Grading immunohistochemical markers p16INK4a and HPV E4 identifies productive and transforming lesions caused by low- and high-risk HPV within high-grade anal squamous intraepithelial lesions.

OBJECTIVES: Because current guidelines recognise high-grade anal squamous intraepithelial lesions (HSILs) and low-grade SILs (LSILs), and recommend treatment of all HSILs although not all progress to cancer, this study aims to distinguish transforming and productive HSILs by grading immunohistochemical (IHC) biomarkers p16INK 4a (p16) and E4 in low-risk human papillomavirus (lrHPV) and high-risk (hr)HPV-associated SILs as a potential basis for more selective treatment. METHODS: Immunostaining for p16 and HPV E4 was performed and graded in 183 biopsies from 108 HIV-positive men who have sex with men. The causative HPV genotype of the worst lesion was identified using the HPV SPF10-PCR-DEIA-LiPA25 version 1 system, with laser capture microdissection for multiple infections. The worst lesions were scored for p16 (0-4) to identify activity of the hrHPV E7 gene, and panHPV E4 (0-2) to mark HPV production and life cycle completion. RESULTS: There were 37 normal biopsies, 60 LSILs and 86 HSILs, with 85% of LSILs caused by lrHPV and 93% of HSILs by hrHPV. No normal biopsy showed E4, but 43% of LSILs and 37% of HSILs were E4 positive. No differences in E4 positivity rates were found between lrHPV and hrHPV lesions. Most of the lesions caused by lrHPV (90%) showed very extensive patchy p16 staining; p16 grade in HSILs was variable, with frequency of productive HPV infection dropping with increasing p16 grade. CONCLUSIONS: Combined p16/E4 IHC identifies productive and nonproductive HSILs associated with hrHPV within the group of HSILs defined by the Lower Anogenital Squamous Terminology recommendations. This opens the possibility of investigating selective treatment of advanced transforming HSILs caused by hrHPV, and a 'wait and see' policy for productive HSILs. What's already known about this topic? For preventing anal cancer in high-risk populations, all patients with high-grade squamous intraepithelial lesions (HSILs) are treated, even though this group of lesions is heterogeneous, the histology is variable and regression is frequent. What does this study add? By adding human papillomavirus (HPV) E4 immunohistochemistry to p16 INK4a (p16), and grading expression of both markers, different biomarker expression patterns that reflect the heterogeneity of HSILs can be identified. Moreover, p16/E4 staining can separate high-risk HPV-associated HSILs into productive and more advanced transforming lesions, providing a potential basis for selective treatment.

Anal Squamous Intraepithelial Lesions (SILs) in Human Immunodeficiency Virus-Positive Men Who Have Sex With Men: Incidence and Risk Factors of SIL and of Progression and Clearance of Low-Grade SILs.

BACKGROUND: Human immunodeficiency virus (HIV)-positive men who have sex with men (MSM) are at risk of anal squamous cell carcinoma. Data are limited on the natural history of the precursor to this carcinoma, anal squamous intraepithelial lesions (SILs). METHODS: HIV-positive MSM were screened for histopathological SILs by means of high-resolution anoscopy (HRA). For participants without SILs at baseline, we estimated the cumulative incidence and risk factors for SILs. For those with low-grade SILs (LSILs) at baseline, the risk of progression to high-grade SILs (HSILs) and the clearance rate were estimated at the lesion level. RESULTS: Of 807 men without SILs at baseline, 107 underwent follow-up HRA between 1 to 4.5 years later. At the second visit 18 men (16.8%) showed LSIL, and 25 (23.4%) HSIL. Age was associated with incident LSILs (adjusted odds ratio [aOR], 2.10 per 10-year increase in age; P = .01). Of 393 men with LSILs at baseline, 114 underwent follow-up HRA 0.5 to 2.5 years later. Of the 177 LSILs found at baseline, 87 (49.2%) had cleared at the second visit, and 29 (16.4%) had progressed to HSILs. CONCLUSION: Incident LSILs and HSILs were common during follow-up among HIV-positive MSM without dysplasia at baseline. Among men with LSILs at baseline, nearly half of these lesions cleared, and a small portion progressed.

Acute hepatitis C in the Netherlands: characteristics of the epidemic in 2014.

Within the Dutch Acute HCV in HIV Study, a surveillance system was initiated to estimate the incidence of hepatitis C virus (HCV) infections in 2014. Following the Dutch HIV treatment guidelines, HIV-positive men having sex with men (MSM) in 19 participating centers were screened. Ninety-nine acute HCV infections were reported, which resulted in a mean incidence of 11 per 1000 patient-years of follow-up. Unfortunately, the HCV epidemic among Dutch HIV-positive MSM is not coming to a halt.

Randomized comparison of metabolic and renal effects of saquinavir/r or atazanavir/r plus tenofovir/emtricitabine in treatment-naïve HIV-1-infected patients.

