The endogenous circadian temperature period length (tau) in delayed sleep phase disorder compared to good sleepers

The currently assumed aetiology for delayed sleep phase disorder (DSPD) is a delay of the circadian system. Clinicians have sought to use bright light therapy, exogenous melatonin or chronotherapy to correct the disorder. However, these treatments have achieved unreliable outcomes for DSPD patients and, as such, one suggestion has been that the disorder may be caused by a longer than normal circadian rhythm period length (i.e. tau). The present study investigated this premise using a 78‐h ultradian, ultra‐short sleep–wake cycle. This constant bedrest routine was used to simulate a series of 1‐h long ‘days’ by alternating 20‐min sleep opportunities and 40 min of enforced wakefulness. Thirteen participants were recruited for the study including, six people diagnosed with DSPD according to the International Classification of Sleep Disorders—2 [mean age = 22.0, standard deviation (SD) = 3.3] and seven good sleepers (mean age = 23.1, SD = 3.9) with normal sleep timing. The DSPD participants' core temperature rhythm tau (mean = 24 h 54 min, SD = 23 min) was significantly longer (t = ?2.33, P = 0.04, Cohen's d = 1.91) than the good sleepers' (mean 24 h 29 min, SD = 16 min). The temperature rhythm of the DSPD participants delayed more rapidly (i.e. >25 min day^?1) than the good sleepers'. These findings provide an explanation for the difficulty that DSPD patients have in phase advancing to a more conventional sleep time and their frequent relapse following treatment. The outcomes of this study support a vigorous and continued application of chronobiological and behavioural therapies to entrain DSPD patients to their desired earlier sleep times.     

Upper urinary tract transitional cell carcinoma: location is not correlated with prognosis

Study Type – Therapy (case series) Level of Evidence 4 What's known on the subject? and What does the study add? Tumour location has been shown to be of prognostic importance in UUT‐TCC, with tumours of renal pelvis having a better prognosis than ureteral tumours. Patients from Balkan Endemic Nephropathy (BEN) areas had a higher frequency of pelvis tumours. Also, we found that belonging to a BEN area is an independent predictor of disease recurrence.

OBJECTIVE

• ? To identify the impact of tumour location on the disease recurrence and survival of patients who were treated surgically for upper urinary tract transitional cell carcinoma (UUT‐TCC).

PATIENTS AND METHODS

• ? A single‐centre series of 189 consecutive patients who were treated surgically for UUT‐TCC between January 1999 and December 2009 was evaluated.
• ? Patients who had previously undergone radical cystectomy, preoperative chemotherapy or contralateral UUT‐TCC were excluded.
• ? In all, 133 patients were available for evaluation. Tumour location was categorized as renal pelvis or ureter based on the location of the dominant tumour.
• ? Recurrence‐free probabilities and cancer‐specific survival were estimated using the Kaplan–Meier method and Cox regression analyses.

RESULTS

• ? The 5‐year recurrence‐free and cancer‐specific survival estimates for the cohort in the present study were 66% and 62%, respectively.
• ? The 5‐year bladder‐only recurrence‐free probability was 76%. Using multivariate analysis, only pT classification (hazard ratio, HR, 2.46; P= 0.04) and demographic characteristics (HR, 2.86 for areas of Balkan endemic nephropathy, vs non‐Balkan endemic nephropathy areas; 95% confidence interval, 1.37–5.98; P= 0.005) were associated with disease recurrence
• ? Tumour location was not associated with disease recurrence in any of the analyses.
• ? There was no difference in cancer‐specific survival between renal pelvis and ureteral tumours (P= 0.476).
• ? Using multivariate analysis, pT classification (HR, 8.04; P= 0.001) and lymph node status (HR, 4.73; P= 0.01) were the only independent predictors associated with a worse cancer‐specific survival.

CONCLUSION

• ? Tumour location is unable to predict outcomes in a single‐centre series of consecutive patients who were treated with radical nephroureterectomy for UUT‐TCC.

     

Low-grade fibromyxoid sarcoma of the liver: A case report

BACKGROUNDLow grade fibromyxoid sarcoma (LGFMS) is a rare and benign mesenchymal tumor with indolent course, most commonly found in young or middle-aged men. The majority of the LGFMSs are located in the trunk and deep soft tissue of the lower extremities. They appear as well circumscribed, although not encapsulated, which often leads to incomplete surgical resection. Despite their seemingly benign appearance, these tumors have aggressive behavior with high metastatic and recurrence rates. Accurate histopathologic examination of the specimen and its immunohistochemical analysis are mandatory for a precise diagnosis. CASE SUMMARYWe report a case of a 38 year-old-man who presented with jaundice and upper abdominal discomfort. Multi-detector computed tomography and magnetic resonance imaging showed a large left liver tumor mass, extending to the hepatoduodenal ligament. Left hepatectomy was performed with resection and reconstruction of hepatic artery and preservation of middle hepatic vein. Histopathologic examination confirmed the tumor being a low-grade fibromyxoid sarcoma. Three and a half years after surgery, the patient died after being diagnosed with spine metastasis.CONCLUSIONDue to poor response to all modalities of adjuvant treatment, we consider that the focus of treatment should be on surgery as the only option for curing the disease.     

