Homozygous and compound heterozygous mutations in the ATP6V1B1 gene in patients with renal tubular acidosis and sensorineural hearing loss

Mohebbi N, Vargas‐Poussou R, Hegemann SCA, Schuknecht B, Kistler AD, Wüthrich RP, Wagner CA. Homozygous and compound heterozygous mutations in the ATP6V1B1 gene in patients with renal tubular acidosis and sensorineural hearing loss. Distal renal tubular acidosis (dRTA) is characterized by the inability to excrete acid in the renal collecting ducts resulting in inappropriately alkaline urine and hyperchloremic (normal anion gap) metabolic acidosis in the context of a normal (or near‐normal) glomerular filtration rate. Inborn dRTA can be due to autosomal dominant or recessive gene defects. Clinical symptoms vary from mild acidosis, incidental detection of kidney stones or renal tract calcification to severe findings such as failure to thrive, severe metabolic acidosis, and nephrocalcinosis. The majority of patients with recessive dRTA present with sensorineural hearing loss (SNHL). Few cases with abnormal widening of the vestibular aqueduct have been described with dRTA. Mutations in three different genes have been identified, namely SLC4A1, ATP6V1B1, and ATP6V0A4. Patients with mutations in the ATP6V1B1 proton pump subunit develop dRTA and in most of the cases sensorineural hearing loss early in childhood. We present two patients from two different and non‐consanguineous families with dRTA and SNHL. Direct sequencing of the ATP6V1B1 gene revealed that one patient harbors two homozygous mutations and the other one is a compound heterozygous. To our knowledge, this is the first case in the literature describing homozygosity in the same dRTA gene on both alleles.     

Ganglioglioma anaplásico: diseminación leptomeníngea cervico-dorso-lumbar. A propósito de un caso

Gangliogliomas are well-differentiated, slow-growing tumors. The majority are grade I of WHO. It appears predominantly in children and young adults. Most are located at the temporal lobe, and as symptomatology more frequent epileptic seizures of difficult pharmacological control. In general, they have a good prognosis after surgical resection. The anaplasic variant, considered to be grade III of the WHO, presents greater clinical and radiological aggressiveness. Leptomeningeal dissemination is exceptional in these types of tumors, but when diagnosed it presents a rapidly progressive and fatal course for the patient.     

Meta‐analysis of Duct‐to‐duct versus Roux‐en‐Y biliary reconstruction following liver transplantation for primary sclerosing cholangitis

This meta‐analysis aimed to compare outcomes following bile duct reconstruction in patients with primary sclerosing cholangitis (PSC) undergoing liver transplantation depending on whether duct‐to‐duct or Roux‐en‐Y anastomosis was utilized. An electronic search was performed of the MEDLINE, EMBASE, PubMed databases using both subject headings (MeSH) and truncated word searches. Pooled risk ratios and mean difference were calculated using the fixed‐effects and random‐effects models for meta‐analysis. Ten studies including 910 patients met the inclusion criteria. There was no difference in the overall incidence of biliary strictures between the two groups [odds ratio (OR) 1.06 (0.68, 1.66); (P = 0.80)]. The anastomotic stricture rate was similar, [OR 1.18 (0.56, 2.50); (P = 0.67)]. Ascending cholangitis was higher in the Roux–en‐Y group [OR 2.91 (1.17, 7.23); (P = 0.02)]. Anastomotic bile leak rates, graft survival, PSC recurrence and number of patients diagnosed with cholangiocarcinoma following transplantation were comparable between both groups. Duct‐to‐duct and Roux‐en‐Y reconstruction had comparable outcomes. Both techniques are associated with similar incidence of biliary stricture. The bilioenteric reconstruction was associated with a higher risk of cholangitis. The incidence of de novo cholangiocarcinoma was similar in both groups. Duct‐to‐duct reconstruction should be considered when feasible in patients with PSC.     

Effectiveness of methyl-GAG (methylglyoxal-bis[guanylhydrazone]) in patients with advanced malignant lymphoma

We treated 51 patients with advanced malignant lymphoma refractory to conventional therapy with methyl-glyoxal-bis(guanylhydrazone) (methyl- GAG) at doses ranging from 400 to 800 mg/sq m. Therapy was started on a weekly schedule and was switched to every other week in responding patients at the onset of toxicity. Partial responses were observed in 6 of 13 evaluable patients with Hodgkin's disease (46%), 5 of 10 patients with diffuse poorly differentiated lymphocytic lymphoma (50%), 2 of 4 patients with nodular poorly differentiated lymphocytic lymphoma (50%), and 3 of 13 patients with diffuse histiocytic lymphoma (23%). Two of six patients with mycosis fungoides showed objective improvement in cutaneous disease. Toxicity was generally mild and included muscular weakness, myalgia, mucositis, and diarrhea; two patients developed bronchospasm following drug infusions. We conclude that methyl-GAG has major antitumor activity when administered on this schedule to patients with advanced malignant lymphoma. The low degree of toxicity, unique mechanism of action, and minimal myelosuppressive effects suggest that methyl-GAG will prove useful in future trials of combination chemotherapy regimens for the treatment of lymphoma.     

