Genomic characterization of high-count MBL cases indicates that early detection of driver mutations and subclonal expansion are predictors of adverse clinical outcome.

High-count monoclonal B-cell lymphocytosis (MBL) is an asymptomatic expansion of clonal B cells in the peripheral blood without other manifestations of chronic lymphocytic leukemia (CLL). Yearly, 1% of MBLs evolve to CLL requiring therapy; thus being critical to understand the biological events that determine which MBLs progress to intermediate/advanced CLL. In this study, we performed targeted deep sequencing on 48 high-count MBLs, 47 of them with 2-4 sequential samples analyzed, exploring the mutation status of 21 driver genes and evaluating clonal evolution. We found somatic non-synonymous mutations in 25 MBLs (52%) at the initial time point analyzed, including 12 (25%) with >1 mutated gene. In cases that subsequently progressed to CLL, mutations were detected 41 months (median) prior to progression. Excepting NOTCH1, TP53 and XPO1, which showed a lower incidence in MBL, genes were mutated with a similar prevalence to CLL, indicating the early origin of most driver mutations in the MBL/CLL continuum. MBLs with mutations at the initial time point analyzed were associated with shorter time-to-treatment (TTT). Furthermore, MBLs showing subclonal expansion of driver mutations on sequential evaluation had shorter progression time to CLL and shorter TTT. These findings support that clonal evolution has prognostic implications already at the pre-malignant MBL stage, anticipating which individuals will progress earlier to CLL.

Longitudinal analysis of 25 sequential sample-pairs using a custom multiple myeloma mutation sequencing panel (M(3)P).

Recent advances in genomic sequencing technologies now allow results from deep next-generation sequencing to be obtained within clinically meaningful timeframes, making this an attractive approach to better guide personalized treatment strategies. No multiple myeloma-specific gene panel has been established so far; we therefore designed a 47-gene-targeting gene panel, containing 39 genes known to be mutated in ≥3 % of multiple myeloma cases and eight genes in pathways therapeutically targeted in multiple myeloma (MM). We performed targeted sequencing on tumor/germline DNA of 25 MM patients in which we also had a sequential sample post treatment. Mutation analysis revealed KRAS as the most commonly mutated gene (36 % in each time point), followed by NRAS (20 and 16 %), TP53 (16 and 16 %), DIS3 (16 and 16 %), FAM46C (12 and 16 %), and SP140 (12 and 12 %). We successfully tracked clonal evolution and identified mutation acquisition and/or loss in FAM46C, FAT1, KRAS, NRAS, SPEN, PRDM1, NEB, and TP53 as well as two mutations in XBP1, a gene associated with bortezomib resistance. Thus, we present the first longitudinal analysis of a MM-specific targeted sequencing gene panel that can be used for individual tumor characterization and for tracking clonal evolution over time.

Chronic ulcerative stomatitis: diagnostic and management challenges--four new cases and review of literature.

Chronic ulcerative stomatitis (CUS) is a recently described mucocutaneous disease characterized by involvement of mucosal surfaces and skin. The disease usually presents in the form of painful oral ulcers and has been seen predominantly among older women. Clinically, CUS patients may exhibit erosive or ulcerative lesions of oral mucosa resembling erosive lichen planus and/or other vesiculobullous lesions. Routine histology may exhibit features of lichenoid mucositis and is often nondiagnostic. Direct immunofluorescence studies of mucosal or skin biopsies usually reveal a unique pattern of IgG bound to nuclei of keratinocytes of the basal and parabasal cell layers. Chronic ulcerative stomatitis exhibits a unique resistance to standard treatments available, including topical and systemic corticosteroids and immunomodulatory medications. However, long-lasting favorable clinical responses may be achieved with hydroxychloroquine pharmacotherapy. We present the clinicoimmunopathologic findings of four cases of CUS and discuss the varied clinical, microscopic spectrum, and treatment for this chronic, debilitating, and often recalcitrant condition. A systematic review of the literature, including 35 previously reported cases, is presented.

Comparative studies of boerhaavia diffusa L. And boerhaavia verticillata poir. (Nyctaginaceae).

Comparative taxonomical and phytochemical studies of B diffusa ands B. verticillata are described in this article.

Evaluation of the diuretic activity of boerhaavia verticillata.

The present investigation was undertaken to evaluate the potential diuretic activity of Boerhaavia verticillata . The ethanolic and aqueous extracts of B. verticillata were administered in doses of 50 and 100 mg/kg, i.p., to normal and adult albino rats, which were monitored over a period of 24 h. Experimental results confirmed that both the ethanol and aqueous extracts have diuretic properties, but the ethanol extract seems to have less diuretic and natriuretic activity than the aqueous extract.

A review of the history of prameha and diabetes mellitus.

Several diseases of polyuric nature were described in Ayurveda. Collectively called Prameha, this group includes an entity called Madhumeha which is the equivalent of diabetes mellitus. The medical history of the two diseases is described in the article.