Overexpression of CD123 correlates with the hyperdiploid genotype in acute lymphoblastic leukemia

We evaluated CD123 expression in 95 pediatric and 24 adult ALL patients and compared the results with the CD123 expression in normal B-cell precursors. Early B-cell precursors were negative while intermediate precursors and mature B cells showed weak CD123 expression. Leukemic blasts in 31% of precursor-B ALL samples exhibited strong expression of CD123, 61% had moderate CD123 expression and 8% were negative; 81.5% of ALL with hyperdiploid karyotype (≥ 52 chromosomes) showed strong CD123 overexpression. In contrast, cases with ETV6/RUNX1 rearrangement had weak CD123 expression. Our study suggests that overexpression of CD123 is an aberrant phenotype present in a subset of precursor-B ALL with hyperdiploid genotype, and represents an additional marker of good prognosis in pediatric precursor-B ALL. Moreover, aberrant CD123 expression in ALL is a good marker for monitoring of minimal residual disease.     

Characterization and optimization of experimental variables within a reproducible bladder encrustation model and in vitro evaluation of the efficacy of urease inhibitors for the prevention of medical device-related encrustation

This study presents a reproducible, cost-effective in vitro encrustation model and, furthermore, describes the effects of components of the artificial urine and the presence of agents that modify the action of urease on encrustation on commercially available ureteral stents. The encrustation model involved the use of small-volume reactors (700 mL) containing artificial urine and employing an orbital incubator (at 37 degrees C) to ensure controlled stirring. The artificial urine contained sources of calcium and magnesium (both as chlorides), albumin and urease. Alteration of the ratio (% w/w) of calcium salt to magnesium salt affected the mass of encrustation, with the greatest encrustation noted whenever magnesium was excluded from the artificial urine. Increasing the concentration of albumin, designed to mimic the presence of protein in urine, significantly decreased the mass of both calcium and magnesium encrustation until a plateau was observed. Finally, exclusion of urease from the artificial urine significantly reduced encrustation due to the indirect effects of this enzyme on pH. Inclusion of the urease inhibitor, acetohydroxamic acid, or urease substrates (methylurea or ethylurea) into the artificial medium markedly reduced encrustation on ureteral stents. In conclusion, this study has described the design of a reproducible, cost-effective in vitro encrustation model. Encrustation was markedly reduced on biomaterials by the inclusion of agents that modify the action of urease. These agents may, therefore, offer a novel clinical approach to the control of encrustation on urological medical devices.     

Mortality among HIV-1- and human herpesvirus type 8-affected mother-infant pairs in Zambia

OBJECTIVE: To determine the respective trends in mortality of Zambian mother-infant pairs based on maternal infection with HIV-1 and human herpesvirus type 8 (HHV-8). METHODS: A prospective cohort study was done on Zambian mother-infant pairs, stratified by maternal serologic status and followed from 6 weeks postdelivery for 48 months. Statistical analysis of the differences in the calculated mortality rates among the four groups was done using Stata 7.0. Kaplan-Meier analysis and Cox proportional hazard models were used to measure subject survival time. RESULTS: Between September 1998 and March 2002, a total of 1,425 mother-infant pairs were enrolled. The crude mortality rate among children born to dually infected mothers was approximately 9 times higher (245.90 deaths per 1,000 live births) when compared with the death ratio of children born to seronegative mothers (24.63 deaths per 1,000 live births). The incidence rate for death was 0.34/1,000 in infants of co-infected mothers in comparison with 0.32/1,000 among HIV-1-infected mothers, 0.0336/1,000 among uninfected mothers, and 0.0403/1,000 among HHV-8-infected mothers (chi(2) = 154.56; P < 0.01). Infants of co-infected mothers had a comparable risk of death in comparison with infants infected with HIV-1 alone [hazard ratio, 9.91 [95% confidence interval (95% CI), 5.08-19.37] for co-infected versus 9.26 [95% CI, 4.75-18.07] for HIV-1-infected alone]. Infants of mothers infected only with HHV-8 also had comparable survival in comparison with uninfected infants (hazard ratio, 1.21; 95% CI, 0.56-2.61). CONCLUSION: Infants born to mothers dually infected with both HIV-1 and HHV-8 have comparable survival with infants exposed to HIV-1 alone. Infants born to mothers infected only with HHV-8 have comparable survival with uninfected infants.     