OBJECTIVES: The aim of the study was to compare the effects on lipids, body composition and renal function of once-daily ritonavir-boosted saquinavir (SQV/r) or atazanavir (ATV/r) in combination with tenofovir/emtricitabine (TDF/FTC) over 48 weeks. METHODS: An investigator-initiated, randomized, open-label, multinational trial comparing SQV/r 2000/100 mg and ATV/r 300/100 mg once daily, both in combination with TDF/FTC, in 123 treatment-naïve HIV-1-infected adults was carried out. The primary endpoint was to demonstrate noninferiority of SQV/r compared with ATV/r with respect to the change in fasting cholesterol after 24 weeks. Secondary outcome measures were changes in metabolic abnormalities, body composition, renal function, and virological and immunological efficacy over 48 weeks. Patients who had used at least one dose of trial drug were included in the analysis. RESULTS: Data for 118 patients were analysed (57 patients on SQV/r and 61 on ATV/r). At week 24, changes in lipids were modest, without increases in triglycerides, including a significant rise in high-density lipoprotein (HDL) cholesterol and a nonsignificant decrease in the total:HDL cholesterol ratio in both arms with no significant difference between arms. Lipid changes at week 48 were similar to the changes observed up to week 24, with no significant change in the homeostasis model assessment (HOMA) index. Adipose tissue increased regardless of the regimen, particularly in the peripheral compartment and to a lesser extent in the central abdominal compartment, with an increase in adipose tissue reaching statistical significance in the ATV/r arm. A slight decline in the estimated glomerular filtration rate (eGFR) was observed in both arms during the first 24 weeks, with no progression thereafter. The immunological and virological responses were similar over the 48 weeks. CONCLUSIONS: Combined with TDF/FTC, both SQV/r 2000/100 mg and ATV/r 300/100 mg had comparable modest effects on lipids, had little effect on glucose metabolism, conserved adipose tissue, and similarly reduced eGFR. The virological efficacy was similar.

Can reduction in hypertriglyceridaemia slow progression of microalbuminuria in patients with non-insulin-dependent diabetes mellitus?

The objective of this study was to investigate whether reduction in hypertriglyceridaemia is associated with a slower rate of progression of microalbuminuria in patients with non-insulin-dependent diabetes mellitus (NIDDM). Fifteen normotensive NIDDM patients with hypertriglyceridaemia (> 2.5 mmol L-1) and microalbuminuria were randomly selected to receive either placebo (eight patients) or gemfibrozil 600 mg b.i.d. (seven patients). Progression of microalbuminuria was assessed during a 12-month follow-up period with measurements, consisting of blood tests and triplicate 24-h urine collections, at 1, 3, 6, 9 and 12 months. All but one patient in the treatment group showed a favourable response (> or = 20% reduction) of hypertriglyceridaemia to gemfibrozil. One patient in the placebo group showed a spontaneous reduction in triglyceride levels. Progression of microalbuminuria was lower, although not statistically significantly so, in the treatment group (36%) than in the placebo group (65%). In the group with > or = 20% reduction in triglyceride levels, progression of MA was significantly lower than in the group with stable or increasing triglyceride levels (+1%, range -56% to +49% vs. +97%, range -35% to +202% respectively) (P = 0.03). Continued follow-up data of patients switching from placebo to gemfibrozil after the trial further support the role of serum triglyceride reduction in stabilizing albumin excretion. In conclusion, the results indicate that, in microalbuminuric NIDDM patients, effective treatment of dyslipidaemia could be associated with stabilization of urinary albumin excretion.

An endoscopic evaluation of the effects of etodolac and diclofenac on the gastric and duodenal mucosa.

The effects of two nonsteroidal anti-inflammatory drugs on the gastroduodenal mucosa were evaluated by endoscopy and direct photography in 36 healthy men who were randomly assigned to receive 150 mg of diclofenac, 1,200 mg of etodolac, or 600 mg of etodolac daily for seven days. Endoscopy was performed on days 1 and 8. Mild gastric lesions were observed in six subjects. The mean (+/- SD) endoscopy scores on a five-point scale were 0.08 +/- 0.27 after 600 mg of etodolac, 0.25 +/- 0.53 after 1,200 mg of etodolac, and 0.33 +/- 0.62 after diclofenac. No between-group differences were statistically significant. No duodenal lesions were seen. A strong correlation was found between endoscopy scores and photographic reviews. The results indicate that both etodolac and diclofenac cause minimal changes on the gastric mucosa.

The 'lung in shock' as a result of hypovolemic-traumatic shock in baboons.

The "lung in shock" syndrome is a constellation of early morphologic changes in the lung within 1 hour after polytrauma as indicated by human lung biopsies. A hypovolemic-traumatic (soft-tissue trauma together with bone fractures) baboon model with reinfusion was established to study these morphologic and associated pathophysiologic events. This model was developed in order to test the efficacy of therapeutic modalities in future studies. Nineteen baboons (eight sham, 11 shock) were anesthetized with spontaneous respiration while complete hemodynamic and blood gas monitoring was performed, along with light and electron microscopic studies of the lungs. Besides the usual shock-related hemodynamic disturbances and the metabolic acidosis, pathologic changes were found both on light and electron microscopy of the lungs but not on X-rays and measurements of blood oxygenation. In the shock group, morphologic evidence of endothelial and interstitial edema was associated with significant increases in lung weight. The fluid accumulation occurred in spite of careful control of pulmonary artery pressures during the study. More striking histologic findings were significant cellular infiltration of lung tissue, especially by leukocytes, showing evidence of degranulation. This baboon study, similar to studies undertaken in canines, shows that the hypovolemic (hemorrhagic) shock in association with trauma (fracture, soft-tissue trauma) causes ultrastructural morphologic changes that may precede potentially life-threatening functional changes in the lung.

