Decreased bioavailability of rifampin and other antituberculosis drugs in patients with advanced human immunodeficiency virus disease

We evaluated the effects of human immunodeficiency virus (HIV) disease on pharmacokinetics of antituberculosis medications by measuring concentrations of isoniazid and rifampin in blood and of pyrazinamide and ethambutol in urine. Peak concentration and exposure were reduced for rifampin, and rapid acetylators of isoniazid had lower drug levels. HIV and HIV-tuberculosis patients who have diarrhea and cryptosporidial infection exhibit decreased bioavailability of antituberculosis drugs.     

Current Allogeneic Hematopoietic Stem Cell Transplantation for Pediatric Acute Lymphocytic Leukemia: Success,Failure and Future Perspectives—A Single-Center Experience, 2008 to 2016

Hematopoietic stem cell transplantation (HSCT) is the only curative option for a subset of patients with high-risk or relapsed acute lymphoblastic leukemia (ALL). Given evolving practices, it is important to continually evaluate outcomes for pediatric ALL following HSCT. Outcomes after HSCT are influenced by the type of donor used as this determines the degree and method of T cell depletion used and, consequently, specific transplant-related morbidities. We retrospectively analyzed HSCT data from our center for transplants performed between January 2008 and May 2016, comparing outcomes among different donor types. One hundred and twenty-four pediatric patients underwent HSCT from a matched sibling donor (MSD; n?=?48), an unrelated matched donor (UMD; n?=?56), or a haploidentical donor (n?=?20). We observed a similar 3-year event-free survival (EFS) for MSD recipients (of .64) and for UMD recipients (.62), but a significantly lower EFS for recipients of haploidentical transplants (.35; P?=?.01). Relapse was the main cause of HSCT failure and was significantly higher in the haploidentical donor group (.47 versus .19 for MSD and .24 for UMD; P?=?.02). Treatment-related mortality was evenly distributed among the donor groups (.17, .16, and .15 for the MSD, UMD, and haploidentical groups, respectively). Rates of infection-related mortality were lower than previously reported. Relapse is the main obstacle for successful HSCT in the contemporary era, and this effect is most evident in recipients of haploidentical donor grafts. Newer methods to improve graft-versus-leukemia effect are being evaluated and will need to be incorporated into the management of high-risk patients.     

Studies on cell-mediated immunity in women using different fertility regulating methods

Cell-mediated immunity (CMI) was assessed in women using fertility regulating methods for 1-5 months, 6-11 months or 12-18 months. The CMI as assessed by phytohaemagglutin in (PHA)-induced lymphocyte transformation of treated groups were compared with that of normal subjects who were not using any contraceptive methods and women on conventional methods of contraception. The data obtained indicates that there is no significant alteration of CMI in women fitted with IUCD or women on estrogen progestogen combination. However, a significant suppression of CMI is observed in women in progestogen pills for 12-18 months. The short term therapy did not affect the CMI. In a prospective study it was found that the CMI in women before and after the use of combination therapy for 1-5 and 6-11 months revealed no change. Estradiol and progesterone at concentration on 1 microgram/ml in culture medium suppressed PHA-induced lymphocyte transformation.     

Unstable genes unstable mind: beyond the central dogma of molecular biology

Schizophrenia has a polygenic mode of inheritance and an estimated heritability of over 80%, but success in understanding its genetic underpinnings to date has been modest. Unlike in trinucleotide neurodegenerative disorders, the phenomenon of genetic anticipation observed in schizophrenia or bipolar disorder has not been explained. For the first time, we provide a plausible molecular explanation of genetic anticipation and pathophysiology of schizophrenia, at least in part, with supporting evidence. We postulate that abnormally increased numbers of CAG repeats in many genes being expressed in the brain, coding for glutamine, cumulatively press for higher demand of glutamine in the respective brain cells, resulting in a metabolic crisis and dysregulation of the glutamate-glutamine cycle. This can adversely affect the functioning of both glutamate and GABA receptors, which are known to be involved in psychosis, and may also affect glutathione levels, increasing oxidative stress. The resulting psychosis (gain in function), originating from unstable genes, is described as an effect “beyond the central dogma of molecular biology”. The hypothesis explains genetic anticipation, as further expansions in subsequent generations may result in increased severity and earlier occurrence. Many other well described findings provide proof of concept. This is a testable hypothesis, does not deny any known facts and opens up new avenues of research.     

Tubeless percutaneous nephrolithotomy: 3 years of experience with 454 patients

OBJECTIVE

To present our experience with 454 patients who had tubeless percutaneous nephrolithotomy (TPCNL) over last 3 years.

PATIENTS AND METHODS

From September 2004 to August 2007, all patients aged >14 years and undergoing PCNL were considered for TPCNL. Exclusion criteria were the presence of pyonephrosis, matrix calculi, significant bleeding or residual stone burden and need for three of more percutaneous accesses. These patients had a nephrostomy tube placed after PCNL (control group). The remaining patients undergoing TPCNL (study group) had antegrade ureteric stenting. Demographic and perioperative data were compared retrospectively.

RESULTS

Of 840 patients who had PCNL during the study period, 454 had TPCNL. The two groups had comparable demographic data except for a smaller stone burden (322.8 vs 832.2 mm²) and fewer staghorn calculi (94 vs 154) in patients undergoing TPCNL (P < 0.001). The mean number of tracts per renal unit and operative duration were statistically higher in patients undergoing standard PCNL (1.5 vs 1.1, and 68.8 vs 52.2 min, respectively). The decrease in haemoglobin, complication and stone‐free rates were comparable. TPCNL was associated with less postoperative pain, analgesia requirement and earlier discharge (P < 0.001).

CONCLUSIONS

TPCNL can be used with a favourable outcome and no increase in complications in selected patients, with the potential advantages of decreased postoperative pain, analgesia requirement and hospital stay. Its application can be extended to patients with a solitary kidney, previous ipsilateral open surgery, raised serum creatinine level, in the presence of three renal accesses or supracostal access, and in patients undergoing bilateral synchronous PCNL or contralateral endourological stone treatment.     

The ubiquitin-proteasome pathway in health and disease of the nervous system

In recent years, proteolysis by the ubiquitin-proteasome pathway has attained prominence as a new molecular mechanism that regulates many vital functions of the nervous system, including development of synaptic connections and synaptic plasticity. Here, we review the latest findings on the role of proteolysis in sculpting the nervous system through control of axonal growth, axonal and dendritic pruning, and regulation of synaptic size and number. We also discuss how protein degradation functions in synaptic plasticity and the roles of local proteolysis in neuronal compartments. In addition, we describe how proteolysis is associated with Alzheimer's disease and ataxia. Furthermore, we highlight the recent approaches that exploit components of the ubiquitin-proteasome pathway for amelioration of these diseases in animal models.     

Multiple fourth ventricular hydatidosis

Hydatid disease caused by ingestion of eggs of the cestode Echinococcus granulosus is endemic in the Middle East, Mediterranean countries, South America, North Africa and Australia.¹ Infratentorial occurrence of hydatid cyst is rare. We present a report of an extremely rare case of multiple exclusive fourth ventricular hydatid cysts, both primary and secondary, and discuss problems with the diagnosis and management of this condition.