Thoracoscopic long oesophageal myotomy for nutcracker oesophagus: initial experience of a new surgical approach.

A thoracoscopic technique is described for the execution of long oesophageal myotomy for nutcracker oesophagus causing odynophagia and non-cardiac chest pain. The technique is based on a multipuncture method and a left thoracoscopic approach. It has been performed on three patients with complete symptomatic relief in the short term, although the follow-up period is short (maximum 12 months). No complications were encountered and discharge from hospital occurred by the fifth day after operation.     

Hepatic cryotherapy for liver tumors

A high-efficiency hepatic cryosurgical unit has been developed and evaluated. It is capable of simultaneously driving three implantable insulated cryoneedle probes. The system has been used to treat 18 patients with secondary and 4 patients with primary liver cancer: open (n=12), total laparoscopic (n=6), laparoscopic assisted (n=4). In three patient laparoscopic cryotherapy was repeated inside 6 months.Intraoperative bleeding was encountered in three patients undergoing high-volume hepatic freezing but the bleeding was easily controlled. A fall in the core body temperature was encountered in 10 out of 22 patients and averaged 0.4°;C. There was one postoperative death from liver failure in an 80-year-old patient in whom a large hepatoma was frozen. The most consistent postoperative biochemical change was hyperbilirubinaemia (n=3). A right-sided pleural effusion developed in two patients after freezing of lesions on the superior surface of the right lobe.A survival benefit was encountered in three patients, one with central cholangiocarcinoma and the other two with large solitary secondary deposits (melanoma, colon cancer). Seven patients with multiple metastases and two patients with large hepatomas developed recurrence at the frozen site or elsewhere in the liver inside 12 months of follow-up and no clinical benefit could be demonstrated by cryotherapy in this group. In nine patients, the follow-up has been too short (<18 months) to permit any conclusion on outcome. The current limitations of hepatic cryotherapy are largely due to incomplete tumor destruction. The use of insulated laparoscopic cryoprobes which can be positioned under visual control through the parietes in the optimal site for maximal tumor ablation should enhance the therapeutic efficiency of cryotherapy for both primary and secondary hepatic tumors.     

Laparoscopic cardiomyotomy for achalasia.

A technique of laparoscopic cardiomyotomy is described. The procedure has been performed in a patient with manometrically confirmed classical achalasia with complete relief of episodic total dysphagia and no untoward symptoms including reflux. The procedure was followed by minimal postoperative discomfort and the patient was discharged on the third postoperative day. Laparoscopic cardiomyotomy has the advantage of diminished surgical trauma with accelerated recovery, constitutes definitive therapy comparable to standard myotomy, and by being less disruptive of the lower oesophageal fixation it is prone to precipitate gastro-oesophageal reflux.     

Detecting impaired glucose tolerance or type 2 diabetes mellitus by means of an oral glucose tolerance test in HIV‐infected patients

Objective

As a proactive diagnosis of diabetes mellitus (DM) may prevent the onset of severe complications, we used an oral glucose tolerance test (OGTT) to check for impaired glucose tolerance (IGT) and DM in patients with long‐standing HIV infection and long durations of exposure to antiretroviral drugs with normal fasting plasma glucose (FPG) levels.

Methods

This was a cross‐sectional, single‐centre study. The homeostatic model assessment for insulin resistance (HOMA‐IR) and 2‐h post‐load glucose levels were used to evaluate patients with known HIV‐1 infection since before 1988 and no previous diagnosis of DM for whom data on hepatitis C virus (HCV) and hepatitis B virus (HBV) infection were available.

Results

Eighty‐four Caucasian patients [67 (80%) male; median age 45.7 years; range 43.8–49.1 years] were able to be evaluated; 65 (77%) were coinfected with HCV, and seven (8%) were coinfected with HBV. Median (interquartile range [IQR]) exposure to antiretrovirals was 12.8 (10.4–16.5) years. Fifteen patients (18%) had a previous AIDS‐defining event, 64 (76%) had HIV RNA<50 copies/mL, and the median (IQR) CD4 count was 502 (327–628) cells/μL. The median [IQR] FPG was 81 mg/dL (4.5 mmol/L) [75–87 mg/dL (4.2–4.8 mmol/L)], and the median (IQR) HOMA‐IR was 2.82 (1.89–4.02). After OGTT, nine patients (11%) were diagnosed as having IGT (6) or DM (3). A first multivariable analysis showed that CD4 cell count (P=0.038) and HOMA‐IR (P=0.035) were associated with IGT or DM, but a second model including only the variables with a P‐value of <0.2 in the univariable analysis (CD4 cell count, HBV coinfection, and HOMA‐IR) found that only HOMA‐IR independently predicted IGT or DM.

Conclusions

In patients with long‐standing HIV infection and normal FPG levels, an OGTT can reveal IGT or DM.     

Evolution patterns of raltegravir-resistant mutations after integrase inhibitor interruption

The objective of this study was to address the evolution of human immunodeficiency virus type 1 (HIV-1) mutations resistant to the integrase inhibitor raltegravir after drug interruption. Thirteen HIV-1 infected patients undergoing virological failure due to the selection of raltegravir-resistant variants, who had interrupted raltegravir treatment, were enrolled. For all patients, the virological failure was associated with the selection of variants, with mutations conferring resistance to all of the drugs present in their regimens. Patients were prospectively monitored at baseline (raltegravir interruption) and every 4–24 weeks for clinical, virological and immunological parameters, including HIV-1 viraemia, CD4⁺ T-cell counts, and sequence analysis of the HIV-1 integrase sequence. Reversion to the wild-type HIV-1 integrase sequence genotype was observed between 4 and 36 weeks after raltegravir withdrawal in eight out of the 13 patients. Reversion was not observed in three patients. In two patients, reversion was partial at week 24 from raltegravir interruption. These results highlight that in eight out of 13 patients under treatment with raltegravir and experiencing a virological failure, HIV-1 variants harbouring mutations associated with raltegravir resistance become undetectable after drug interruption within a few weeks (in some cases, very rapidly). This occurs under different therapy regimens and in patients receiving 3TC mono-therapy. In the other patients, complete reversion of the integrase sequence is not observed, and either primary or secondary resistance mutations are fixed in the replication competent viral population in vivo also for long time, suggesting that other factors may influence this dynamic process.     

The role of nuclear lamin B1 in cell proliferation and senescence

Nuclear lamin B1 (LB1) is a major structural component of the nucleus that appears to be involved in the regulation of many nuclear functions. The results of this study demonstrate that LB1 expression in WI-38 cells decreases during cellular senescence. Premature senescence induced by oncogenic Ras also decreases LB1 expression through a retinoblastoma protein (pRb)-dependent mechanism. Silencing the expression of LB1 slows cell proliferation and induces premature senescence in WI-38 cells. The effects of LB1 silencing on proliferation require the activation of p53, but not pRb. However, the induction of premature senescence requires both p53 and pRb. The proliferation defects induced by silencing LB1 are accompanied by a p53-dependent reduction in mitochondrial reactive oxygen species (ROS), which can be rescued by growth under hypoxic conditions. In contrast to the effects of LB1 silencing, overexpression of LB1 increases the proliferation rate and delays the onset of senescence of WI-38 cells. This overexpression eventually leads to cell cycle arrest at the G1/S boundary. These results demonstrate the importance of LB1 in regulating the proliferation and senescence of human diploid cells through a ROS signaling pathway.