Patients with irritable bowel syndrome have greater pain tolerance than normal subjects.

A low tolerance for pain has been postulated as a factor in the expression of symptoms in patients with irritable bowel syndrome. This has been based on previous work demonstrating reduced intestinal thresholds for rectal pain induced by balloon distention in patients with irritable bowel syndrome. As the disease may alter the rectal response to distention, inferences regarding pain perception and reporting behavior cannot be drawn from these data. In this study, using electrocutaneous stimulation, we found that patients with irritable bowel syndrome had pain reporting behavior comparable to patients with Crohn's disease. Both patient groups were less likely than normals to report a noxious stimulus as painful. This suggests that pain perception and reporting is attenuated in patients with chronic abdominal pain and, accordingly, a generalized reduction in the threshold for reporting pain is not a factor in the expression of symptoms in the irritable bowel syndrome.

Marked suppression of stimulated gastric acid and pepsin secretion by enisoprost, a new PGE1 analogue.

The gastric antisecretory effects of three different doses of enisoprost, a new synthetic PGE1 analogue, were compared with placebo and misoprostol in 20 healthy male volunteers. Enisoprost 100, 200 and 400 micrograms all significantly (P less than 0.0001; ANOVA) suppressed histamine-stimulated acid and pepsin output when compared with placebo or misoprostol 200 micrograms. Misoprostol produced a significant decrease of stimulated acid output when compared with placebo (P = 0.0012). The concentration of pepsin in gastric juice was significantly (P less than 0.0001) decreased by enisoprost at the commencement of histamine stimulation. This effect was short-lived, and was maximal with enisoprost 400 micrograms. There was a significant dose-response relationship for enisoprost for inhibition of stimulated acid output (P = 0.0065). Enisoprost was well tolerated, and no consistent drug-related adverse effects were detected. The profile of antisecretory effect of enisoprost, producing marked suppression of both acid and pepsin secretion independently, is unusual. This combination of activity along with any mucosal protective properties might be particularly effective in the treatment of peptic ulcer disease.

Inspiration: expiration ratio. Is mean airway pressure the difference?

Mechanical ventilation with different ratios of inspiratory to expiratory times (I:E ratio) and levels of positive end-expiratory pressure (PEEP) were applied to 9 dogs after the aspiration of fresh water and then were compared. The dogs were ventilated with an I:E ratio of 2:1 with 0 PEEP; an I:E ratio of 2:1 with 5 torr PEEP; and an I:E ratio of 1:2 with 5 torr PEEP. Peak airway pressures were regulated to maintain a mean airway pressure of 13 mm Hg. Arterial oxygenation was better with an I:E ratio of 1:2 with PEEP than with an I:E ratio of 2:1 either with or without PEEP (60 +/- 15 torr as compared with 42 +/- 11 torr and 43 +/- 10 torr). Cardiac index was depressed with all ventilatory modes, but oxygen delivery did not significantly differ among all the modes of ventilation. A ratio of prolonged I:E was not seen to benefit blood gas tension.

Hypnosis with etomidate during total intravenous anaesthesia.

Etomidate (Hypnomidate; Ethnor) in an alcoholic solution was used as the hypnotic component of a technique of total intravenous anaesthesia in an open pilot evaluation in 50 patients undergoing surgery. No anaesthetic gases were used. Despite cardiovascular stability, lack of respiratory depression and a short awakening time, unwanted movements by the patients made total intravenous anaesthesia with this technique unsatisfactory.

Shrapnel wound of the heart: a case report.

A case of cardiac injury in which a missile penetrated the inferior surface of the left ventricle and lodged in the interventricular septum is described. This unusual location, plus the fact that a piece of shrapnel at high velocity quickly loses speed owing to its aerodynamic instability, becoming a low-velocity missle, possible contributed to saving the patient's life.

A clinical comparison between etomidate and methohexitone for anaesthetic induction.

A comparison study of the induction properties of the new propylene glycol formulation of etomidate (Hypnomidate) and methohexitone in 80 patients who underwent elective surgical procedures is reported. Both agents gave uniformly good inductions. Methohexitone induction was associated with an elevation in heart rate, but in the etomidate group no cardiovascular instability was seen. In both groups there was a 20-25% incidence of pain on injection, but this was almost exclusively confined to the patients who were injected through the dorsal vein of the hand rather than the antecubital vein. In only 1 patient in the etomidate group did slight involuntary movements occur, but 11 patients (28%) in the methohexitone group showed this side-effect.