EFFECTIVENESS OF A MOTOR CONTROL THERAPEUTIC EXERCISE PROGRAM COMBINED WITH MOTOR IMAGERY ON THE SENSORIMOTOR FUNCTION OF THE CERVICAL SPINE: A RANDOMIZED CONTROLLED TRIAL

Background

Motor control therapeutic exercise (MCTE) for the neck is a motor relearning program that emphasizes the coordination and contraction of specific neck flexor, extensor, and shoulder girdle muscles. Because motor imagery (MI) improves sensorimotor function and it improves several motor aspects, such as motor learning, neuromotor control, and acquisition of motor skills, the authors hypothesized that a combination of MCTE and MI would improve the sensorimotor function of the cervical spine more effectively than a MCTE program alone.

Purpose

The purpose of this study was to investigate the influence of MI combined with a MCTE program on sensorimotor function of the craniocervical region in asymptomatic subjects.

Study Design

This study was a single‐blinded randomized controlled trial.

Methods

Forty asymptomatic subjects were assigned to a MCTE group or a MCTE+MI group. Both groups received the same MCTE program for the cervical region (60 minutes), but the MCTE+MI group received an additional intervention based on MI (15 minutes). The primary outcomes assessed were craniocervical neuromotor control (activation pressure value and highest pressure value), cervical kinesthetic sense (joint position error [JPE]), and the subjective perception of fatigue after effort.

Results

Intra‐group significant differences were obtained between pre‐ and post interventions for all evaluated variables (p<0.01) in the MCTE+MI and MCTE groups, except for craniocervical neuromotor control and the subjective perception of fatigue after effort in the MCTE group. In the MCTE+MI group a large effect size was found for craniocervical neuromotor control (d between ‐0.94 and ‐1.41), cervical kinesthetic sense (d between 0.97 and 2.14), neck flexor muscle endurance test (d = ‐1.50), and subjective perception of fatigue after effort (d = 0.79). There were significant inter‐group differences for the highest pressure value, joint position error (JPE) extension, JPE left rotation, and subjective perception of fatigue after effort.

Conclusion

The combined MI and MCTE intervention produced statistically significant changes in sensorimotor function variables of the craniocervical region (highest pressure value, JPE extension and JPE left rotation) and the perception of subjective fatigue compared to MCTE alone. Both groups showed statistically significant changes in all variables measured, except for craniocervical neuromotor control and the subjective perception of fatigue after effort in the MCTE group

Level of Evidence

1b     

Immunohistochemical localization of membrane and alpha-granule proteins in human megakaryocytes: application to plastic-embedded bone marrow biopsy specimens

Using a new technique for antigen localization, we have demonstrated platelet proteins in megakaryocytes in plastic-embedded biopsy specimens of normal human bone marrow. In a series of 25 specimens, megakaryocytes showed labeling with antibodies to the integral membrane glycoproteins IIIa, IIb, and the IIb-IIIa complex; granule membrane protein 140; and five alpha-granule matrix proteins: thrombospondin, factor VIII-related antigen, beta-thromboglobulin, platelet factor 4, and fibrinogen. The antibodies to the membrane glycoproteins IIIa, IIb, and IIb-IIIa produced diffuse cytoplasmic staining and heavier staining on the plasma membrane, whereas the antibodies to the alpha-granule matrix proteins produced a distinct granular staining within the cytoplasm. Staining for granule membrane protein 140 was also granular in distribution. Rare mononuclear cells consistent with megakaryocyte precursors were labeled with these markers. Other enzyme histochemical and lectin-binding studies showed that the enzyme alpha-naphthyl acetate esterase, the lectin Ulex europaeus I, and the periodic-acid Schiff reaction were consistent, but not specific, markers of megakaryocytes. This immunohistochemical technique should facilitate the examination of qualitative and quantitative changes in megakaryocytes in a variety of physiologic and pathologic processes.     

Vasoactive intestinal peptide and pituitary adenylate cyclase- activating polypeptides (PACAP27) and PACAP38) protect CD4+CD8+ thymocytes from glucocorticoid-induced apoptosis

In the present study, the effects of vasoactive intestinal peptide (VIP) and the pituitary adenylate cyclase-activating polypeptides, PACAP27 and PACAP38, in a concentration range from 10(-13) to 10(-6) mol/L were studied in vitro on the spontaneous and dexamethasone (DEX)- induced apoptosis in rat thymocytes. The results show that VIP and both PACAPs inhibit significantly and in a similar way the DNA fragmentation characteristic of glucocorticoid-induced apoptosis and increase the cell survival of thymocytes, with a maximal effect observed at 10(-8) to 10(-9) mol/L. This study showed the ability of the VIP-receptor (VIP- R) antagonist [N-Ac-Tyr1,D-Phe2]-GRF(1-29) amide to partially reverse the inhibitory effect of VIP and both PACAPs on DEX-induced apoptosis, providing evidence for a specific VIP1-R-mediated response and supporting the involvement of a single receptor for the three neuropeptides. Phenotypic analysis showed that VIP, PACAP27, and PACAP38 protect predominantly CD4+CD8+ thymocytes from glucocorticoid- induced apoptosis. These findings suggest that these neuropeptides could be involved in intrathymic T-cell maturation.