averaged 64 mm Hg (+/- 13 SD). The value rose to that of atmospheric air when a tampon was inserted and gradually fell, giving a mean value of 112 mm Hg (+/- 18 SD) during the following 90 minutes; preinsertion values were reached in about 8 hours. Carbon dioxide rose rapidly to almost preinsertion values (mean value of 50 mm Hg +/- 12 SD) during the 90-minute period and remained steady at this level during extended periods. As in vitro studies have indicated an oxygen-dependent production of a toxin-like protein from Staphylococcus aureus, it is suggested that intravaginal tampons may be a risk factor in the development of toxic shock syndrome by supplying oxygen, thus changing the vaginal microenvironment from anaerobic to aerobic.

Fenoterol inhalation powder and aerosol.

The effect of 0.2 mg of fenoterol inhalation powder and 0.2 mg fenoterol from a metered dose inhaler were compared in a double-dummy, cross-over investigation. Ten patients with chronic obstructive lung disease entered the study, which showed no statistically significant difference between the effect of these two forms of the drug on lung function and pulse rate for a period of up to 6 hours after the inhalation of fenoterol. The patients considered the inhalation of powder by means of a commercial inhaler, the Ingelheim inhaler, was simple.