Analysis of the vasorelaxant action of angiotensin II in the isolated rat renal artery

Taking into consideration that mechanisms involved in the vasodilatator actions of angiotensin II have not yet been completely elucidated, the present study was undertaken in order to examine the mechanisms underlying the angiotensin II-induced relaxation of rat renal artery (RRA). Angiotensin II produced concentration-dependent and endothelium-independent relaxation of isolated RRA. Angiotensin II-induced relaxation was partially reduced by inhibitors of nitric oxide synthase and guanylyl cyclase. The remaining dilatation was inhibited by a potassium channel blocker, charybdotoxin. Precontraction of RRA with high concentration of K(+) partially reduced angiotensin II-evoked relaxation, while indomethacin, glibenclamide, apamin and barium did not alter the angiotensin II concentration-response curve. Losartan had no effect on angiotensin II effect. Oppositely, HOE 140 and PD123319, separately or in combination, partially antagonized vasorelaxation induced by angiotensin II. Complete blockade of RRA response was obtained after simultaneous incubation of all three receptor antagonists HOE-140, PD123319, and losartan; L-NOARG plus HOE-140; or PD123319 plus charybdotoxin. These results indicate that angiotensin II produces endothelium-independent relaxation of RRA, which is most probably mediated by the interaction of the NO-cGMP pathway and K(+) channels. Moreover, we can assume that AT(1), AT(2), and B(2) receptors are involved in the vasorelaxant effect of angiotensin II.     

Cigarette smoke induces bronchoconstrictor hyperresponsiveness to substance P and inactivates airway neutral endopeptidase in the guinea pig. Possible role of free radicals.

We examined the effects of acute exposure to cigarette smoke on the airway responses to substance P in anesthetized guinea pigs and on the activity of airway neutral endopeptidase (NEP). After exposure to air or to cigarette smoke we measured the change in total pulmonary resistance (RL) induced by increasing concentrations of aerosolized substance P in the absence or presence of the NEP inhibitor phosphoramidon. In the absence of phosphramidon the bronchoconstrictor responses to substance P were greater in cigarette smoke-exposed guinea pigs than in air-exposed animals. Phosphoramidon did not further potentiate the responses to substance P in smoke-exposed guinea pigs, whereas it did so in air-exposed animals. In the presence of phosphoramidon, bronchoconstrictor responses to substance P in animals exposed to air or to cigarette smoke were not different. Aerosols of SOD delivered before cigarette smoke exposures dramatically reduced smoke-induced hyperresponsiveness to substance P, whereas heat-inactivated SOD had no effect on smoke-induced hyper-responsiveness to substance P. Cigarette smoke solution inhibited NEP activity from tracheal homogenate in a concentration-dependent fashion, an inhibitory effect that was mostly due to the gas phase of the smoke, but not to nicotine. The mild chemical oxidant N-chlorosuccinimide mimicked the concentration-dependent inhibitory effect of smoke solution on airway NEP activity. We conclude that cigarette smoke causes enhanced airway responsiveness to substance P in vivo by inactivating airway NEP. We suggest that cigarette smoke-induced inhibition of airway NEP is due to effects of free radicals.     

Glutathione S-transferase-P1 expression correlates with increased antioxidant capacity in transitional cell carcinoma of the urinary bladder

OBJECTIVES: Our aim was to perform a comprehensive analysis of the antioxidant capacity of transitional cell carcinoma (TCC) of urinary bladder and discern the role of enzymes associated with glutathione (GSH) in maintaining high GSH levels in these tumours. Because the redox-sensitive protein glutathione S-transferase P1 (GSTP1) might provide an important link between high antioxidant capacity and inhibition of apoptotic pathways, we also explored how the redox state in tumour cells interacts with the expression of GSTP1. METHODS: We examined spectrophotometrically the specific activities of GSH-replenishing enzymes involved in GSH synthesis (gamma-glutamylcysteine synthetase, gamma-GCS), GSH regeneration (glutathione reductase, GR), and antioxidant protection (glutathione peroxidase, GPX; superoxide dismutase, SOD) in the cytosolic fraction of tumours and the surrounding normal tissue of 30 TCC patients. GSTP1-1 expression was also analyzed. RESULTS: We found a significant increase in the activity of both GSH-replenishing and antioxidant enzymes as well as enhanced GSTP1-1 expression in tumours in comparison with adjacent normal uroepithelium. Mean gamma-GCS and GR activities in tumours were about 4- and 2-fold higher, respectively, than in corresponding normal tissue. Expression of GSTP1 correlated significantly with GSH level and gamma-GCS and GR activities. GPX and SOD activities in TCC were also markedly increased. CONCLUSIONS: Enhanced GSH-replenishing pathways account for increased GSH levels in TCC. Upregulated GPX and SOD also contribute to high antioxidant potential in TCC. Under such conditions, expression of redox-sensitive GSTP1 protein is upregulated.