STUDY OF KUSTHA (SAUSSUREA LAPPA, Clarke) IN ISCHAEMIC HEART DISEASE.

This article reports the results obtained from a study of the usefulness of Saussurea Lappa on the treatment of Ichaemic Heart Diseases.

Vascular organization of the head and respiratory organs of the air-breathing catfish, Heteropneustes fossilis.

Light and scanning electron microscopy of vascular replicas from the facultative air-breathing fish Heteropneustes fossilis show modifications in the macrocirculation of the respiratory organs and systemic circulation, whereas, gill microcirculation is similar to that found in typical water-breathing fish. Three and sometimes four ventral aortae arise directly from the bulbus. The most ventral vessel supplies the first pair of arches. Dorsal to this another aorta supplies the second gill arches, and a third, dorsal to, and larger than the other two, supplies the third and fourth arches and the air sacs. Occasionally a small vessel that may be the remnant of a primitive aortic arch arises from the first ventral aorta and proceeds directly to the mandibular region without perfusing gill tissue. The air sac is perfused by a large-diameter extension of the afferent branchial artery of the fourth gill arch and its circulation is in parallel with the gill arches. Blood drains from the air sac into the fourth arch epibranchial artery. A number of arteries also provide direct communication between the efferent air sac artery and the dorsal aorta. All four gill arches are well developed and contain respiratory (lamellar) and nonrespiratory (interlamellar and nutrient) networks common to gills of water-breathing fish. Air sac lamellae are reduced in size. The outer 30% of the air sac lamellar sinusoids are organized into thoroughfare channels; the remaining vasculature, normally embedded in the air sac parenchyma, is discontinuous. A gill-type interlamellar vasculature is lacking in the air sac circulation. Despite the elaborate development of the ventral aortae, there is little other anatomical evidence to suggest that gill and air sac outflow are separated and that dorsal aortic oxygen tensions are maintained when the gills are in a hypoxic environment. Physiological adjustments to hypoxic water conditions probably include temporal regulation of gill and air sac perfusion to be effective, if indeed they are so.

Vasculature of the head and respiratory organs in an obligate air-breathing fish, the swamp eel Monopterus (=Amphipnous) cuchia.

Methyl methacrylate vascular corrosion replicas were used to examine the macrocirculation in the head region and the microcirculation of respiratory vessels in the air-breathing swamp eel Monopterus cuchia. Fixed respiratory tissue was also examined by SEM to verify capillary orientation. The respiratory and systemic circulations are only partially separated, presumably resulting in supply of mixed oxygenated and venous blood to the tissues. A long ventral aorta gives rise directly to the coronary and hypobranchial arteries. Two large shunt vessels connect the ventral aorta to the dorsal aorta, whereas the remaining ventral aortic flow goes to the respiratory islets and gills. Only two pairs of vestigial gill arches remain, equivalent to the second and third arches, yet five pairs of aortic arches were identified. Most aortic arches supply the respiratory islets. Respiratory islet capillaries are tightly coiled spirals with only a fraction of their total length in contact with the respiratory epithelium. Valve-like endothelial cells delimit the capillary spirals and are unlike endothelial cells in other vertebrates. The gills are highly modified in that the lamellae are reduced to a single-channel capillary with a characteristic three-dimensional zig-zag pathway. There are no arterio-arterial lamellar shunts, although the afferent branchial artery supplying the gill arches also supplies respiratory islets distally. A modified interlamellar filamental vasculature is present in gill tissue but absent or greatly reduced in the respiratory islets. The macro- and micro-circulatory systems of M. cuchia have been considerably modified presumably to accommodate aerial respiration. Some of these modifications involve retention of primitive vessel types, whereas others, especially in the microcirculation, incorporate new architectural designs some of whose functions are not readily apparent.

Gill microcirculation of the air-breathing climbing perch, Anabas testudineus (Bloch):relationships with the accessory respiratory organs and systemic circulation.

