Lenalidomide-based response-adapted therapy for older adults without high risk myeloma

Combined lenalidomide and dexamethasone is a standard-of-care therapy for the treatment of older adults with multiple myeloma. Lenalidomide monotherapy has not been evaluated in newly diagnosed myeloma patients. We conducted a phase II study, evaluating a response-adapted therapy for older adults newly diagnosed with multiple myeloma without high-risk features who were ineligible for high-dose therapy and stem cell transplant. Patients were started on single-agent lenalidomide, and low-dose dexamethasone was added in the event of progressive disease, in a response-adapted approach. The primary endpoint was progression-free survival (PFS), and the International Myeloma Working Group's uniform response criteria were used to assess response and progression. Twenty-seven patients were enrolled, and 20 (74%) experienced a partial response or better to this response-adapted therapy. After a median follow-up of 69 months, the median PFS was 36 months [95% confidence interval (CI), 29·8 to not reached], and the median overall survival was 65 months (95% CI, 35·3 to not reached). Grade 3/4 adverse events were mainly haematological in nature. This response-adapted therapy in this patient population is feasible and results in durable responses that compare favourably with concurrent lenalidomide and dexamethasone. These results should be validated in prospective studies.     

Post-dural puncture posterior reversible encephalopathy syndrome

We report the case of a young patient with 36 weeks pregnancy, and an acute respiratory infection with severe bronchospasm, who developed an occipital headache and neck pain on the third day of inadvertent dural puncture during placement of combined epidural spinal anaesthesia for caesarian section. It was diagnosed as post-dural puncture headache until generalised tonic clonic seizures occurred the next day raising the suspicion of postpartum eclampsia or meningitis. Posterior reversible encephalopathy syndrome was diagnosed on MRI of the brain which showed features of reversible ischemia in the posterior region of the brain. With anticonvulsant therapy and antibiotics there was complete resolution of neurological symptoms. We highlight the importance of high index of suspicion of this reversible encephalopathy in obstetric cases with intentional or inadvertent dural puncture, with headache similar to post-dural punctural headache, and the essential role of neuroradiology in confirmation of the diagnosis, as placement of an epidural blood patch would be highly detrimental in these cases.     

Medroxyprogesterone acetate antagonizes estrogen up-regulation of brain mitochondrial function

The impact of clinical progestins used in contraception and hormone therapies on the metabolic capacity of the brain has long-term implications for neurological health in pre- and postmenopausal women. Previous analyses indicated that progesterone and 17β-estradiol (E2) sustain and enhance brain mitochondrial energy-transducing capacity. Herein we determined the impact of the clinical progestin, medroxyprogesterone acetate (MPA), on glycolysis, oxidative stress, and mitochondrial function in brain. Ovariectomized female rats were treated with MPA, E2, E2+MPA, or vehicle with ovary-intact rats serving as a positive control. MPA alone and MPA plus E2 resulted in diminished mitochondrial protein levels for pyruvate dehydrogenase, cytochrome oxidase, ATP synthase, manganese-superoxide dismutase, and peroxiredoxin V. MPA alone did not rescue the ovariectomy-induced decrease in mitochondrial bioenergetic function, whereas the coadministration of E2 and MPA exhibited moderate efficacy. However, the coadministration of MPA was detrimental to antioxidant defense, including manganese-superoxide dismutase activity/expression and peroxiredoxin V expression. Accumulated lipid peroxides were cleared by E2 treatment alone but not in combination with MPA. Furthermore, MPA abolished E2-induced enhancement of mitochondrial respiration in primary cultures of the hippocampal neurons and glia. Collectively these findings indicate that the effects of MPA differ significantly from the bioenergetic profile induced by progesterone and that, overall, MPA induced a decline in glycolytic and oxidative phosphorylation protein and activity. These preclinical findings on the basis of acute exposure to MPA raise concerns regarding neurological health after chronic use of MPA in contraceptive and hormone therapy.     

Upregulation of phagocyte-like NADPH oxidase by cytokines in pancreatic beta-cells: Attenuation of oxidative and nitrosative stress by 2-bromopalmitate

Phagocyte-like NADPH oxidase (Nox2) has been shown to play regulatory roles in the metabolic dysfunction of the islet β-cell under the duress of glucolipotoxic conditions and exposure to proinflammatory cytokines. However, the precise mechanisms underlying Nox2 activation by these stimuli remain less understood. To this end, we report a time-dependent phosphorylation of p47phox, a cytosolic subunit of Nox2, by cytomix (IL-1β + TNFα + IFNγ) in insulin-secreting INS-1 832/13 cells. Furthermore, cytomix induced the expression of gp91phox, a membrane component of Nox2. 2-Bromopalmitate (2-BP), a known inhibitor of protein palmitoylation, markedly attenuated cytokine-induced, Nox2-mediated reactive oxygen species (ROS) generation and inducible nitric oxide synthase (iNOS)-mediated nitric oxide (NO) generation. However, 2-BP failed to exert any significant effects on cytomix-induced CHOP expression, a marker for endoplasmic reticulum stress. Together, our findings identify palmitoyltransferase as a target for inhibition of cytomix-induced oxidative (ROS generation) and nitrosative (NO generation) stress in the pancreatic β-cell.     

Efficacy of Adiantum capillus veneris Linn in chemically induced urolithiasis in rats

Ethnopharmacological relevance: Adiantum capillus veneris Linn has been recommended in ancient literature of Unani system of medicine as an important ingredient of many formulations for the treatment of urolithiasis. Its decoction has long been used for the same purpose by several Unani physicians.     

Blastocystis spp., Cryptosporidium spp., and Entamoeba histolytica exhibit similar symptomatic and epidemiological patterns in healthcare-seeking patients in Karachi

In this study, we collected data on the incidence of enteric parasites in healthcare-seeking individuals along with their symptoms to quantify the potential roles of factors such as age, sex, and seasonality in infection. We performed analysis to identify factors which could help differentiate parasitic infection from other causes of gastrointestinal illness in a community. The size of the patient population (n?=?339), patient selection methodology, collection methods, and statistical analysis followed approaches from similar studies in core clinical journals. Ethical approval was obtained from the University of Karachi’s Ethical Review Board. Fecal specimens (n?=?339) submitted by symptomatic patients were collected from two clinical laboratories, along with information about the patients’ age, sex, and symptoms. We found that symptoms of fever, vomiting, and constipation were 100 % predictive of finding a parasitic infection, while diarrhea was 88 % predictive of a parasitic infection. Gastrointestinal parasite-positive patients reported diarrhea (~60 %), vomiting (~30 %), fever (~25 %) and constipation (~25 %), while parasite-negative patients exhibited a symptomatic profile without fever, vomiting, and constipation. The distribution of symptoms in parasite-positive patients remained relatively invariant regardless of the parasite identified. Blastocystis spp.-mono-infected patients reported a similar profile to patients positive for Entamoeba histolytica/Entamoeba dispar and Cryptosporidium spp. Most parasitic infections exhibited a strong seasonal pattern, with a peak incidence in summer months. Infection by Blastocystis spp. was the most prevalent, and it was the only infection mathematically correlated to rainfall by Pearson’s method. We observed no increase in healthcare-seeking behavior following a stressful community event, namely, the attempted assassination of Benazir Bhutto in Karachi. The data suggest that parasitological testing would produce a high yield of positive results when performed on healthcare-seeking patients in Karachi in 2007 with symptoms of fever, vomiting, or constipation and a low yield when performed on patients noting only abdominal pain. Parasitological testing also produces a higher yield on patients seen in summer months.