The general macrocirculation and branchial microcirculation of the air-breathing climbing perch, Anabas testudineus, was examined by light and scanning electron microscopy of vascular corrosion replicas. The ventral aorta arises from the heart as a short vessel that immediately bifurcates into a dorsal and a ventral branch. The ventral branch distributes blood to gill arches 1 and 2, the dorsal branch to arches 3 and 4. The vascular organization of arches 1 and 2 is similar to that described for aquatic breathing teleosts. The respiratory lamellae are well developed but lack a continuous inner marginal channel. The filaments contain an extensive nutritive and interlamellar network; the latter traverses the filament between, but in register with, the inner lamellar margins. Numerous small, tortuous vessels arise from the efferent filamental and branchial arteries and anastomose with each other to form the nutrient supply for the filament, adductor muscles, and arch supportive tissues. The efferent branchial arteries of arches 1 and 2 supply the accessory air-breathing organs. Arches 3 and 4 are modified to serve primarily as large-bore shunts between the dorsal branch of the ventral aorta and the dorsal aorta. In many filaments from arches 3 and 4, the respiratory lamellae are condensed and have only 1-3 large channels. In some instances in arch 4, shunt vessels arise from the afferent branchial artery and connect directly with the efferent filamental artery. The filamental nutrient and interlamellar systems are poorly developed or absent. The respiratory and systemic pathways in Anabas are arranged in parallel. Blood flows from the ventral branch of the ventral aorta, through gill arches 1 and 2, into the accessory respiratory organs, and then returns to the heart. Blood, after entering the dorsal branch of the ventral aorta, passes through gill arches 3 and 4 and proceeds to the systemic circulation. This arrangement optimizes oxygen delivery to the tissues and minimizes intravascular pressure in the branchial and air-breathing organs. The efficiency of this system is limited by the mixing of respiratory and systemic venous blood at the heart.

Morphology and vascular anatomy of the accessory respiratory organs of the air-breathing climbing perch, Anabas testudineus (Bloch).

The vascular organization and endothelial cell specialization of the air-breathing organs of Anabas testudineus were examined by light and scanning electron microscopy of fixed tissue and vascular corrosion replicas. The vessels supplying blood to the lining of paired suprabranchial chambers and the plicated labyrinthine organs within the chambers are tripartite, having a median artery and paired, lateral veins. Hundreds of respiratory islets, the functional units of gas exchange, cover the surfaces of both the chamber and labyrinthine organ. A median islet artery supplies the central aspect of each islet and gives rise to numerous short arterioles from which the transverse channels are formed. Transverse channels are parallel capillary-sized vessels that extend in two rows away from the medial arterioles and drain laterally into one of two lateral islet veins. Basally situated single rows of endothelial cells lining the transverse channels form thick, evaginated, tongue-like cytoplasmic processes that project freely into the lumen from the tissue side of the channel. Other thin, septate, cytoplasmic extensions of the same cells form valve-like septa that extend across the channel. Both the septa and tongue-like processes appear to direct the red blood cells to the epithelial side of the channel and thus decrease the diffusion distance between the air and red cell. A large sinusoidal space lies under the transverse channels and may support the channels and even elevate them during increased oxygen demand. The epithelium covering the transverse channels is smooth, which enhances air convection and minimizes unstirred layer effects. The epithelium between the channels contains microvilli that may serve to trap bacteria or particulates and to humidify the air chambers.

Effect of indigenous drug (Pushkarmula) on experimentally induced myocardial infarction in rats.

In the present study, myocardial infarction was induced experimentally in rats by isoprenaline injection. Circulating GOT, LDH, CPK, cAMP, Cortisol, pyruvate, lactate glucose and cardiac cAMP adenyl cyclase levels were gradually increased and serum and cardiac cAMP-PDE levels were gradually decreased from 1 hour to 120 hours after the first injection of isoprenaline. In the rats pretreated with ciplar (beta blocker) or Pushkarmula (indigenous drug) these changes were less when compared to untreated infarcted rats. Similar type of results were also observed in the infarcted rats post treated with Pushkarmula. The pretreatment with Pushkarmula was found to be more effective than post treatment which gives a preventive and curative bearing of the drug in myocardial infarction.

Cytochemical differentiation of tonic (slow) and phasic (fast) muscle units in the ocular muscles of a fresh-water carp, Catla catla (Ham.).

1. Functional morphology of the ocular muscles with special reference to their topography, innervation and action have been studied in a fresh-water carp Catla catla. An attempt has also been made to differentiate tonic (slow) and phasic (fast) muscle units in the various ocular muscles by their SDH activities and their lipid contents. 2. Catla catla has large eyes (2 cm in diameter) in a fish measuring 30 cms. There are four recti (inferior, superior, anterior and posterior) and two obliquii (superior and inferior) muscles for the synchronized rotation of the eye ball within the orbit. Anterior and posterior myodomes are well developed. The former accommodates two obliquii muscles, while the latter gives space for the posterior and anterior recti. 3. In this fish, all the ocular muscles are composite in nature being made up of tonic (slow) and phasic (fast) muscle units. The former is made up of red fibers whereas the latter have only white fibers. In the tonic muscle units lipid is more concentrated. 4. The superior and the inferior obliquii muscles rotate the eye ball on its antero-posterior axis. The upward and downward movements of the eye balls are achieved by the superior and the inferior recti. The anterior and posterior recti move the eye ball in the antero-lateral and postero-lateral directions. 5. The superior obliquii contains about 41% of the tonic and 59% of phasic muscle units. The inferior oblique is made up of 25% of tonic and 75% of the phasic muscle units. 6. The Anterior rectus contains greater percentage of tonic muscle fibers (48%) than the superior rectus (40%), the Interior rectus (34%) and the posterior rectus (35%).